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Update on constipation: One treatment does not fit all

Article Type
Article
Changed
Mon, 04/30/2018 - 10:46
Display Headline
Update on constipation: One treatment does not fit all
Author(s)
Amy E. Foxx-Orenstein, DO
Meredythe A. McNally, MD
Suwebatu T. Odunsi, MD

Constipation is both a symptom and, when chronic, a multisymptom disorder, and it can overlap with other gastrointestinal tract disorders such as dyspepsia and gastroesophageal reflux disease. Furthermore, one should keep in mind the possibility of cancer and be alert for its warning signs.

Since constipation has a variety of causes and forms, one treatment does not fit all patients. Conservative measures such as recommending that the patient increase his or her intake of dietary fiber and water and engage in more physical activity are still the cornerstone of treatment, but they do not help all patients. On the other hand, polyethylene glycol and stimulant laxatives, which are traditionally given only for a short time, can be safe and effective when given long-term if other agents fail. New agents have become available or are in development.

In this article we outline our approach to constipation, as a guide for internists.

CONSTIPATION IS COMMON, BUT HOW SHOULD WE DEFINE IT?

Constipation affects 2% to 27% (average 14.8%) of the North American adult population—approximately 63 million people.1 It is more common than many other chronic diseases, including hypertension (48 million people), migraine (33 million), obesity (50 million), and diabetes mellitus (15 million).1–3

Constipation affects more women than men (2.1:1 ratio) and more nonwhites than whites (1.68:1).1 It occurs in all age groups but is more common in those older than 65 years and younger than 4 years.4,5

Constipation accounts for more than 2.5 million office visits and more than $500 million spent on laxatives per year.6,7 Also, people with constipation may report decreased productivity and increased absenteeism.8

The broad range in the prevalence of constipation cited above reflects differences in how it is defined and, in particular, a lack of agreement between how patients and physicians perceive it.1,9 Physicians mainly define constipation on the basis of stool frequency, considering fewer than three bowel movements per week to be abnormal.1 In contrast, patients typically define it on the basis of bothersome symptoms such as straining, passage of hard stool, unproductive urges, inability to defecate at will, and sensations of incomplete evacuation or abdominal bloating.1,9,10

The Rome III diagnostic criteria were developed to provide a consistent diagnostic approach for use in clinical practice and clinical trials.11 The Rome III criteria define functional chronic constipation as a chronic bowel disorder characterized by two or more of the following:

  • Straining
  • Lumpy or hard stools
  • Sensations of incomplete evacuation
  • Sensations of anorectal obstruction or blockage
  • Use of manual maneuvers to facilitate defecation (eg, digital evacuation, support of the pelvic floor) during at least 25% of defecations
  • Fewer than three bowel movements per week.

In addition, loose stools should rarely occur without the use of laxatives, and there should be insufficient criteria for irritable bowel syndrome.11 Chronicity is established by symptom onset within the previous 6 months and symptom duration of at least 3 months.

In contrast, patients with irritable bowel syndrome, also a functional bowel disorder, experience recurrent abdominal pain and discomfort associated with two or more of the following: symptom improvement with defecation, symptom onset associated with a change in the frequency of bowel movements, and a change in the form or appearance of the stool.

THREE TYPES OF IDIOPATHIC CONSTIPATION

There are three types of primary or idiopathic constipation5,9,12,13:

  • Functional
  • Slow-transit
  • Outlet dysfunction.

Functional constipation includes functional chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. It presents with a sense of difficult or delayed evacuation, hard stools, or abdominal bloating or discomfort.6,9,13 The predominant symptom of constipation-predominant irritable bowel syndrome is severe discomfort or pain; in chronic idiopathic constipation, pain and discomfort may be present but are not the primary symptom.

Slow-transit constipation (or delayed-transit constipation) is associated with a prolonged time between bowel movements. Its symptoms include low stool frequency, lack of urge to defecate, abdominal distention, bloating, and abdominal discomfort.14

Outlet dysfunction. Disorders of defecation can be due to mechanical causes such as Hirschsprung disease, anal stricture, cancer, prolapse, and large rectoceles, or from pelvic floor dysfunction. Pelvic floor dysfunction may be due to inadequate or excessive perineal descent or to inadequate propulsive forces, as may occur in neurologic or neuromuscular conditions and dyssynergia.

Pelvic floor dyssynergia, also called anorectal dyssynergia, dyssynergic defecation, and anismus, results from a functional defect in coordinated evacuation. The characteristic symptom is a feeling of being unable to adequately empty the rectum.14 Other symptoms such as excessive straining and manual disimpaction indicate but are not unique to pelvic floor dyssynergia.14,15

Combined forms. Patients may have more than one type of primary constipation and presentation, and pelvic floor dyssynergia has been shown to prolong intestinal transit, which may improve with treatment.

Secondary constipation can be due to causes such as diet, lifestyle, certain medications (calcium channel blockers, beta-blockers, opioids, diuretics, antidepressants, anticonvulsants, antacids, anticholinergics, and antispasmodics),5,16 underlying medical conditions (diabetes, hypothyroidism, multiple sclerosis, parkinsonism),16,17 pregnancy, and advanced age.18

 

 

NEUROTRANSMITTERS MAY PLAY A ROLE

Among the mechanisms thought to cause chronic constipation are impaired gastrointestinal motility,19–22 reduced intestinal secretions,21–23 and inadequate reflex relaxation of the pelvic floor muscles.22,24

Neurotransmitters such as serotonin, somatostatin, peptide YY, and vasoactive intestinal peptide affect intestinal secretion and motility.25,26 Hyperactivity of these neurotransmitters associated with increased secretion and motility results in diarrhea, whereas hypoactivity leads to decreased secretion, delayed transit, and constipation.23

Serotonin has a role in regulating visceral pain perception and intestinal motility, as well as secretion.26–28 Clinical trials have shown that activation of serotonin receptors in the gut enhances gastrointestinal motility, inhibits visceral sensitivity, and stimulates intestinal secretion.26,27,29

A hypothesis has recently been proposed that degeneration of enteric neurons may also play a role in the development of severe idiopathic constipation.30

DIAGNOSIS IS MOSTLY CLINICAL

The history and physical examination remain the cornerstones in the diagnosis and subsequent treatment of chronic constipation.

History

The history may provide clues as to a primary cause. The patient interview yields information about the frequency and consistency of stool (Table 1),31 the need to strain or manually disimpact, the sense of incomplete evacuation, pain, bleeding, or prolapse.

Risk factors for primary and secondary constipation to note during the interview include age (< 4 years, > 65 years); low-fiber diet; female sex; lack of physical activity; history of childhood constipation, endocrine and neuromuscular disorders, abuse, depression, or anxiety; family history of cancer; and personal history of pelvic surgery.

Since drugs can also cause chronic constipation, especially in elderly or immobile patients, medication lists should be reviewed and adjustments should be made if necessary (or possible) before recommending laxatives or invasive testing, if no alarm signs are present.

Alarm signs such as weight loss, hematochezia, melena, change in bowel habits, and symptoms refractory to therapy may represent colon cancer and indicate the need for early diagnostic testing.

Physical examination

Physical examination should always include inspection of the perianal area for evidence of hemorrhoids or fissures. Digital rectal examination may reveal a contracted sphincter or a puborectalis muscle that contracts with the Valsalva maneuver, suggesting dysfunction.

Laboratory testing

If the history and physical examination suggest that the constipation may be secondary, or if the patient is 50 years of age or older, then laboratory studies such as a complete blood cell count, serum electrolyte levels, blood sugar level, and thyroid function studies may help rule out a metabolic, endocrine, or organic cause.

Colonoscopy, other tests

At present, little evidence suggests that routine testing is warranted in patients without evidence of secondary constipation and without alarm signs. However, diagnostic studies are indicated in patients 50 years of age and older, as well as in those with alarm symptoms such as hematochezia, anemia, a positive fecal occult blood test, unintentional loss of more than 10 pounds, family history of colon cancer or inflammatory bowel disease, fever, nausea, vomiting, acute onset (especially in the elderly), and lack of improvement with conventional therapies regardless of age.2

The full length of the colon should be inspected by colonoscopy or by flexible sigmoidoscopy paired with a barium enema study to rule out structural disease. Of note, all patients 50 years of age or older should be screened for colon cancer.

If the patient does not respond to therapy, further tests such as colonic transit studies, anorectal manometry with balloon expulsion, and, possibly, defecating proctography or dynamic pelvic magnetic resonance imaging may be considered. These patients would likely also benefit from referral to a gastroenterologist for further management

DIET AND LIFESTYLE AS TREATMENT

For many years, health care providers have provided reassurance and recommended diet and lifestyle modifications as treatment for constipation. Increased water intake, increased activity, and a scheduled attempt at defecation when motor activity in the colon is highest, ie, in the morning or after eating, have all been recommended.

Data on the efficacy of these recommendations are scarce and often contradictory. Studies have shown that increasing water intake or daily exercise is not always helpful.32–34 Nevertheless, many patients who comply with dietary and exercise recommendations have improvement in symptoms. Eating fewer meals per day (and hence taking in fewer calories) has been shown to be associated with constipation in the elderly. However, no relationships between fiber or fluid intake and constipation were noted.35

In a study in which chronically constipated patients were fed a standardized diet that contained 25 g of fiber a day, stool frequency increased significantly and laxative use decreased.36 While on a high-fiber diet, the patients were divided into two groups, one that drank 1.1 L of fluid per day and one that drank 2.1 L of mineral water per day. Both groups experienced further improvements in stool frequency and decreases in laxative use, with the mineral-water group benefiting the most.36

Recently, Murakami and others37 found, in a cross-sectional study in young Japanese women with low daily fiber intake (6.4 g/day), that low water intake from foods and low magnesium intake were associated with an increasing prevalence of functional constipation as defined by the Rome III criteria. Constipation was also found to be significantly associated with low intake of fruits and vegetables in a study from Singapore.38

Moderate physical activity and high fiber intake may be associated with a lower prevalence of constipation in women. In the Nurses’ Health Study, more than 62,000 women between the ages of 36 and 61 were surveyed, and those who said they engaged in daily physical activity had a lower prevalence of constipation (prevalence ratio [PR] = 0.56, 95% confidence interval [CI] 0.44–0.70), as did those with a median fiber intake of 20 g/day (PR = 0.64, 95% CI 0.57–0.73).39

 

 

BULK LAXATIVES (FIBER SUPPLEMENTS): THE FIRST-LINE TREATMENT

Fiber remains the first-line treatment for constipation. It may relieve or improve symptoms in functional constipation. However, fewer than 30% of patients with either slow-transit constipation or pelvic floor dysfunction have improvement in symptoms with fiber, and in these types of constipation it can even worsen symptoms.40

There is much confusion about what types of fiber should be recommended and how the various types of fiber perform in resolving constipation.

Insoluble fiber

Insoluble fiber resists bacterial degradation in the colon and can retain more water than soluble fiber can.

Bran 20 g/day increased the frequency of bowel movements by 55%, increased fecal weight by 157%, and decreased intestinal transit time by 50% in women who had three or fewer bowel movements per week.41

Muller-Lissner42 and others performed a meta-analysis and found that bran (25 g/day) increased stool weight and decreased transit time in both healthy controls and patients with chronic constipation. Yet constipated patients taking bran still had lower stool weights and slower transit times than did healthy subjects.

When bran 20 g/day was compared with placebo in chronically constipated patients, bowel frequency and stool weight increased with both treatments,43 suggesting that factors other than intake may affect bowel function and transit time. However, bran was more effective than placebo in decreasing oroanal transit time.

Elderly constipated patients who received bran 10 g twice a day had significantly shorter transit times (89 hours vs 126 hours) than did those who received psyllium (a soluble fiber) 6 g twice daily. They also needed less additional laxative.44

Soluble fiber

Soluble fiber also affects the bowel habits of both healthy and constipated patients.

Methylcellulose, given to healthy volunteers at a dose of 4 g/day, resulted in statistically significant increases in stool weight, fecal water weight, and fecal solids.45 In constipated patients, methylcellulose 1 g/day was as effective as psyllium 3.4 g/day at increasing stool frequency, fecal water weight, and fecal solids.45

Konjac glucomannan was also shown to significantly increase stool frequency, water weight, and fecal solids.46

Psyllium. In a study that randomly assigned 22 patients with chronic constipation to receive either psyllium 5 g twice daily or placebo for 8 weeks, followed by a 4-week washout phase in which placebo was given,47 those who received psyllium reported significant improvements in stool consistency and pain with defecation, as well as significant increases in both stool frequency (3.8 vs 2.9 per week, P < .05) and stool weight (665 g vs 405 g, P < .05). However, colonic transit times and anorectal manometric measurements did not differ significantly between those who received psyllium vs placebo.47

Fiber may not help everyone

Others have also shown that while fiber may improve stool characteristics, it may not significantly alter the sensorimotor functions of the colon and pelvic floor.

Cheskin et al48 performed a crossover study in 10 constipated men and women in the community. Patients received either 24 g of psyllium fiber daily or a placebo fiber for 1 month and then crossed over to the other treatment for the next month. The most common cause of constipation in this study was pelvic floor dysfunction. Total gut transit time was significantly increased by psyllium fiber, and there was a trend toward increased stool frequency, demonstrating that psyllium clinically improved constipation. However, pelvic floor dysfunction, as measured by rectal manometry, was not improved.

It may be that only people with normal-transit constipation, not those with underlying slow-transit constipation or pelvic floor dysfunction, are helped by additional dietary fiber. Voderholzer and others40 studied 149 consecutive patients with chronic constipation and evaluated their response to at least 6 weeks of psyllium (Plantago ovata seeds 15 to 30 g/day) by serial symptom measurements, oroanal transit times, and functional rectoanal evaluation with defecography, manometry, and sigmoidoscopy. Of the patients with no evidence of pelvic floor dysfunction or slow-transit constipation, 85% improved. However, 80% of those with slow-transit constipation and 63% of those with pelvic floor dysfunction did not improve with the use of fiber. The authors concluded that it is reasonable to try dietary fiber in patients with constipation and, if no improvement is noted, to then consider further investigation for other subtypes of constipation (ie, slow-transit or pelvic-floor dysfunction).

Adverse effects may limit the use of fiber and may differ depending on the type of fiber used. Soluble fiber may be better tolerated, especially in patients with constipation-predominant irritable bowel syndrome.49 Side effects include the sensation of bloating and distention, excessive gas production, and abdominal cramping.

Our recommendations on fiber

We recommend the following regarding fiber in constipated patients:

  • Increase fiber intake from natural foods up to 20 g/day. This increase should be completed over 2 to 3 weeks to minimize adverse effects.
  • Consider adding a fiber supplement, such as psyllium, if increasing the intake of natural fiber does not relieve constipation-related symptoms.
  • If symptoms persist despite the use of fiber supplements and diet and lifestyle modification, then further structural and functional investigation of the colon (anorectal manometry, colonoscopy, defecography, colon manometry) should be considered.
 

 

OSMOTIC LAXATIVES

Osmotic laxatives are molecules that are either not absorbed or poorly absorbed and that draw water into the intestinal lumen to maintain isotonicity between the intestinal contents and the serum. Examples are polyethylene glycol, sodium phosphate (Fleet phosphosoda), magnesium hydroxide, magnesium citrate, the sugars lactulose and sorbitol, and glycerin.

Certain formulations of this class of laxative can cause bloating, diarrhea, electrolyte disturbances, volume overload, or dehydration. These effects limit their use, and these medications should be used with caution in patients prone to renal insufficiency or cardiac abnormalities.

Polyethylene glycol

Polyethylene glycol is an exception. It is not absorbed and lacks electrolytes, making it an attractive option in patients with underlying renal or cardiac dysfunction. In several placebo-controlled trials,50–52 various formulations significantly increased stool frequency while significantly decreasing straining, use of other laxatives, and colonic transit. No increase in adverse effects was noted compared with placebo.

Compared with lactulose, polyethylene glycol at about 21 g/day significantly increased bowel movement frequency while significantly decreasing the sense of straining with bowel movements and flatus due to laxative use.51 Both polyethylene glycol and lactulose accelerate colonic transit, although polyethylene glycol does so to a greater extent.53

Polyethylene glycol has been safe and effective when used for up to 6 months.54

Lactulose and sorbitol

Carbohydrate or sugar-based laxatives, if taken in sufficient doses, have a cathartic effect through two mechanisms: a primary osmotic effect of the sugar itself and a secondary osmotic effect as a substrate for colonic bacteria to cleave to acid metabolites, which exert an osmotic effect in the colon. This secondary effect will be discussed in a later section.

Lactulose and sorbitol are sugars that are poorly absorbed by the intestine. Lactulose has been shown to be more effective than placebo in increasing stool frequency, volume, weight, and consistency in chronically constipated patients.55 In a head-to-head comparison between sugar laxatives, 70% sorbitol was as effective as lactulose in increasing the frequency of bowel movements, and it was similar in its adverse effects56; 70% sorbitol is a cost-effective alternative to lactulose in the elderly nursing home population.57

Compared with fiber alone, lactulose use leads to a significantly higher number of bowel movements and better stool consistency.58 However, when lactulose was compared with a combination of fiber and a stimulant laxative, it was less effective than the combination therapy.59,60

Sugar laxatives, while effective, may have dose-limiting or use-limiting adverse effects such as abdominal bloating and flatulence.

Phosphate, magnesium

Sodium phosphate, like polyethylene glycol, is often used as a bowel preparation before colonoscopy, for which it is about as good or slightly better than polyethylene glycol.61,62

Although magnesium and sodium phosphate preparations are effective, there are multiple reports of clinically significant electrolyte abnormalities, renal failure, and congestive heart failure occurring with these preparations. Therefore, they must be used with discretion and caution in appropriate patients with frequent monitoring.

STIMULANT (IRRITANT) LAXATIVES

Stimulant laxatives are usually reserved for use when bulking agents and osmotic laxatives fail. Their mechanism of action involves the alteration of intestinal motility and intestinal fluid secretion.

Anthraquinones (cascara, aloe, and senna), castor oil, and diphenylmethanes (bisacodyl) are the most commonly used stimulant laxatives. They work relatively quickly, often eliciting a bowel movement 2 to 8 hours after they are taken.

This class of laxatives has historically been underused or given for only short periods of time, owing to concern about impairing colonic function, damaging the enteric nervous system, causing laxative dependency, causing cathartic colon, and even causing colon cancer. However, there is very little evidence to support these concerns. Stimulant laxatives can be used on a more regular basis when bulking or osmotic agents fail.63

Possibly of greatest concern is the potential for the overuse and abuse of stimulant laxatives. Excessive use can cause electrolyte disturbances brought about by high-volume watery diarrhea. Risk factors for overuse and abuse include underlying psychiatric disturbances and eating disorders. Prescribing other types of laxatives or cathartic agents may reduce risk, but the potential for abuse exists with all categories of laxatives.

TEGASEROD: GONE BUT STILL AVAILABLE, ON A CONTROLLED BASIS

Tegaserod (Zelnorm), a serotonin (5-HT4) agonist, was used predominantly in women with constipation-predominant irritable bowel syndrome and in men and women with chronic constipation. However, it was suspended from the market in the United States in March 2007 owing to concern about a high risk of adverse cardiovascular effects compared with placebo.

In a double-blind, randomized controlled trial, men with chronic constipation who received tegaserod 6 mg twice a day for 12 weeks had more spontaneous bowel movements than those receiving placebo (P = .04).64

Lin et al65 evaluated the use of tegaserod 6 mg twice daily for 4 weeks in both men and women with chronic constipation. Those receiving tegaserod had significantly more spontaneous bowel movements per week, less straining, and better stool consistency than those receiving placebo.

Tegaserod can still be obtained for appropriate patients via a treatment investigational new drug application. Safety data are under further review by the US Food and Drug Administration. Studies of other serotonin agonists are under way.

 

 

LUBIPROSTONE

Lubiprostone (Amitiza) is an agonist of the chloride channel subtype 2, found on the apical membrane of intestinal epithelial cells. It causes increased chloride secretion into the intestinal lumen, enhancing intestinal fluid secretion. It has been shown to be effective in chronic constipation by improving stool consistency and increasing the motility of the small intestine and colon.66 It is approved for treating chronic constipation in adults.

In randomized, double-blind trials, patients receiving lubiprostone 24 fig twice daily for 4 weeks had significantly more bowel movements per week, reported significantly better stool consistency and less abdominal bloating and straining, and rated their constipation as less severe than did patients receiving placebo.67–69

More recently, in an open-label study, lubiprostone improved constipation symptoms when taken for up to 48 weeks.70

The drug is well tolerated, but its adverse effects include nausea (which appears to be dose-dependent and may diminish over time or if the drug is taken with food), diarrhea, and headache.68 Of note, the drug appears to be well tolerated by older people (65 years of age and older), in whom adverse effects occur less often than in younger users.71 However, adverse events may cause up to 20% of patients to stop taking the drug.69 When lubiprostone is discontinued, patients may once again revert to their baseline bowel habit.72

Lubiprostone has not been compared with conventional laxatives, and cost may prohibit it from becoming a first-line drug for chronic constipation.73

OTHER PROMOTILITY AGENTS

Several promotility agents have been studied for treating chronic idiopathic constipation.

Cisapride (Propulsid), a 5-HT3 receptor antagonist and 5-HT4 receptor agonist, and prucalopride, a 5-HT4 agonist, were effective in relieving symptoms associated with chronic constipation.74–76 However, safety issues (cardiac arrhythmias) necessitated withdrawal of cisapride from the US market in 2000. Prucalopride is undergoing clinical trials.77

Renzapride, a mixed 5-HT4 receptor agonist and 5-HT3 receptor antagonist, has been shown to improve stool consistency and to increase colonic transit in patients with constipation-predominant irritable bowel syndrome.78 Renzapride has been studied in patients with this condition,78–81 but not in patients with chronic constipation. Renzapride is in phase III clinical development in the United States for treating constipation-predominant irritable bowel syndrome.

EMERGING TREATMENTS

New drugs with novel mechanisms of action are being investigated for the treatment of chronic idiopathic constipation.

Neurotrophin-3, a neurotrophic factor, modulates the development of the nervous system by regulating the survival and differentiation of nerves.82 In patients with functional constipation, subcutaneous doses of neurotrophin-3 improved stool frequency, the number of complete spontaneous bowel movements, and stool consistency.83

Alvimopan is a selective antagonist of the muopioid receptor that is being studied for opiate-related constipation and postoperative ileus.84,85 Little of this drug is systemically absorbed and it does not cross the blood-brain barrier; thus, it relieves the opiate-related side effects, ie, bloating, abdominal discomfort, and reduced stool frequency, without interfering with the central analgesic effects.

Linaclotide (MD 1100), a poorly absorbed guanylate cyclase agonist, is also being investigated as a treatment for chronic constipation.86 Linaclotide increases intestinal fluid secretion and transit via stimulation of cyclic guanosine monophosphate production and activation of the cystic fibrosis transmembrane conductance regulator.86,87 In preliminary studies, linaclotide increased stool frequency and the Bristol Stool Form Scale consistency score (Table 1) by increasing intestinal fluid secretion and transit.86

Chenodeoxycholic acid is a bile acid that is synthesized from cholesterol.88 Treatment of constipation with chenodeoxycholic acid has been proposed, given its laxative effect. A study by Bazzoli et al89 showed increased stool frequency and a decrease in stool consistency in chronic constipation patients given chenodeoxycholic acid 10 mg/kg/day. The main side effect was diarrhea. Chenodeoxycholic acid may be worthwhile in the management of constipation, but more studies are needed.

PROBIOTICS AND PREBIOTICS

The bacteria of the colon influence peristalsis of the colon.90 Probiotics (live bacterial preparations) and prebiotics (nondigestible preparations that stimulate the growth or activity of beneficial colonic bacteria) have been gaining interest as potential therapies for constipation.91,92

Probiotic bacterial preparations are generally composed of strains of Bifodobacterium,93,94Lactobacillus,95 and combinations thereof, and are available as mixed preparations of multiple bacterial strains of Lactobacillus, Bifodobacterium, and Streptococcus species, such as VSL#3.96

Probiotics may help relieve constipation, but their effect may depend on the strain of bacteria used and the population being studied.97 In a double-blind parallel study in 70 healthy adults, ingestion of 375 g/day of milk fermented with B animalis strain DN-173 010 for 11 days reduced colon transit time by 20% from baseline. The effect was more pronounced in women, particularly in those with longer baseline transit.98

Lactic acid-producing bacteria are considered commensal organisms with essentially no pathogenic potential.99 A review of the safety of bifodobacteria and lactobacilli concluded there was no health risk to consumers.100

Prebiotics are short-chain carbohydrates such as lactulose that stimulate the activity of beneficial colonic bacteria.91 They are thought to have a small laxative effect that is likely both osmotic and due to beneficial actions of bacteria for which they are a substrate. Both konjac glucomannan and lactulose, sugar-based laxatives and prebiotics, have been shown to significantly increase the fecal concentrations of lactobacilli and total bacteria, possibly through increases in stool bulk.46 Prebiotics that have been the focus of research include inulin, fructo-oligosaccharides, and galacto-oligosaccharides.91 Evidence on the efficacy of probiotics and prebiotics at relieving symptoms of constipation, however, is inconclusive because few well-controlled clinical studies have been done.91,92

 

 

STRATEGIES FOR MANAGING CHRONIC CONSTIPATION

In the absence of secondary causes, treatment of chronic constipation is focused on relieving symptoms.

Figure 1. Treatment approaches for chronic constipation.
The first line of treatment includes non-pharmacologic approaches such as increasing fiber in the diet or taking fiber supplements (Figure 1). Additionally, lifestyle changes such as increased physical activity and dietary modification, as well as cognitive behavior therapy (biofeedback and hypnosis), may relieve symptoms in a subset of patients with chronic constipation. Although lacking in clinical evidence, milk of magnesia101 and probiotics are often prescribed.

If symptoms are refractory to these traditional treatments, agents such as lactulose and polyethylene glycol may provide relief.11,21 Although they do not address the underlying cause of constipation, these agents increase the fluid content of the intestine, contributing to improved stool consistency, and consequently increase the frequency of bowel movements.

Lubiprostone similarly increases the fluid content of the colon, contributing to improved stool consistency, reduced fecal transit time, and increased frequency of bowel movements.66,70,102 Unlike lactulose and polyethylene glycol, which are indicated only for short-term use, lubiprostone has been found to be safe and effective when used for up to 48 weeks.70,71

Biofeedback is the preferred treatment for pelvic floor dyssynergia, in which it has a success rate of 70% to 81% and in which it is superior to standard treatment (laxatives, fiber, and education).103–105 In an instrument-based training program, patients receive auditory or visual feedback or both to help train the pelvic floor and relax the anal sphincter while simulating defecation. It also improves rectal sensation to assist in proper evacuation. The best outcomes are achieved when committed patients receive instruction from empathetic, properly trained physical therapists or other technicians. Studies show that the benefits of biofeedback are long-lasting.104 It does not improve slow-transit constipation, though pelvic floor dyssynergia and slow-transit constipation can overlap.

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  76. Altabas K, Biliæ A, Jurciæ D, et al. The efficacy of cisapride vs. placebo and diet in patients with chronic constipation. Coll Antropol 2003; 27:197–204.
  77. Camilleri M, Kerstens R, Rykx A, Vandeplassche L. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med 2008; 358:2344–2354.
  78. Camilleri M, McKinzie S, Fox J, et al. Effect of renzapride on transit in constipation-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol 2004; 2:895–904.
  79. Tack J, Middleton SJ, Horne MC, et al. Pilot study of the efficacy of renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2006; 23:1655–1665.
  80. Henderson JC, Palmer RM, Meyers NL, Spiller RC. A phase IIb clinical study of renzapride in mixed symptom (alternating) irritable bowel syndrome [abstract]. Gastroenterology 2004; 126 suppl 2:A644.
  81. Meyers NL, Palmer RMJ, George A. Efficacy and safety of renzapride in patients with constipation-predominant IBS: a phase IIb study in the UK primary healthcare setting [abstract]. Gastroenterology 2004; 126 suppl 2:A640.
  82. Coulie B, Szarka LA, Camilleri M, et al. Recombinant human neurotrophic factors accelerate colonic transit and relieve constipation in humans. Gastroenterology 2000; 119:41–50.
  83. Parkman HP, Rao SS, Reynolds JC, et al. Neurotrophin-3 improves functional constipation. Am J Gastroenterol 2003; 98:1338–1347.
  84. Camilleri M. Alvimopan, a selective peripherally acting muopioid antagonist. Neurogastroenterol Motil 2005; 17:157–165.
  85. Holzer P. Opioids and opioid receptors in the enteric nervous system: from a problem in opioid analgesia to a possible new prokinetic therapy in humans. Neurosci Lett 2004; 361:192–195.
  86. Kurtz C, Fitch D, Busby R, et al. Effects of multidose administration of MD-1100 on safety, tolerability, exposure and pharmacodynamics in healthy subjects [abstract]. Gastroenterology 2006; 130 suppl 2:A26.
  87. Eutamene H, Theodorou V, Tondereau V, et al. Influence of guanylate cyclase C binding ligand MD-1100 on TNBS-induced visceral hypersensitivity in WT vs. KO guanylate cyclase C deficient mice [abstract]. Gastroenterology 2006; 130 suppl 2:A597.
  88. Broughton G. Chenodeoxycholate: the bile acid. The drug. a review. Am J Med Sci 1994; 307:54–63.
  89. Bazzoli F, Malavolti M, Petronelli A, Barbara L, Roda E. Treatment of constipation with chenodeoxycholic acid. J Int Med Res 1983; 11:120–123.
  90. Picard C, Fioramonti J, Francois A, Robinson T, Neant F, Matuchansky C. Review article: bifidobacteria as probiotic agents – physiological effects and clinical benefits. Aliment Pharmacol Ther 2005; 22:495–512.
  91. Macfarlane S, Macfarlane GT, Cummings JH. Review article: prebiotics in the gastrointestinal tract. Aliment Pharmacol Ther 2006; 24:701–714.
  92. Ouwehand A, Lagstrom H, Suomalainen T, Salminen S. Effect of probiotics on constipation, fecal azoreductase activity and fecal mucin content in the elderly. Ann Nutr Metab 2002; 46:159–162.
  93. Whorwell P, Altringer L, Morel J, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol 2006; 101:1581–1590.
  94. O'Mahony L, McCarthy J, Kelly P, et al. Lactobacillus and Bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology 2005; 128:541–551.
  95. Koebnick C, Wagner I, Leitzmann P, Stern U, Zunft H. Probiotic beverage containing Lactobacillus casei Shirota improves gastrointestinal symptoms in patients with chronic constipation. Can J Gastroenterol 2003; 17:655–659.
  96. Kim HJ, Camilleri M, McKinzie S, et al. A randomized controlled trial of a probiotic, VSL#3, on gut transit and symptoms in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2003; 17:895–904.
  97. Fernández-Bañares F. Nutritional care of the patient with constipation. Best Pract Res Clin Gastroenterol 2006; 20:575–587.
  98. Bouvier M, Meance S, Bouley C, Berta J, Grimaud J. Effects of consumption of milk fermented by the probiotic strain Bifidobacterium animalis DN-173 010 on colonit transit times in healthy humans. Biosci Microflor 2001; 20 2:43–48.
  99. Makelainen H, Tahvonen R, Salminen S, Ouwehand AC. In vivo safety assessment of two Bifidobacterium longum strains. Microbiol Immunol 2003; 47:911–914.
  100. Borriello SP, Hammes WP, Holzapfel W, et al. Safety of probiotics that contain lactobacilli or bifidobacteria. Clin Infect Dis 2003; 36:775–780.
  101. Ramkumar D, Rao S. Efficacy and safety of traditional medical therapies for chronic constipation: systematic review. Am J Gastroenterol 2005; 100:936–971.
  102. Ueno R, Osama H, Habe T, Engelke K, Patchen M. Oral SPI-0211 increases intestinal fluid secretion and chloride concentration without altering serum electrolyte levels [abstract]. Gastroenterology 2004; 126 suppl 2:A298.
  103. Rao SS, Seaton K, Miller M, et al. Randomized controlled trial of biofeedback, sham biofeedback, and standard therapy for dyssynergic defecation. Clin Gastroenterol Hepatol 2007; 5:331–338.
  104. Chiarioni G, Whitehead WE, Pezza V, Morelli A, Bassotti G. Biofeedback is superior to laxatives for normal transit constipation due to pelvic floor dyssynergia. Gastroenterology 2006; 130:657–664.
  105. Heymen S, Scarlett Y, Jones K, Ringel Y, Drossman D, Whitehead WE. Randomized, controlled trial shows biofeedback to be superior to alternative treatments for patients with pelvic floor dyssynergia-type constipation. Dis Colon Rectum 2007; 50:428–441.
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Department of Gastroenterology, Cleveland Clinic

Suwebatu T. Odunsi, MD
Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, Rochester, MN

Address: Amy E. Foxx-Orenstein, DO, Associate Professor of Medicine, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905; e-mail [email protected]

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Associate Professor of Medicine, Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, Rochester, MN

Meredythe A. McNally, MD
Department of Gastroenterology, Cleveland Clinic

Suwebatu T. Odunsi, MD
Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, Rochester, MN

Address: Amy E. Foxx-Orenstein, DO, Associate Professor of Medicine, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905; e-mail [email protected]

Dr. Foxx-Orenstein has disclosed that she has received honoraria from the GlaxoSmithKline and Novartis corporations for serving on advisory committees or review panels.

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Associate Professor of Medicine, Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, Rochester, MN

Meredythe A. McNally, MD
Department of Gastroenterology, Cleveland Clinic

Suwebatu T. Odunsi, MD
Division of Gastroenterology and Hepatology, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, Rochester, MN

Address: Amy E. Foxx-Orenstein, DO, Associate Professor of Medicine, Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905; e-mail [email protected]

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Constipation is both a symptom and, when chronic, a multisymptom disorder, and it can overlap with other gastrointestinal tract disorders such as dyspepsia and gastroesophageal reflux disease. Furthermore, one should keep in mind the possibility of cancer and be alert for its warning signs.

Since constipation has a variety of causes and forms, one treatment does not fit all patients. Conservative measures such as recommending that the patient increase his or her intake of dietary fiber and water and engage in more physical activity are still the cornerstone of treatment, but they do not help all patients. On the other hand, polyethylene glycol and stimulant laxatives, which are traditionally given only for a short time, can be safe and effective when given long-term if other agents fail. New agents have become available or are in development.

In this article we outline our approach to constipation, as a guide for internists.

CONSTIPATION IS COMMON, BUT HOW SHOULD WE DEFINE IT?

Constipation affects 2% to 27% (average 14.8%) of the North American adult population—approximately 63 million people.1 It is more common than many other chronic diseases, including hypertension (48 million people), migraine (33 million), obesity (50 million), and diabetes mellitus (15 million).1–3

Constipation affects more women than men (2.1:1 ratio) and more nonwhites than whites (1.68:1).1 It occurs in all age groups but is more common in those older than 65 years and younger than 4 years.4,5

Constipation accounts for more than 2.5 million office visits and more than $500 million spent on laxatives per year.6,7 Also, people with constipation may report decreased productivity and increased absenteeism.8

The broad range in the prevalence of constipation cited above reflects differences in how it is defined and, in particular, a lack of agreement between how patients and physicians perceive it.1,9 Physicians mainly define constipation on the basis of stool frequency, considering fewer than three bowel movements per week to be abnormal.1 In contrast, patients typically define it on the basis of bothersome symptoms such as straining, passage of hard stool, unproductive urges, inability to defecate at will, and sensations of incomplete evacuation or abdominal bloating.1,9,10

The Rome III diagnostic criteria were developed to provide a consistent diagnostic approach for use in clinical practice and clinical trials.11 The Rome III criteria define functional chronic constipation as a chronic bowel disorder characterized by two or more of the following:

  • Straining
  • Lumpy or hard stools
  • Sensations of incomplete evacuation
  • Sensations of anorectal obstruction or blockage
  • Use of manual maneuvers to facilitate defecation (eg, digital evacuation, support of the pelvic floor) during at least 25% of defecations
  • Fewer than three bowel movements per week.

In addition, loose stools should rarely occur without the use of laxatives, and there should be insufficient criteria for irritable bowel syndrome.11 Chronicity is established by symptom onset within the previous 6 months and symptom duration of at least 3 months.

In contrast, patients with irritable bowel syndrome, also a functional bowel disorder, experience recurrent abdominal pain and discomfort associated with two or more of the following: symptom improvement with defecation, symptom onset associated with a change in the frequency of bowel movements, and a change in the form or appearance of the stool.

THREE TYPES OF IDIOPATHIC CONSTIPATION

There are three types of primary or idiopathic constipation5,9,12,13:

  • Functional
  • Slow-transit
  • Outlet dysfunction.

Functional constipation includes functional chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. It presents with a sense of difficult or delayed evacuation, hard stools, or abdominal bloating or discomfort.6,9,13 The predominant symptom of constipation-predominant irritable bowel syndrome is severe discomfort or pain; in chronic idiopathic constipation, pain and discomfort may be present but are not the primary symptom.

Slow-transit constipation (or delayed-transit constipation) is associated with a prolonged time between bowel movements. Its symptoms include low stool frequency, lack of urge to defecate, abdominal distention, bloating, and abdominal discomfort.14

Outlet dysfunction. Disorders of defecation can be due to mechanical causes such as Hirschsprung disease, anal stricture, cancer, prolapse, and large rectoceles, or from pelvic floor dysfunction. Pelvic floor dysfunction may be due to inadequate or excessive perineal descent or to inadequate propulsive forces, as may occur in neurologic or neuromuscular conditions and dyssynergia.

Pelvic floor dyssynergia, also called anorectal dyssynergia, dyssynergic defecation, and anismus, results from a functional defect in coordinated evacuation. The characteristic symptom is a feeling of being unable to adequately empty the rectum.14 Other symptoms such as excessive straining and manual disimpaction indicate but are not unique to pelvic floor dyssynergia.14,15

Combined forms. Patients may have more than one type of primary constipation and presentation, and pelvic floor dyssynergia has been shown to prolong intestinal transit, which may improve with treatment.

Secondary constipation can be due to causes such as diet, lifestyle, certain medications (calcium channel blockers, beta-blockers, opioids, diuretics, antidepressants, anticonvulsants, antacids, anticholinergics, and antispasmodics),5,16 underlying medical conditions (diabetes, hypothyroidism, multiple sclerosis, parkinsonism),16,17 pregnancy, and advanced age.18

 

 

NEUROTRANSMITTERS MAY PLAY A ROLE

Among the mechanisms thought to cause chronic constipation are impaired gastrointestinal motility,19–22 reduced intestinal secretions,21–23 and inadequate reflex relaxation of the pelvic floor muscles.22,24

Neurotransmitters such as serotonin, somatostatin, peptide YY, and vasoactive intestinal peptide affect intestinal secretion and motility.25,26 Hyperactivity of these neurotransmitters associated with increased secretion and motility results in diarrhea, whereas hypoactivity leads to decreased secretion, delayed transit, and constipation.23

Serotonin has a role in regulating visceral pain perception and intestinal motility, as well as secretion.26–28 Clinical trials have shown that activation of serotonin receptors in the gut enhances gastrointestinal motility, inhibits visceral sensitivity, and stimulates intestinal secretion.26,27,29

A hypothesis has recently been proposed that degeneration of enteric neurons may also play a role in the development of severe idiopathic constipation.30

DIAGNOSIS IS MOSTLY CLINICAL

The history and physical examination remain the cornerstones in the diagnosis and subsequent treatment of chronic constipation.

History

The history may provide clues as to a primary cause. The patient interview yields information about the frequency and consistency of stool (Table 1),31 the need to strain or manually disimpact, the sense of incomplete evacuation, pain, bleeding, or prolapse.

Risk factors for primary and secondary constipation to note during the interview include age (< 4 years, > 65 years); low-fiber diet; female sex; lack of physical activity; history of childhood constipation, endocrine and neuromuscular disorders, abuse, depression, or anxiety; family history of cancer; and personal history of pelvic surgery.

Since drugs can also cause chronic constipation, especially in elderly or immobile patients, medication lists should be reviewed and adjustments should be made if necessary (or possible) before recommending laxatives or invasive testing, if no alarm signs are present.

Alarm signs such as weight loss, hematochezia, melena, change in bowel habits, and symptoms refractory to therapy may represent colon cancer and indicate the need for early diagnostic testing.

Physical examination

Physical examination should always include inspection of the perianal area for evidence of hemorrhoids or fissures. Digital rectal examination may reveal a contracted sphincter or a puborectalis muscle that contracts with the Valsalva maneuver, suggesting dysfunction.

Laboratory testing

If the history and physical examination suggest that the constipation may be secondary, or if the patient is 50 years of age or older, then laboratory studies such as a complete blood cell count, serum electrolyte levels, blood sugar level, and thyroid function studies may help rule out a metabolic, endocrine, or organic cause.

Colonoscopy, other tests

At present, little evidence suggests that routine testing is warranted in patients without evidence of secondary constipation and without alarm signs. However, diagnostic studies are indicated in patients 50 years of age and older, as well as in those with alarm symptoms such as hematochezia, anemia, a positive fecal occult blood test, unintentional loss of more than 10 pounds, family history of colon cancer or inflammatory bowel disease, fever, nausea, vomiting, acute onset (especially in the elderly), and lack of improvement with conventional therapies regardless of age.2

The full length of the colon should be inspected by colonoscopy or by flexible sigmoidoscopy paired with a barium enema study to rule out structural disease. Of note, all patients 50 years of age or older should be screened for colon cancer.

If the patient does not respond to therapy, further tests such as colonic transit studies, anorectal manometry with balloon expulsion, and, possibly, defecating proctography or dynamic pelvic magnetic resonance imaging may be considered. These patients would likely also benefit from referral to a gastroenterologist for further management

DIET AND LIFESTYLE AS TREATMENT

For many years, health care providers have provided reassurance and recommended diet and lifestyle modifications as treatment for constipation. Increased water intake, increased activity, and a scheduled attempt at defecation when motor activity in the colon is highest, ie, in the morning or after eating, have all been recommended.

Data on the efficacy of these recommendations are scarce and often contradictory. Studies have shown that increasing water intake or daily exercise is not always helpful.32–34 Nevertheless, many patients who comply with dietary and exercise recommendations have improvement in symptoms. Eating fewer meals per day (and hence taking in fewer calories) has been shown to be associated with constipation in the elderly. However, no relationships between fiber or fluid intake and constipation were noted.35

In a study in which chronically constipated patients were fed a standardized diet that contained 25 g of fiber a day, stool frequency increased significantly and laxative use decreased.36 While on a high-fiber diet, the patients were divided into two groups, one that drank 1.1 L of fluid per day and one that drank 2.1 L of mineral water per day. Both groups experienced further improvements in stool frequency and decreases in laxative use, with the mineral-water group benefiting the most.36

Recently, Murakami and others37 found, in a cross-sectional study in young Japanese women with low daily fiber intake (6.4 g/day), that low water intake from foods and low magnesium intake were associated with an increasing prevalence of functional constipation as defined by the Rome III criteria. Constipation was also found to be significantly associated with low intake of fruits and vegetables in a study from Singapore.38

Moderate physical activity and high fiber intake may be associated with a lower prevalence of constipation in women. In the Nurses’ Health Study, more than 62,000 women between the ages of 36 and 61 were surveyed, and those who said they engaged in daily physical activity had a lower prevalence of constipation (prevalence ratio [PR] = 0.56, 95% confidence interval [CI] 0.44–0.70), as did those with a median fiber intake of 20 g/day (PR = 0.64, 95% CI 0.57–0.73).39

 

 

BULK LAXATIVES (FIBER SUPPLEMENTS): THE FIRST-LINE TREATMENT

Fiber remains the first-line treatment for constipation. It may relieve or improve symptoms in functional constipation. However, fewer than 30% of patients with either slow-transit constipation or pelvic floor dysfunction have improvement in symptoms with fiber, and in these types of constipation it can even worsen symptoms.40

There is much confusion about what types of fiber should be recommended and how the various types of fiber perform in resolving constipation.

Insoluble fiber

Insoluble fiber resists bacterial degradation in the colon and can retain more water than soluble fiber can.

Bran 20 g/day increased the frequency of bowel movements by 55%, increased fecal weight by 157%, and decreased intestinal transit time by 50% in women who had three or fewer bowel movements per week.41

Muller-Lissner42 and others performed a meta-analysis and found that bran (25 g/day) increased stool weight and decreased transit time in both healthy controls and patients with chronic constipation. Yet constipated patients taking bran still had lower stool weights and slower transit times than did healthy subjects.

When bran 20 g/day was compared with placebo in chronically constipated patients, bowel frequency and stool weight increased with both treatments,43 suggesting that factors other than intake may affect bowel function and transit time. However, bran was more effective than placebo in decreasing oroanal transit time.

Elderly constipated patients who received bran 10 g twice a day had significantly shorter transit times (89 hours vs 126 hours) than did those who received psyllium (a soluble fiber) 6 g twice daily. They also needed less additional laxative.44

Soluble fiber

Soluble fiber also affects the bowel habits of both healthy and constipated patients.

Methylcellulose, given to healthy volunteers at a dose of 4 g/day, resulted in statistically significant increases in stool weight, fecal water weight, and fecal solids.45 In constipated patients, methylcellulose 1 g/day was as effective as psyllium 3.4 g/day at increasing stool frequency, fecal water weight, and fecal solids.45

Konjac glucomannan was also shown to significantly increase stool frequency, water weight, and fecal solids.46

Psyllium. In a study that randomly assigned 22 patients with chronic constipation to receive either psyllium 5 g twice daily or placebo for 8 weeks, followed by a 4-week washout phase in which placebo was given,47 those who received psyllium reported significant improvements in stool consistency and pain with defecation, as well as significant increases in both stool frequency (3.8 vs 2.9 per week, P < .05) and stool weight (665 g vs 405 g, P < .05). However, colonic transit times and anorectal manometric measurements did not differ significantly between those who received psyllium vs placebo.47

Fiber may not help everyone

Others have also shown that while fiber may improve stool characteristics, it may not significantly alter the sensorimotor functions of the colon and pelvic floor.

Cheskin et al48 performed a crossover study in 10 constipated men and women in the community. Patients received either 24 g of psyllium fiber daily or a placebo fiber for 1 month and then crossed over to the other treatment for the next month. The most common cause of constipation in this study was pelvic floor dysfunction. Total gut transit time was significantly increased by psyllium fiber, and there was a trend toward increased stool frequency, demonstrating that psyllium clinically improved constipation. However, pelvic floor dysfunction, as measured by rectal manometry, was not improved.

It may be that only people with normal-transit constipation, not those with underlying slow-transit constipation or pelvic floor dysfunction, are helped by additional dietary fiber. Voderholzer and others40 studied 149 consecutive patients with chronic constipation and evaluated their response to at least 6 weeks of psyllium (Plantago ovata seeds 15 to 30 g/day) by serial symptom measurements, oroanal transit times, and functional rectoanal evaluation with defecography, manometry, and sigmoidoscopy. Of the patients with no evidence of pelvic floor dysfunction or slow-transit constipation, 85% improved. However, 80% of those with slow-transit constipation and 63% of those with pelvic floor dysfunction did not improve with the use of fiber. The authors concluded that it is reasonable to try dietary fiber in patients with constipation and, if no improvement is noted, to then consider further investigation for other subtypes of constipation (ie, slow-transit or pelvic-floor dysfunction).

Adverse effects may limit the use of fiber and may differ depending on the type of fiber used. Soluble fiber may be better tolerated, especially in patients with constipation-predominant irritable bowel syndrome.49 Side effects include the sensation of bloating and distention, excessive gas production, and abdominal cramping.

Our recommendations on fiber

We recommend the following regarding fiber in constipated patients:

  • Increase fiber intake from natural foods up to 20 g/day. This increase should be completed over 2 to 3 weeks to minimize adverse effects.
  • Consider adding a fiber supplement, such as psyllium, if increasing the intake of natural fiber does not relieve constipation-related symptoms.
  • If symptoms persist despite the use of fiber supplements and diet and lifestyle modification, then further structural and functional investigation of the colon (anorectal manometry, colonoscopy, defecography, colon manometry) should be considered.
 

 

OSMOTIC LAXATIVES

Osmotic laxatives are molecules that are either not absorbed or poorly absorbed and that draw water into the intestinal lumen to maintain isotonicity between the intestinal contents and the serum. Examples are polyethylene glycol, sodium phosphate (Fleet phosphosoda), magnesium hydroxide, magnesium citrate, the sugars lactulose and sorbitol, and glycerin.

Certain formulations of this class of laxative can cause bloating, diarrhea, electrolyte disturbances, volume overload, or dehydration. These effects limit their use, and these medications should be used with caution in patients prone to renal insufficiency or cardiac abnormalities.

Polyethylene glycol

Polyethylene glycol is an exception. It is not absorbed and lacks electrolytes, making it an attractive option in patients with underlying renal or cardiac dysfunction. In several placebo-controlled trials,50–52 various formulations significantly increased stool frequency while significantly decreasing straining, use of other laxatives, and colonic transit. No increase in adverse effects was noted compared with placebo.

Compared with lactulose, polyethylene glycol at about 21 g/day significantly increased bowel movement frequency while significantly decreasing the sense of straining with bowel movements and flatus due to laxative use.51 Both polyethylene glycol and lactulose accelerate colonic transit, although polyethylene glycol does so to a greater extent.53

Polyethylene glycol has been safe and effective when used for up to 6 months.54

Lactulose and sorbitol

Carbohydrate or sugar-based laxatives, if taken in sufficient doses, have a cathartic effect through two mechanisms: a primary osmotic effect of the sugar itself and a secondary osmotic effect as a substrate for colonic bacteria to cleave to acid metabolites, which exert an osmotic effect in the colon. This secondary effect will be discussed in a later section.

Lactulose and sorbitol are sugars that are poorly absorbed by the intestine. Lactulose has been shown to be more effective than placebo in increasing stool frequency, volume, weight, and consistency in chronically constipated patients.55 In a head-to-head comparison between sugar laxatives, 70% sorbitol was as effective as lactulose in increasing the frequency of bowel movements, and it was similar in its adverse effects56; 70% sorbitol is a cost-effective alternative to lactulose in the elderly nursing home population.57

Compared with fiber alone, lactulose use leads to a significantly higher number of bowel movements and better stool consistency.58 However, when lactulose was compared with a combination of fiber and a stimulant laxative, it was less effective than the combination therapy.59,60

Sugar laxatives, while effective, may have dose-limiting or use-limiting adverse effects such as abdominal bloating and flatulence.

Phosphate, magnesium

Sodium phosphate, like polyethylene glycol, is often used as a bowel preparation before colonoscopy, for which it is about as good or slightly better than polyethylene glycol.61,62

Although magnesium and sodium phosphate preparations are effective, there are multiple reports of clinically significant electrolyte abnormalities, renal failure, and congestive heart failure occurring with these preparations. Therefore, they must be used with discretion and caution in appropriate patients with frequent monitoring.

STIMULANT (IRRITANT) LAXATIVES

Stimulant laxatives are usually reserved for use when bulking agents and osmotic laxatives fail. Their mechanism of action involves the alteration of intestinal motility and intestinal fluid secretion.

Anthraquinones (cascara, aloe, and senna), castor oil, and diphenylmethanes (bisacodyl) are the most commonly used stimulant laxatives. They work relatively quickly, often eliciting a bowel movement 2 to 8 hours after they are taken.

This class of laxatives has historically been underused or given for only short periods of time, owing to concern about impairing colonic function, damaging the enteric nervous system, causing laxative dependency, causing cathartic colon, and even causing colon cancer. However, there is very little evidence to support these concerns. Stimulant laxatives can be used on a more regular basis when bulking or osmotic agents fail.63

Possibly of greatest concern is the potential for the overuse and abuse of stimulant laxatives. Excessive use can cause electrolyte disturbances brought about by high-volume watery diarrhea. Risk factors for overuse and abuse include underlying psychiatric disturbances and eating disorders. Prescribing other types of laxatives or cathartic agents may reduce risk, but the potential for abuse exists with all categories of laxatives.

TEGASEROD: GONE BUT STILL AVAILABLE, ON A CONTROLLED BASIS

Tegaserod (Zelnorm), a serotonin (5-HT4) agonist, was used predominantly in women with constipation-predominant irritable bowel syndrome and in men and women with chronic constipation. However, it was suspended from the market in the United States in March 2007 owing to concern about a high risk of adverse cardiovascular effects compared with placebo.

In a double-blind, randomized controlled trial, men with chronic constipation who received tegaserod 6 mg twice a day for 12 weeks had more spontaneous bowel movements than those receiving placebo (P = .04).64

Lin et al65 evaluated the use of tegaserod 6 mg twice daily for 4 weeks in both men and women with chronic constipation. Those receiving tegaserod had significantly more spontaneous bowel movements per week, less straining, and better stool consistency than those receiving placebo.

Tegaserod can still be obtained for appropriate patients via a treatment investigational new drug application. Safety data are under further review by the US Food and Drug Administration. Studies of other serotonin agonists are under way.

 

 

LUBIPROSTONE

Lubiprostone (Amitiza) is an agonist of the chloride channel subtype 2, found on the apical membrane of intestinal epithelial cells. It causes increased chloride secretion into the intestinal lumen, enhancing intestinal fluid secretion. It has been shown to be effective in chronic constipation by improving stool consistency and increasing the motility of the small intestine and colon.66 It is approved for treating chronic constipation in adults.

In randomized, double-blind trials, patients receiving lubiprostone 24 fig twice daily for 4 weeks had significantly more bowel movements per week, reported significantly better stool consistency and less abdominal bloating and straining, and rated their constipation as less severe than did patients receiving placebo.67–69

More recently, in an open-label study, lubiprostone improved constipation symptoms when taken for up to 48 weeks.70

The drug is well tolerated, but its adverse effects include nausea (which appears to be dose-dependent and may diminish over time or if the drug is taken with food), diarrhea, and headache.68 Of note, the drug appears to be well tolerated by older people (65 years of age and older), in whom adverse effects occur less often than in younger users.71 However, adverse events may cause up to 20% of patients to stop taking the drug.69 When lubiprostone is discontinued, patients may once again revert to their baseline bowel habit.72

Lubiprostone has not been compared with conventional laxatives, and cost may prohibit it from becoming a first-line drug for chronic constipation.73

OTHER PROMOTILITY AGENTS

Several promotility agents have been studied for treating chronic idiopathic constipation.

Cisapride (Propulsid), a 5-HT3 receptor antagonist and 5-HT4 receptor agonist, and prucalopride, a 5-HT4 agonist, were effective in relieving symptoms associated with chronic constipation.74–76 However, safety issues (cardiac arrhythmias) necessitated withdrawal of cisapride from the US market in 2000. Prucalopride is undergoing clinical trials.77

Renzapride, a mixed 5-HT4 receptor agonist and 5-HT3 receptor antagonist, has been shown to improve stool consistency and to increase colonic transit in patients with constipation-predominant irritable bowel syndrome.78 Renzapride has been studied in patients with this condition,78–81 but not in patients with chronic constipation. Renzapride is in phase III clinical development in the United States for treating constipation-predominant irritable bowel syndrome.

EMERGING TREATMENTS

New drugs with novel mechanisms of action are being investigated for the treatment of chronic idiopathic constipation.

Neurotrophin-3, a neurotrophic factor, modulates the development of the nervous system by regulating the survival and differentiation of nerves.82 In patients with functional constipation, subcutaneous doses of neurotrophin-3 improved stool frequency, the number of complete spontaneous bowel movements, and stool consistency.83

Alvimopan is a selective antagonist of the muopioid receptor that is being studied for opiate-related constipation and postoperative ileus.84,85 Little of this drug is systemically absorbed and it does not cross the blood-brain barrier; thus, it relieves the opiate-related side effects, ie, bloating, abdominal discomfort, and reduced stool frequency, without interfering with the central analgesic effects.

Linaclotide (MD 1100), a poorly absorbed guanylate cyclase agonist, is also being investigated as a treatment for chronic constipation.86 Linaclotide increases intestinal fluid secretion and transit via stimulation of cyclic guanosine monophosphate production and activation of the cystic fibrosis transmembrane conductance regulator.86,87 In preliminary studies, linaclotide increased stool frequency and the Bristol Stool Form Scale consistency score (Table 1) by increasing intestinal fluid secretion and transit.86

Chenodeoxycholic acid is a bile acid that is synthesized from cholesterol.88 Treatment of constipation with chenodeoxycholic acid has been proposed, given its laxative effect. A study by Bazzoli et al89 showed increased stool frequency and a decrease in stool consistency in chronic constipation patients given chenodeoxycholic acid 10 mg/kg/day. The main side effect was diarrhea. Chenodeoxycholic acid may be worthwhile in the management of constipation, but more studies are needed.

PROBIOTICS AND PREBIOTICS

The bacteria of the colon influence peristalsis of the colon.90 Probiotics (live bacterial preparations) and prebiotics (nondigestible preparations that stimulate the growth or activity of beneficial colonic bacteria) have been gaining interest as potential therapies for constipation.91,92

Probiotic bacterial preparations are generally composed of strains of Bifodobacterium,93,94Lactobacillus,95 and combinations thereof, and are available as mixed preparations of multiple bacterial strains of Lactobacillus, Bifodobacterium, and Streptococcus species, such as VSL#3.96

Probiotics may help relieve constipation, but their effect may depend on the strain of bacteria used and the population being studied.97 In a double-blind parallel study in 70 healthy adults, ingestion of 375 g/day of milk fermented with B animalis strain DN-173 010 for 11 days reduced colon transit time by 20% from baseline. The effect was more pronounced in women, particularly in those with longer baseline transit.98

Lactic acid-producing bacteria are considered commensal organisms with essentially no pathogenic potential.99 A review of the safety of bifodobacteria and lactobacilli concluded there was no health risk to consumers.100

Prebiotics are short-chain carbohydrates such as lactulose that stimulate the activity of beneficial colonic bacteria.91 They are thought to have a small laxative effect that is likely both osmotic and due to beneficial actions of bacteria for which they are a substrate. Both konjac glucomannan and lactulose, sugar-based laxatives and prebiotics, have been shown to significantly increase the fecal concentrations of lactobacilli and total bacteria, possibly through increases in stool bulk.46 Prebiotics that have been the focus of research include inulin, fructo-oligosaccharides, and galacto-oligosaccharides.91 Evidence on the efficacy of probiotics and prebiotics at relieving symptoms of constipation, however, is inconclusive because few well-controlled clinical studies have been done.91,92

 

 

STRATEGIES FOR MANAGING CHRONIC CONSTIPATION

In the absence of secondary causes, treatment of chronic constipation is focused on relieving symptoms.

Figure 1. Treatment approaches for chronic constipation.
The first line of treatment includes non-pharmacologic approaches such as increasing fiber in the diet or taking fiber supplements (Figure 1). Additionally, lifestyle changes such as increased physical activity and dietary modification, as well as cognitive behavior therapy (biofeedback and hypnosis), may relieve symptoms in a subset of patients with chronic constipation. Although lacking in clinical evidence, milk of magnesia101 and probiotics are often prescribed.

If symptoms are refractory to these traditional treatments, agents such as lactulose and polyethylene glycol may provide relief.11,21 Although they do not address the underlying cause of constipation, these agents increase the fluid content of the intestine, contributing to improved stool consistency, and consequently increase the frequency of bowel movements.

Lubiprostone similarly increases the fluid content of the colon, contributing to improved stool consistency, reduced fecal transit time, and increased frequency of bowel movements.66,70,102 Unlike lactulose and polyethylene glycol, which are indicated only for short-term use, lubiprostone has been found to be safe and effective when used for up to 48 weeks.70,71

Biofeedback is the preferred treatment for pelvic floor dyssynergia, in which it has a success rate of 70% to 81% and in which it is superior to standard treatment (laxatives, fiber, and education).103–105 In an instrument-based training program, patients receive auditory or visual feedback or both to help train the pelvic floor and relax the anal sphincter while simulating defecation. It also improves rectal sensation to assist in proper evacuation. The best outcomes are achieved when committed patients receive instruction from empathetic, properly trained physical therapists or other technicians. Studies show that the benefits of biofeedback are long-lasting.104 It does not improve slow-transit constipation, though pelvic floor dyssynergia and slow-transit constipation can overlap.

Constipation is both a symptom and, when chronic, a multisymptom disorder, and it can overlap with other gastrointestinal tract disorders such as dyspepsia and gastroesophageal reflux disease. Furthermore, one should keep in mind the possibility of cancer and be alert for its warning signs.

Since constipation has a variety of causes and forms, one treatment does not fit all patients. Conservative measures such as recommending that the patient increase his or her intake of dietary fiber and water and engage in more physical activity are still the cornerstone of treatment, but they do not help all patients. On the other hand, polyethylene glycol and stimulant laxatives, which are traditionally given only for a short time, can be safe and effective when given long-term if other agents fail. New agents have become available or are in development.

In this article we outline our approach to constipation, as a guide for internists.

CONSTIPATION IS COMMON, BUT HOW SHOULD WE DEFINE IT?

Constipation affects 2% to 27% (average 14.8%) of the North American adult population—approximately 63 million people.1 It is more common than many other chronic diseases, including hypertension (48 million people), migraine (33 million), obesity (50 million), and diabetes mellitus (15 million).1–3

Constipation affects more women than men (2.1:1 ratio) and more nonwhites than whites (1.68:1).1 It occurs in all age groups but is more common in those older than 65 years and younger than 4 years.4,5

Constipation accounts for more than 2.5 million office visits and more than $500 million spent on laxatives per year.6,7 Also, people with constipation may report decreased productivity and increased absenteeism.8

The broad range in the prevalence of constipation cited above reflects differences in how it is defined and, in particular, a lack of agreement between how patients and physicians perceive it.1,9 Physicians mainly define constipation on the basis of stool frequency, considering fewer than three bowel movements per week to be abnormal.1 In contrast, patients typically define it on the basis of bothersome symptoms such as straining, passage of hard stool, unproductive urges, inability to defecate at will, and sensations of incomplete evacuation or abdominal bloating.1,9,10

The Rome III diagnostic criteria were developed to provide a consistent diagnostic approach for use in clinical practice and clinical trials.11 The Rome III criteria define functional chronic constipation as a chronic bowel disorder characterized by two or more of the following:

  • Straining
  • Lumpy or hard stools
  • Sensations of incomplete evacuation
  • Sensations of anorectal obstruction or blockage
  • Use of manual maneuvers to facilitate defecation (eg, digital evacuation, support of the pelvic floor) during at least 25% of defecations
  • Fewer than three bowel movements per week.

In addition, loose stools should rarely occur without the use of laxatives, and there should be insufficient criteria for irritable bowel syndrome.11 Chronicity is established by symptom onset within the previous 6 months and symptom duration of at least 3 months.

In contrast, patients with irritable bowel syndrome, also a functional bowel disorder, experience recurrent abdominal pain and discomfort associated with two or more of the following: symptom improvement with defecation, symptom onset associated with a change in the frequency of bowel movements, and a change in the form or appearance of the stool.

THREE TYPES OF IDIOPATHIC CONSTIPATION

There are three types of primary or idiopathic constipation5,9,12,13:

  • Functional
  • Slow-transit
  • Outlet dysfunction.

Functional constipation includes functional chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. It presents with a sense of difficult or delayed evacuation, hard stools, or abdominal bloating or discomfort.6,9,13 The predominant symptom of constipation-predominant irritable bowel syndrome is severe discomfort or pain; in chronic idiopathic constipation, pain and discomfort may be present but are not the primary symptom.

Slow-transit constipation (or delayed-transit constipation) is associated with a prolonged time between bowel movements. Its symptoms include low stool frequency, lack of urge to defecate, abdominal distention, bloating, and abdominal discomfort.14

Outlet dysfunction. Disorders of defecation can be due to mechanical causes such as Hirschsprung disease, anal stricture, cancer, prolapse, and large rectoceles, or from pelvic floor dysfunction. Pelvic floor dysfunction may be due to inadequate or excessive perineal descent or to inadequate propulsive forces, as may occur in neurologic or neuromuscular conditions and dyssynergia.

Pelvic floor dyssynergia, also called anorectal dyssynergia, dyssynergic defecation, and anismus, results from a functional defect in coordinated evacuation. The characteristic symptom is a feeling of being unable to adequately empty the rectum.14 Other symptoms such as excessive straining and manual disimpaction indicate but are not unique to pelvic floor dyssynergia.14,15

Combined forms. Patients may have more than one type of primary constipation and presentation, and pelvic floor dyssynergia has been shown to prolong intestinal transit, which may improve with treatment.

Secondary constipation can be due to causes such as diet, lifestyle, certain medications (calcium channel blockers, beta-blockers, opioids, diuretics, antidepressants, anticonvulsants, antacids, anticholinergics, and antispasmodics),5,16 underlying medical conditions (diabetes, hypothyroidism, multiple sclerosis, parkinsonism),16,17 pregnancy, and advanced age.18

 

 

NEUROTRANSMITTERS MAY PLAY A ROLE

Among the mechanisms thought to cause chronic constipation are impaired gastrointestinal motility,19–22 reduced intestinal secretions,21–23 and inadequate reflex relaxation of the pelvic floor muscles.22,24

Neurotransmitters such as serotonin, somatostatin, peptide YY, and vasoactive intestinal peptide affect intestinal secretion and motility.25,26 Hyperactivity of these neurotransmitters associated with increased secretion and motility results in diarrhea, whereas hypoactivity leads to decreased secretion, delayed transit, and constipation.23

Serotonin has a role in regulating visceral pain perception and intestinal motility, as well as secretion.26–28 Clinical trials have shown that activation of serotonin receptors in the gut enhances gastrointestinal motility, inhibits visceral sensitivity, and stimulates intestinal secretion.26,27,29

A hypothesis has recently been proposed that degeneration of enteric neurons may also play a role in the development of severe idiopathic constipation.30

DIAGNOSIS IS MOSTLY CLINICAL

The history and physical examination remain the cornerstones in the diagnosis and subsequent treatment of chronic constipation.

History

The history may provide clues as to a primary cause. The patient interview yields information about the frequency and consistency of stool (Table 1),31 the need to strain or manually disimpact, the sense of incomplete evacuation, pain, bleeding, or prolapse.

Risk factors for primary and secondary constipation to note during the interview include age (< 4 years, > 65 years); low-fiber diet; female sex; lack of physical activity; history of childhood constipation, endocrine and neuromuscular disorders, abuse, depression, or anxiety; family history of cancer; and personal history of pelvic surgery.

Since drugs can also cause chronic constipation, especially in elderly or immobile patients, medication lists should be reviewed and adjustments should be made if necessary (or possible) before recommending laxatives or invasive testing, if no alarm signs are present.

Alarm signs such as weight loss, hematochezia, melena, change in bowel habits, and symptoms refractory to therapy may represent colon cancer and indicate the need for early diagnostic testing.

Physical examination

Physical examination should always include inspection of the perianal area for evidence of hemorrhoids or fissures. Digital rectal examination may reveal a contracted sphincter or a puborectalis muscle that contracts with the Valsalva maneuver, suggesting dysfunction.

Laboratory testing

If the history and physical examination suggest that the constipation may be secondary, or if the patient is 50 years of age or older, then laboratory studies such as a complete blood cell count, serum electrolyte levels, blood sugar level, and thyroid function studies may help rule out a metabolic, endocrine, or organic cause.

Colonoscopy, other tests

At present, little evidence suggests that routine testing is warranted in patients without evidence of secondary constipation and without alarm signs. However, diagnostic studies are indicated in patients 50 years of age and older, as well as in those with alarm symptoms such as hematochezia, anemia, a positive fecal occult blood test, unintentional loss of more than 10 pounds, family history of colon cancer or inflammatory bowel disease, fever, nausea, vomiting, acute onset (especially in the elderly), and lack of improvement with conventional therapies regardless of age.2

The full length of the colon should be inspected by colonoscopy or by flexible sigmoidoscopy paired with a barium enema study to rule out structural disease. Of note, all patients 50 years of age or older should be screened for colon cancer.

If the patient does not respond to therapy, further tests such as colonic transit studies, anorectal manometry with balloon expulsion, and, possibly, defecating proctography or dynamic pelvic magnetic resonance imaging may be considered. These patients would likely also benefit from referral to a gastroenterologist for further management

DIET AND LIFESTYLE AS TREATMENT

For many years, health care providers have provided reassurance and recommended diet and lifestyle modifications as treatment for constipation. Increased water intake, increased activity, and a scheduled attempt at defecation when motor activity in the colon is highest, ie, in the morning or after eating, have all been recommended.

Data on the efficacy of these recommendations are scarce and often contradictory. Studies have shown that increasing water intake or daily exercise is not always helpful.32–34 Nevertheless, many patients who comply with dietary and exercise recommendations have improvement in symptoms. Eating fewer meals per day (and hence taking in fewer calories) has been shown to be associated with constipation in the elderly. However, no relationships between fiber or fluid intake and constipation were noted.35

In a study in which chronically constipated patients were fed a standardized diet that contained 25 g of fiber a day, stool frequency increased significantly and laxative use decreased.36 While on a high-fiber diet, the patients were divided into two groups, one that drank 1.1 L of fluid per day and one that drank 2.1 L of mineral water per day. Both groups experienced further improvements in stool frequency and decreases in laxative use, with the mineral-water group benefiting the most.36

Recently, Murakami and others37 found, in a cross-sectional study in young Japanese women with low daily fiber intake (6.4 g/day), that low water intake from foods and low magnesium intake were associated with an increasing prevalence of functional constipation as defined by the Rome III criteria. Constipation was also found to be significantly associated with low intake of fruits and vegetables in a study from Singapore.38

Moderate physical activity and high fiber intake may be associated with a lower prevalence of constipation in women. In the Nurses’ Health Study, more than 62,000 women between the ages of 36 and 61 were surveyed, and those who said they engaged in daily physical activity had a lower prevalence of constipation (prevalence ratio [PR] = 0.56, 95% confidence interval [CI] 0.44–0.70), as did those with a median fiber intake of 20 g/day (PR = 0.64, 95% CI 0.57–0.73).39

 

 

BULK LAXATIVES (FIBER SUPPLEMENTS): THE FIRST-LINE TREATMENT

Fiber remains the first-line treatment for constipation. It may relieve or improve symptoms in functional constipation. However, fewer than 30% of patients with either slow-transit constipation or pelvic floor dysfunction have improvement in symptoms with fiber, and in these types of constipation it can even worsen symptoms.40

There is much confusion about what types of fiber should be recommended and how the various types of fiber perform in resolving constipation.

Insoluble fiber

Insoluble fiber resists bacterial degradation in the colon and can retain more water than soluble fiber can.

Bran 20 g/day increased the frequency of bowel movements by 55%, increased fecal weight by 157%, and decreased intestinal transit time by 50% in women who had three or fewer bowel movements per week.41

Muller-Lissner42 and others performed a meta-analysis and found that bran (25 g/day) increased stool weight and decreased transit time in both healthy controls and patients with chronic constipation. Yet constipated patients taking bran still had lower stool weights and slower transit times than did healthy subjects.

When bran 20 g/day was compared with placebo in chronically constipated patients, bowel frequency and stool weight increased with both treatments,43 suggesting that factors other than intake may affect bowel function and transit time. However, bran was more effective than placebo in decreasing oroanal transit time.

Elderly constipated patients who received bran 10 g twice a day had significantly shorter transit times (89 hours vs 126 hours) than did those who received psyllium (a soluble fiber) 6 g twice daily. They also needed less additional laxative.44

Soluble fiber

Soluble fiber also affects the bowel habits of both healthy and constipated patients.

Methylcellulose, given to healthy volunteers at a dose of 4 g/day, resulted in statistically significant increases in stool weight, fecal water weight, and fecal solids.45 In constipated patients, methylcellulose 1 g/day was as effective as psyllium 3.4 g/day at increasing stool frequency, fecal water weight, and fecal solids.45

Konjac glucomannan was also shown to significantly increase stool frequency, water weight, and fecal solids.46

Psyllium. In a study that randomly assigned 22 patients with chronic constipation to receive either psyllium 5 g twice daily or placebo for 8 weeks, followed by a 4-week washout phase in which placebo was given,47 those who received psyllium reported significant improvements in stool consistency and pain with defecation, as well as significant increases in both stool frequency (3.8 vs 2.9 per week, P < .05) and stool weight (665 g vs 405 g, P < .05). However, colonic transit times and anorectal manometric measurements did not differ significantly between those who received psyllium vs placebo.47

Fiber may not help everyone

Others have also shown that while fiber may improve stool characteristics, it may not significantly alter the sensorimotor functions of the colon and pelvic floor.

Cheskin et al48 performed a crossover study in 10 constipated men and women in the community. Patients received either 24 g of psyllium fiber daily or a placebo fiber for 1 month and then crossed over to the other treatment for the next month. The most common cause of constipation in this study was pelvic floor dysfunction. Total gut transit time was significantly increased by psyllium fiber, and there was a trend toward increased stool frequency, demonstrating that psyllium clinically improved constipation. However, pelvic floor dysfunction, as measured by rectal manometry, was not improved.

It may be that only people with normal-transit constipation, not those with underlying slow-transit constipation or pelvic floor dysfunction, are helped by additional dietary fiber. Voderholzer and others40 studied 149 consecutive patients with chronic constipation and evaluated their response to at least 6 weeks of psyllium (Plantago ovata seeds 15 to 30 g/day) by serial symptom measurements, oroanal transit times, and functional rectoanal evaluation with defecography, manometry, and sigmoidoscopy. Of the patients with no evidence of pelvic floor dysfunction or slow-transit constipation, 85% improved. However, 80% of those with slow-transit constipation and 63% of those with pelvic floor dysfunction did not improve with the use of fiber. The authors concluded that it is reasonable to try dietary fiber in patients with constipation and, if no improvement is noted, to then consider further investigation for other subtypes of constipation (ie, slow-transit or pelvic-floor dysfunction).

Adverse effects may limit the use of fiber and may differ depending on the type of fiber used. Soluble fiber may be better tolerated, especially in patients with constipation-predominant irritable bowel syndrome.49 Side effects include the sensation of bloating and distention, excessive gas production, and abdominal cramping.

Our recommendations on fiber

We recommend the following regarding fiber in constipated patients:

  • Increase fiber intake from natural foods up to 20 g/day. This increase should be completed over 2 to 3 weeks to minimize adverse effects.
  • Consider adding a fiber supplement, such as psyllium, if increasing the intake of natural fiber does not relieve constipation-related symptoms.
  • If symptoms persist despite the use of fiber supplements and diet and lifestyle modification, then further structural and functional investigation of the colon (anorectal manometry, colonoscopy, defecography, colon manometry) should be considered.
 

 

OSMOTIC LAXATIVES

Osmotic laxatives are molecules that are either not absorbed or poorly absorbed and that draw water into the intestinal lumen to maintain isotonicity between the intestinal contents and the serum. Examples are polyethylene glycol, sodium phosphate (Fleet phosphosoda), magnesium hydroxide, magnesium citrate, the sugars lactulose and sorbitol, and glycerin.

Certain formulations of this class of laxative can cause bloating, diarrhea, electrolyte disturbances, volume overload, or dehydration. These effects limit their use, and these medications should be used with caution in patients prone to renal insufficiency or cardiac abnormalities.

Polyethylene glycol

Polyethylene glycol is an exception. It is not absorbed and lacks electrolytes, making it an attractive option in patients with underlying renal or cardiac dysfunction. In several placebo-controlled trials,50–52 various formulations significantly increased stool frequency while significantly decreasing straining, use of other laxatives, and colonic transit. No increase in adverse effects was noted compared with placebo.

Compared with lactulose, polyethylene glycol at about 21 g/day significantly increased bowel movement frequency while significantly decreasing the sense of straining with bowel movements and flatus due to laxative use.51 Both polyethylene glycol and lactulose accelerate colonic transit, although polyethylene glycol does so to a greater extent.53

Polyethylene glycol has been safe and effective when used for up to 6 months.54

Lactulose and sorbitol

Carbohydrate or sugar-based laxatives, if taken in sufficient doses, have a cathartic effect through two mechanisms: a primary osmotic effect of the sugar itself and a secondary osmotic effect as a substrate for colonic bacteria to cleave to acid metabolites, which exert an osmotic effect in the colon. This secondary effect will be discussed in a later section.

Lactulose and sorbitol are sugars that are poorly absorbed by the intestine. Lactulose has been shown to be more effective than placebo in increasing stool frequency, volume, weight, and consistency in chronically constipated patients.55 In a head-to-head comparison between sugar laxatives, 70% sorbitol was as effective as lactulose in increasing the frequency of bowel movements, and it was similar in its adverse effects56; 70% sorbitol is a cost-effective alternative to lactulose in the elderly nursing home population.57

Compared with fiber alone, lactulose use leads to a significantly higher number of bowel movements and better stool consistency.58 However, when lactulose was compared with a combination of fiber and a stimulant laxative, it was less effective than the combination therapy.59,60

Sugar laxatives, while effective, may have dose-limiting or use-limiting adverse effects such as abdominal bloating and flatulence.

Phosphate, magnesium

Sodium phosphate, like polyethylene glycol, is often used as a bowel preparation before colonoscopy, for which it is about as good or slightly better than polyethylene glycol.61,62

Although magnesium and sodium phosphate preparations are effective, there are multiple reports of clinically significant electrolyte abnormalities, renal failure, and congestive heart failure occurring with these preparations. Therefore, they must be used with discretion and caution in appropriate patients with frequent monitoring.

STIMULANT (IRRITANT) LAXATIVES

Stimulant laxatives are usually reserved for use when bulking agents and osmotic laxatives fail. Their mechanism of action involves the alteration of intestinal motility and intestinal fluid secretion.

Anthraquinones (cascara, aloe, and senna), castor oil, and diphenylmethanes (bisacodyl) are the most commonly used stimulant laxatives. They work relatively quickly, often eliciting a bowel movement 2 to 8 hours after they are taken.

This class of laxatives has historically been underused or given for only short periods of time, owing to concern about impairing colonic function, damaging the enteric nervous system, causing laxative dependency, causing cathartic colon, and even causing colon cancer. However, there is very little evidence to support these concerns. Stimulant laxatives can be used on a more regular basis when bulking or osmotic agents fail.63

Possibly of greatest concern is the potential for the overuse and abuse of stimulant laxatives. Excessive use can cause electrolyte disturbances brought about by high-volume watery diarrhea. Risk factors for overuse and abuse include underlying psychiatric disturbances and eating disorders. Prescribing other types of laxatives or cathartic agents may reduce risk, but the potential for abuse exists with all categories of laxatives.

TEGASEROD: GONE BUT STILL AVAILABLE, ON A CONTROLLED BASIS

Tegaserod (Zelnorm), a serotonin (5-HT4) agonist, was used predominantly in women with constipation-predominant irritable bowel syndrome and in men and women with chronic constipation. However, it was suspended from the market in the United States in March 2007 owing to concern about a high risk of adverse cardiovascular effects compared with placebo.

In a double-blind, randomized controlled trial, men with chronic constipation who received tegaserod 6 mg twice a day for 12 weeks had more spontaneous bowel movements than those receiving placebo (P = .04).64

Lin et al65 evaluated the use of tegaserod 6 mg twice daily for 4 weeks in both men and women with chronic constipation. Those receiving tegaserod had significantly more spontaneous bowel movements per week, less straining, and better stool consistency than those receiving placebo.

Tegaserod can still be obtained for appropriate patients via a treatment investigational new drug application. Safety data are under further review by the US Food and Drug Administration. Studies of other serotonin agonists are under way.

 

 

LUBIPROSTONE

Lubiprostone (Amitiza) is an agonist of the chloride channel subtype 2, found on the apical membrane of intestinal epithelial cells. It causes increased chloride secretion into the intestinal lumen, enhancing intestinal fluid secretion. It has been shown to be effective in chronic constipation by improving stool consistency and increasing the motility of the small intestine and colon.66 It is approved for treating chronic constipation in adults.

In randomized, double-blind trials, patients receiving lubiprostone 24 fig twice daily for 4 weeks had significantly more bowel movements per week, reported significantly better stool consistency and less abdominal bloating and straining, and rated their constipation as less severe than did patients receiving placebo.67–69

More recently, in an open-label study, lubiprostone improved constipation symptoms when taken for up to 48 weeks.70

The drug is well tolerated, but its adverse effects include nausea (which appears to be dose-dependent and may diminish over time or if the drug is taken with food), diarrhea, and headache.68 Of note, the drug appears to be well tolerated by older people (65 years of age and older), in whom adverse effects occur less often than in younger users.71 However, adverse events may cause up to 20% of patients to stop taking the drug.69 When lubiprostone is discontinued, patients may once again revert to their baseline bowel habit.72

Lubiprostone has not been compared with conventional laxatives, and cost may prohibit it from becoming a first-line drug for chronic constipation.73

OTHER PROMOTILITY AGENTS

Several promotility agents have been studied for treating chronic idiopathic constipation.

Cisapride (Propulsid), a 5-HT3 receptor antagonist and 5-HT4 receptor agonist, and prucalopride, a 5-HT4 agonist, were effective in relieving symptoms associated with chronic constipation.74–76 However, safety issues (cardiac arrhythmias) necessitated withdrawal of cisapride from the US market in 2000. Prucalopride is undergoing clinical trials.77

Renzapride, a mixed 5-HT4 receptor agonist and 5-HT3 receptor antagonist, has been shown to improve stool consistency and to increase colonic transit in patients with constipation-predominant irritable bowel syndrome.78 Renzapride has been studied in patients with this condition,78–81 but not in patients with chronic constipation. Renzapride is in phase III clinical development in the United States for treating constipation-predominant irritable bowel syndrome.

EMERGING TREATMENTS

New drugs with novel mechanisms of action are being investigated for the treatment of chronic idiopathic constipation.

Neurotrophin-3, a neurotrophic factor, modulates the development of the nervous system by regulating the survival and differentiation of nerves.82 In patients with functional constipation, subcutaneous doses of neurotrophin-3 improved stool frequency, the number of complete spontaneous bowel movements, and stool consistency.83

Alvimopan is a selective antagonist of the muopioid receptor that is being studied for opiate-related constipation and postoperative ileus.84,85 Little of this drug is systemically absorbed and it does not cross the blood-brain barrier; thus, it relieves the opiate-related side effects, ie, bloating, abdominal discomfort, and reduced stool frequency, without interfering with the central analgesic effects.

Linaclotide (MD 1100), a poorly absorbed guanylate cyclase agonist, is also being investigated as a treatment for chronic constipation.86 Linaclotide increases intestinal fluid secretion and transit via stimulation of cyclic guanosine monophosphate production and activation of the cystic fibrosis transmembrane conductance regulator.86,87 In preliminary studies, linaclotide increased stool frequency and the Bristol Stool Form Scale consistency score (Table 1) by increasing intestinal fluid secretion and transit.86

Chenodeoxycholic acid is a bile acid that is synthesized from cholesterol.88 Treatment of constipation with chenodeoxycholic acid has been proposed, given its laxative effect. A study by Bazzoli et al89 showed increased stool frequency and a decrease in stool consistency in chronic constipation patients given chenodeoxycholic acid 10 mg/kg/day. The main side effect was diarrhea. Chenodeoxycholic acid may be worthwhile in the management of constipation, but more studies are needed.

PROBIOTICS AND PREBIOTICS

The bacteria of the colon influence peristalsis of the colon.90 Probiotics (live bacterial preparations) and prebiotics (nondigestible preparations that stimulate the growth or activity of beneficial colonic bacteria) have been gaining interest as potential therapies for constipation.91,92

Probiotic bacterial preparations are generally composed of strains of Bifodobacterium,93,94Lactobacillus,95 and combinations thereof, and are available as mixed preparations of multiple bacterial strains of Lactobacillus, Bifodobacterium, and Streptococcus species, such as VSL#3.96

Probiotics may help relieve constipation, but their effect may depend on the strain of bacteria used and the population being studied.97 In a double-blind parallel study in 70 healthy adults, ingestion of 375 g/day of milk fermented with B animalis strain DN-173 010 for 11 days reduced colon transit time by 20% from baseline. The effect was more pronounced in women, particularly in those with longer baseline transit.98

Lactic acid-producing bacteria are considered commensal organisms with essentially no pathogenic potential.99 A review of the safety of bifodobacteria and lactobacilli concluded there was no health risk to consumers.100

Prebiotics are short-chain carbohydrates such as lactulose that stimulate the activity of beneficial colonic bacteria.91 They are thought to have a small laxative effect that is likely both osmotic and due to beneficial actions of bacteria for which they are a substrate. Both konjac glucomannan and lactulose, sugar-based laxatives and prebiotics, have been shown to significantly increase the fecal concentrations of lactobacilli and total bacteria, possibly through increases in stool bulk.46 Prebiotics that have been the focus of research include inulin, fructo-oligosaccharides, and galacto-oligosaccharides.91 Evidence on the efficacy of probiotics and prebiotics at relieving symptoms of constipation, however, is inconclusive because few well-controlled clinical studies have been done.91,92

 

 

STRATEGIES FOR MANAGING CHRONIC CONSTIPATION

In the absence of secondary causes, treatment of chronic constipation is focused on relieving symptoms.

Figure 1. Treatment approaches for chronic constipation.
The first line of treatment includes non-pharmacologic approaches such as increasing fiber in the diet or taking fiber supplements (Figure 1). Additionally, lifestyle changes such as increased physical activity and dietary modification, as well as cognitive behavior therapy (biofeedback and hypnosis), may relieve symptoms in a subset of patients with chronic constipation. Although lacking in clinical evidence, milk of magnesia101 and probiotics are often prescribed.

If symptoms are refractory to these traditional treatments, agents such as lactulose and polyethylene glycol may provide relief.11,21 Although they do not address the underlying cause of constipation, these agents increase the fluid content of the intestine, contributing to improved stool consistency, and consequently increase the frequency of bowel movements.

Lubiprostone similarly increases the fluid content of the colon, contributing to improved stool consistency, reduced fecal transit time, and increased frequency of bowel movements.66,70,102 Unlike lactulose and polyethylene glycol, which are indicated only for short-term use, lubiprostone has been found to be safe and effective when used for up to 48 weeks.70,71

Biofeedback is the preferred treatment for pelvic floor dyssynergia, in which it has a success rate of 70% to 81% and in which it is superior to standard treatment (laxatives, fiber, and education).103–105 In an instrument-based training program, patients receive auditory or visual feedback or both to help train the pelvic floor and relax the anal sphincter while simulating defecation. It also improves rectal sensation to assist in proper evacuation. The best outcomes are achieved when committed patients receive instruction from empathetic, properly trained physical therapists or other technicians. Studies show that the benefits of biofeedback are long-lasting.104 It does not improve slow-transit constipation, though pelvic floor dyssynergia and slow-transit constipation can overlap.

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References
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  2. Brandt LJ, Prather CM, Quigley EM, Schiller LR, Schoenfeld P, Talley NJ. Systematic review on the management of chronic constipation in North America. Am J Gastroenterol 2005; 100 suppl 1:S5–S21.
  3. Pleis JR, Lethbridge-Cejku M. Summary health statistics for U.S. adults: National Health Interview Survey, 2005. Vital Health Stat 10 2006; 232:1–153.
  4. Dennison C, Prasad M, Lloyd A, Bhattacharyya SK, Dhawan R, Coyne K. The health-related quality of life and economic burden of constipation. Pharmacoeconomics 2005; 23:461–476.
  5. Arce DA, Ermocilla CA, Costa H. Evaluation of constipation. Am Fam Physician 2002; 65:2283–2290.
  6. Johanson JF, Sonnenberg A, Koch TR. Clinical epidemiology of chronic constipation. J Clin Gastroenterol 1989; 11:525–536.
  7. Harari D, Gurwitz JH, Minaker KL. Constipation in the elderly. J Am Geriatr Soc 1993; 41:1130–1140.
  8. Johanson JF, Kralstein J. Chronic constipation: a survey of the patient perspective. Aliment Pharmacol Ther 2007; 25:599–608.
  9. Lembo A, Camilleri M. Chronic constipation. N Engl J Med 2003; 349:1360–1368.
  10. Sandler RS, Drossman DA. Bowel habits in young adults not seeking health care. Dig Dis Sci 1987; 32:841–845.
  11. Longstreth GF, Thompson WG, Chey WD, Houghton LA, Mearin F, Spiller RC. Functional bowel disorders. Gastroenterology 2006; 130:1480–1491.
  12. Locke GR, Pemberton JH, Phillips SF. AGA technical review on constipation. Gastroenterology 2000; 119:1766–1778.
  13. Rao SS. Constipation: evaluation and treatment. Gastroenterol Clin North Am 2003; 32:659–683.
  14. Locke GR, Pemberton JH, Phillips SF. American Gastroenterological Association Medical Position Statement: guidelines on constipation. Gastroenterology 2000; 119:1761–1766.
  15. Prather CM. Subtypes of constipation: sorting out the confusion. Rev Gastroenterol Disord 2004; 4 suppl 2:S11–S16.
  16. Talley NJ, Jones M, Nuyts G, Dubois D. Risk factors for chronic constipation based on a general practice sample. Am J Gastroenterol 2003; 98:1107–1111.
  17. Bharucha AE. Treatment of severe and intractable constipation. Curr Treat Options Gastroenterol 2004; 7:291–298.
  18. Borum ML. Constipation: evaluation and management. Prim Care 2001; 28:577–590.
  19. Camilleri M, Ford MJ. Review article: colonic sensorimotor physiology in health, and its alteration in constipation and diarrhoeal disorders. Aliment Pharmacol Ther 1998; 12:287–302.
  20. Knowles CH, Martin JE. Slow transit constipation: a model of human gut dysmotility. Review of possible aetiologies. Neurogastroenterology Motility 2000; 12:181–196.
  21. Schiller LR. Review article: the therapy of constipation. Aliment Pharmacol Ther 2001; 15:749–763.
  22. Crowell MD. Pathogenesis of slow transit and pelvic floor dysfunction: from bench to bedside. Rev Gastroenterol Disord 2004; 4 suppl 2:S17–S27.
  23. Wood JD. Neuropathophysiology of irritable bowel syndrome. J Clin Gastroenterol 2002; 35 suppl 1:S11–S22.
  24. Chitkara DK, Bredenoord AJ, Cremonini F, et al. The role of pelvic floor dysfunction and slow colonic transit in adolescents with refractory constipation. Am J Gastroenterol 2004; 99:1579–1584.
  25. El-Salhy M. Gastrointestinal transit in an animal model of human diabetes type 2: relationship to gut neuroendocrine peptide contents. Ups J Med Sci 2002; 107:101–110.
  26. Crowell MD. Role of serotonin in the pathophysiology of the irritable bowel syndrome. Br J Pharmacol 2004; 141:1285–1293.
  27. Gershon MD. Review article: roles played by 5-hydroxytryptamine in the physiology of the bowel. Aliment Pharmacol Ther 1999; 13 suppl 2:15–30.
  28. Gershon MD. Serotonin and its implication for the management of irritable bowel syndrome. Rev Gastroenterol Disord 2003; 3 suppl 2:S25–S34.
  29. Grider JR, Foxx-Orenstein AE, Jin JG. 5-Hydroxytryptamine4 receptor agonists initiate the peristaltic reflex in human, rat, and guinea pig intestine. Gastroenterology 1998; 115:370–380.
  30. Krishnamurthy S, Schuffler MD, Rohrmann CA, Pope CE. Severe idiopathic constipation is associated with a distinctive abnormality of the colonic myenteric plexus. Gastroenterology 1985; 88:26–34.
  31. O'Donnell LJ, Virjee J, Heaton KW. Detection of pseudodiarrhoea by simple clinical assessment of intestinal transit rate. BMJ 1990; 300:439–440.
  32. Meshkinpour H, Selod S, Movahedi H, Nami N, James N, Wilson A. Effects of regular exercise in management of chronic idopathic constipation. Dig Dis Sci 1998; 43:2379–2383.
  33. Young RJ, Beerman LE, Vanderhoff JA. Increasing oral fluids in chronic constipation in children. Gastroenterol Nurs 1998; 21:156–161.
  34. Tuteja AK, Talley NJ, Joos SK, Woehl JV, Hickam DH. Is constipation associated with decreased physical activity in normally active subjects? Am J Gastroenterol 2005; 100:124–129.
  35. Towers AL, Burgio KL, Locher JL, Merkel IS, Safaeian M, Wald A. Constipation in the elderly: influence of dietary, psychological, and physiological factors. J Am Geriatr Soc 1994; 42:701–706.
  36. Anti J, Pignataro G, Armuzzi A, et al. Water supplementation enhances the effect of high-fiber diet on stool frequency and laxative consumption in adult patients with functional constipation. Hepatogastroenterology 1998; 45:727–732.
  37. Murakami K, Sasaki S, Okubo H, et al. Association between dietary fiber, water and magnesium intake and functional constipation among young Japanese women. Eur J Clin Nutr 2007; 61:616–622.
  38. Wong ML, Wee S, Pin CH, Gan GL, Ye HC. Sociodemographic and lifestyle factors associated with constipation in an elderly Asian community. Am J Gastroenterol 1999; 94:1283–1291.
  39. Dukas L, Willett WC, Giovannucci EL. Association between physical activity, fiber intake, and other lifestyle variables and constipation in a study of women. Am J Gastroenterol 2003; 98:1790–1796.
  40. Voderholzer WA, Schatke W, Muhldorfer BE, et al. Clinical response to dietary fiber treatment of chronic constipation. Am J Gastroenterol 1997; 92:95–98.
  41. Graham DY, Moser SE, Estes MK. The effect of bran on bowel function in constipation. Am J Gastroenterol 1982; 77:599–603.
  42. Muller-Lissner SA. Effect of wheat bran on weight of stool and gastrointestinal transit time: a meta analysis. Br Med J (Clin Res Ed) 1988; 296:615–617.
  43. Badiali D, Corazziari E, Habib FI, et al. Effect of wheat bran in treatment of chronic nonorganic constipation. A double-blind controlled trial. Dig Dis Sci 1995; 40:349–356.
  44. Andersson H, Basaeus I, Falkheden T, Melkersson M. Transit time in constipated geriatric patients during treatment with bulk laxative and bran: a comparison. Scand J Gastroenterol 1979; 14:821–826.
  45. Hamilton JW, Wagner J, Burdick BB, Bass P. Clinical evaluation of methyl-cellulose as a bulk laxative. Dig Dis Sci 1988; 33:993–998.
  46. Chen HL, Cheng HC, Liu YJ, Liu SY, Wu WT. Konjac acts as a natural laxative by increasing stool bulk and improving colonic ecology in healthy adults. Nutrition 2006; 22:1112–1119.
  47. Ashraf W, Park F, Lof J, Quigley EM. Effects of psyllium therapy on stool characteristics, colon transit and anorectal function in chronic idiopathic constipation. Aliment Pharmacol Ther 1995; 9:639–647.
  48. Cheskin LJ, Kamal N, Crowell MD, Schuster MM, Whitehead WE. Mechanisms of constipation in older persons and effects of fiber compared with placebo. J Am Geriatr Soc 1995; 43:666–669.
  49. Bijkerk CJ, Muris JW, Knottnerus JA, Hoes AW, de Wit NJ. Systematic review: the role of different types of fiber in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2004; 19:245–251.
  50. Corazziari E, Badiali D, Habib FI, et al. Small volume isosmotic polyethylene glycol electrolyte balanced solution (PMF–100) in treatment of chronic nonorganic constipation. Dig Dis Sci 1996; 41:1636–1642.
  51. Attar A, Lemann M, Ferguson A, et al. Comparison of a low dose polyethylene glycol electrolyte solution with lactulose for treatment of chronic constipation. Gut 1999; 44:226–230.
  52. Corazziari E, Badiali D, Bazzocchi G, et al. Long term efficacy, safety, and tolerabilitity of low daily doses of isosmotic polyethylene glycol electrolyte balanced solution (PMF–100) in the treatment of functional chronic constipation. Gut 2000; 46:522–526.
  53. Fritz E, Hammer HF, Lipp RW, Högenauer C, Stauber R, Hammer J. Effects of lactulose and polyethylene glycol on colonic transit. Aliment Pharmacol Ther 2005; 21:259–268.
  54. DiPalma JA, Cleveland MV, McGowan J, Herrera JL. A randomized, multicenter, placebo-controlled trial of polyethylene glycol laxative for chronic treatment of chronic constipation. Am J Gastroenterol 2007; 102:1436–1441.
  55. Bass P, Dennis S. The laxative effects of lactulose in normal and constipated subjects. J Clin Gastroenterol 1981; 3 suppl 1:23–28.
  56. Lederle FA, Busch DL, Mattox KM, West MJ, Aske DM. Cost-effective treatment of constipation in the elderly: a randomized double-blind comparison of sorbitol and lactulose. Am J Med 1990; 89:597–601.
  57. Volicer L, Lane P, Panke J, Lyman P. Management of constipation in residents with dementia: sorbitol effectiveness and cost. J Am Med Dir Assoc 2004; 5:239–241.
  58. Quah HM, Ooi BS, Seow-Choen F, Sng KK, Ho KS. Prospective randomized crossover trial comparing fibre with lactulose in the treatment of idiopathic chronic constipation. Tech Coloproctol 2006; 10:111–114.
  59. Passmore AP, Davies KW, Flanagan PG, Stoker C, Scott MG. A comparison of Agiolax and lactulose in elderly patients with chronic constipation. Pharmacology 1993; 47 suppl 1:249–252.
  60. Passmore AP, Wilson-Davies K, Stoker C, Scott ME. Chronic constipation in long stay elderly patients: a comparison of lactulose and a senna-fibre combination. BMJ 1993; 307:769–771.
  61. Poon CM, Lee DW, Mak SK, et al. Two liters of polyethylene glycol-electrolyte lavage solution versus sodium phosphate as bowel cleansing regimen for colonoscopy: a prospective randomized controlled trial. Endoscopy 2002; 34:560–563.
  62. Rostom A, Jolicoeur E, Dube C, et al. A randomized prospective trial comparing different regimens of oral sodium phosphate and polyethylene glycol-based lavage solution in the preparation of patients for colonoscopy. Gastrointest Endosc 2006; 64:544–552.
  63. Wald A. Is chronic use of stimulant laxatives harmful to the colon? J Clin Gastroenterol 2003; 36:386–389.
  64. Fried M, Johanson JF, Gwee KA, Wagner A, Pecher E, Rueegg P. Efficacy of tegaserod in chronic constipation in men. Am J Gastroenterol 2007; 102:362–370.
  65. Lin SR, Ke MY, Luo JY, et al. A randomized, double-blind, placebo-controlled trial assessing the efficacy and safety of tegaserod in patients from China with chronic constipation. World J Gastroenterol 2007; 13:732–739.
  66. Camilleri M, Bharucha AE, Ueno R, et al. Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers. Am J Physiol Gastrointest Liver Physiol 2006; 290:G942–G947.
  67. McKeage K, Plosker GL, Siddiqui MA. Lubiprostone. Drugs 2006; 66:873–879.
  68. Johanson JF, Gargano MA, Patchen ML, Ueno R. Efficacy and safety of a novel compound, RU-0211, for the treatment of constipation [abstract]. Gastroenterology 2002; 122 suppl 1:A315.
  69. Johanson JF, Gargano MA, Holland PC, Patchen ML, Ueno R. Multicenter open-label study of oral lubiprostone for the treatment of chronic constipation [abstract]. Am J Gastroenterol 2005; 100 suppl:S331.
  70. Johanson JF, Panas R, Holland P, Ueno R. Long-term efficacy of lubiprostone for the treatment of chronic constipation [abstract]. Gastroenterology 2006; 130 suppl 2:A317.
  71. Ueno R, Panas R, Wahle A, Zhu Y, Holland P. Long-term safety and efficacy of lubiprostone for the treatment of chronic constipation in the elderly [abstract]. Gastroenterology 2006; 130 suppl 2:A188.
  72. Johanson JF, Gargano MA, Holland P, Patchen ML, Ueno R. Phase III, randomized withdrawal study of RU-0211, a novel chloride channel activator for the treatment of constipation [abstract]. Gastroenterology 2004; 126 suppl 2:A100.
  73. Rivkin A, Chagan L. Lubiprostone: chloride channel activator for chronic constipation. Clin Ther 2006; 28:2008–2021.
  74. Johanson JF, Miner PB, Parkman HP, et al. Prucalopride improves bowel movement frequency and symptoms in patients with chronic constipation: results of two double-blind, placebo-controlled trials [abstract]. Gastroenterology 2000; 118 suppl 2:A175.
  75. Cash BD, Chey WD. Review article: the role of serotonergic agents in the treatment of patients with primary chronic constipation. Aliment Pharmacol Ther 2005; 22:1047–1060.
  76. Altabas K, Biliæ A, Jurciæ D, et al. The efficacy of cisapride vs. placebo and diet in patients with chronic constipation. Coll Antropol 2003; 27:197–204.
  77. Camilleri M, Kerstens R, Rykx A, Vandeplassche L. A placebo-controlled trial of prucalopride for severe chronic constipation. N Engl J Med 2008; 358:2344–2354.
  78. Camilleri M, McKinzie S, Fox J, et al. Effect of renzapride on transit in constipation-predominant irritable bowel syndrome. Clin Gastroenterol Hepatol 2004; 2:895–904.
  79. Tack J, Middleton SJ, Horne MC, et al. Pilot study of the efficacy of renzapride on gastrointestinal motility and symptoms in patients with constipation-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2006; 23:1655–1665.
  80. Henderson JC, Palmer RM, Meyers NL, Spiller RC. A phase IIb clinical study of renzapride in mixed symptom (alternating) irritable bowel syndrome [abstract]. Gastroenterology 2004; 126 suppl 2:A644.
  81. Meyers NL, Palmer RMJ, George A. Efficacy and safety of renzapride in patients with constipation-predominant IBS: a phase IIb study in the UK primary healthcare setting [abstract]. Gastroenterology 2004; 126 suppl 2:A640.
  82. Coulie B, Szarka LA, Camilleri M, et al. Recombinant human neurotrophic factors accelerate colonic transit and relieve constipation in humans. Gastroenterology 2000; 119:41–50.
  83. Parkman HP, Rao SS, Reynolds JC, et al. Neurotrophin-3 improves functional constipation. Am J Gastroenterol 2003; 98:1338–1347.
  84. Camilleri M. Alvimopan, a selective peripherally acting muopioid antagonist. Neurogastroenterol Motil 2005; 17:157–165.
  85. Holzer P. Opioids and opioid receptors in the enteric nervous system: from a problem in opioid analgesia to a possible new prokinetic therapy in humans. Neurosci Lett 2004; 361:192–195.
  86. Kurtz C, Fitch D, Busby R, et al. Effects of multidose administration of MD-1100 on safety, tolerability, exposure and pharmacodynamics in healthy subjects [abstract]. Gastroenterology 2006; 130 suppl 2:A26.
  87. Eutamene H, Theodorou V, Tondereau V, et al. Influence of guanylate cyclase C binding ligand MD-1100 on TNBS-induced visceral hypersensitivity in WT vs. KO guanylate cyclase C deficient mice [abstract]. Gastroenterology 2006; 130 suppl 2:A597.
  88. Broughton G. Chenodeoxycholate: the bile acid. The drug. a review. Am J Med Sci 1994; 307:54–63.
  89. Bazzoli F, Malavolti M, Petronelli A, Barbara L, Roda E. Treatment of constipation with chenodeoxycholic acid. J Int Med Res 1983; 11:120–123.
  90. Picard C, Fioramonti J, Francois A, Robinson T, Neant F, Matuchansky C. Review article: bifidobacteria as probiotic agents – physiological effects and clinical benefits. Aliment Pharmacol Ther 2005; 22:495–512.
  91. Macfarlane S, Macfarlane GT, Cummings JH. Review article: prebiotics in the gastrointestinal tract. Aliment Pharmacol Ther 2006; 24:701–714.
  92. Ouwehand A, Lagstrom H, Suomalainen T, Salminen S. Effect of probiotics on constipation, fecal azoreductase activity and fecal mucin content in the elderly. Ann Nutr Metab 2002; 46:159–162.
  93. Whorwell P, Altringer L, Morel J, et al. Efficacy of an encapsulated probiotic Bifidobacterium infantis 35624 in women with irritable bowel syndrome. Am J Gastroenterol 2006; 101:1581–1590.
  94. O'Mahony L, McCarthy J, Kelly P, et al. Lactobacillus and Bifidobacterium in irritable bowel syndrome: symptom responses and relationship to cytokine profiles. Gastroenterology 2005; 128:541–551.
  95. Koebnick C, Wagner I, Leitzmann P, Stern U, Zunft H. Probiotic beverage containing Lactobacillus casei Shirota improves gastrointestinal symptoms in patients with chronic constipation. Can J Gastroenterol 2003; 17:655–659.
  96. Kim HJ, Camilleri M, McKinzie S, et al. A randomized controlled trial of a probiotic, VSL#3, on gut transit and symptoms in diarrhoea-predominant irritable bowel syndrome. Aliment Pharmacol Ther 2003; 17:895–904.
  97. Fernández-Bañares F. Nutritional care of the patient with constipation. Best Pract Res Clin Gastroenterol 2006; 20:575–587.
  98. Bouvier M, Meance S, Bouley C, Berta J, Grimaud J. Effects of consumption of milk fermented by the probiotic strain Bifidobacterium animalis DN-173 010 on colonit transit times in healthy humans. Biosci Microflor 2001; 20 2:43–48.
  99. Makelainen H, Tahvonen R, Salminen S, Ouwehand AC. In vivo safety assessment of two Bifidobacterium longum strains. Microbiol Immunol 2003; 47:911–914.
  100. Borriello SP, Hammes WP, Holzapfel W, et al. Safety of probiotics that contain lactobacilli or bifidobacteria. Clin Infect Dis 2003; 36:775–780.
  101. Ramkumar D, Rao S. Efficacy and safety of traditional medical therapies for chronic constipation: systematic review. Am J Gastroenterol 2005; 100:936–971.
  102. Ueno R, Osama H, Habe T, Engelke K, Patchen M. Oral SPI-0211 increases intestinal fluid secretion and chloride concentration without altering serum electrolyte levels [abstract]. Gastroenterology 2004; 126 suppl 2:A298.
  103. Rao SS, Seaton K, Miller M, et al. Randomized controlled trial of biofeedback, sham biofeedback, and standard therapy for dyssynergic defecation. Clin Gastroenterol Hepatol 2007; 5:331–338.
  104. Chiarioni G, Whitehead WE, Pezza V, Morelli A, Bassotti G. Biofeedback is superior to laxatives for normal transit constipation due to pelvic floor dyssynergia. Gastroenterology 2006; 130:657–664.
  105. Heymen S, Scarlett Y, Jones K, Ringel Y, Drossman D, Whitehead WE. Randomized, controlled trial shows biofeedback to be superior to alternative treatments for patients with pelvic floor dyssynergia-type constipation. Dis Colon Rectum 2007; 50:428–441.
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KEY POINTS

  • A high-fiber diet often improves functional constipation, but it may worsen slow-transit constipation or dyssynergia (a failure of the pelvic floor muscles to relax). Nevertheless, fiber remains a mainstay of treatment for its ability to provide homogeneous stool consistency.
  • Drugs approved for treating constipation increase fluid in the lumen, speed intestinal transit, and improve stool consistency, while tegaserod (Zelnorm) additionally acts as a serotonin agonist.
  • Colonoscopy and other tests are reserved for patients with refractory constipation and those with symptoms suggesting colon cancer.
  • Prebiotics (short-chain carbohydrates that stimulate activity of beneficial colonic bacterial flora) and probiotics (live bacterial preparations) are under evaluation as treatments for chronic constipation.
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Evolution and results of aortic valve surgery, and a ‘disruptive’ technology

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Evolution and results of aortic valve surgery, and a ‘disruptive’ technology
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Lars G. Svensson, MD, PhD

Disruptive technologies are innovations that are quickly adopted and that change long-established practices. One example is coronary stenting; another that is emerging is percutaneous aortic valve insertion. The latter is already benefiting patients who would not be able to undergo open heart surgery for valve replacement. However, the technology is still so new that we do not yet know how to define who will benefit from it.

See related article

VALVE SURGERY CONTINUES TO IMPROVE

The first aortic valve replacement procedures, done in the 1960s, carried a mortality rate of 25% to 50%, but over time the results have improved considerably, even for very complex procedures.1–6 Indeed, for minimally invasive surgical aortic valve replacements at Cleveland Clinic, the survival rate is 99.2%, and for complex aortic valve repairs with the modified David reimplantation operation, all 201 patients who underwent the operation up to May 2008 survived hospitalization. Even in elderly patients, the mortality rate is only 1.4% for patients over age 80 undergoing primary replacement and 5.6% for reoperative replacement (Table 1).

Yet despite these excellent results, 30% to 61% of patients with severe symptomatic aortic valve stenosis do not undergo surgical aortic valve replacement because age and comorbid diseases put them at unacceptably high risk, or because they do not want it, or because they were never referred for it.

This concern about high risk is certainly justified, since age and comorbid conditions such as coronary artery disease, oxygen-dependent chronic pulmonary disease, renal disease, and peripheral vascular disease clearly have an adverse affect on outcome. For example, the risk of stroke and death is markedly higher in patients with peripheral vascular disease.1 It was because of the strong influence of comorbid disease in the elderly that we and others4,6 developed the novel approach of replacing the aortic valve with a stented valve via a catheter.

SURGICAL RISK IS HARD TO PREDICT

Decisions about which patients are at very high surgical risk or cannot undergo surgery are often somewhat subjective, based on a surgeon’s own experience.4,6 An algorithm for predicting operative outcomes, the Society for Thoracic Surgery equation score, is a reliable way to calculate the risk of death in patients in need of aortic valve replacement. Another method, the EuroScore, has been shown to be less predictive: in an audit of data for the multicenter Placement of Aortic Transcatheter Valves (PARTNER) trial currently under way to analyze results with these procedures, in 4,892 patients undergoing open surgical repair at Cleveland Clinic and considered at high risk (EuroScore > 10), the calculated expected risk of death was 26%, but the observed death rate was 10.9%—only 42% of the expected rate.

In my personal audit of the last 594 patients who underwent open surgical aortic valve replacement and were considered to be at high risk, the expected risk of death (as calculated by the EuroScore) was 27%, but the observed risk was considerably lower at 7%—only 26% of the predicted rate.

 

 

ENTER THE PERCUTANEOUS DEVICES

In this issue of the Journal, Dr. Singh and colleagues review the options for percutaneous aortic valve insertion in high-risk patients, and their potential outcomes.7 But as the authors note, much study still needs to be done regarding this technique.

In an initial feasibility study of 55 high-risk or inoperable patients undergoing transfemoral aortic valve insertion under a protocol approved by the US Food and Drug Administration (FDA), the mortality rate was 7.2% and the stroke rate was 9.2%. For the FDA-approved study of 40 patients underoing transapical valve placement, the mortality rate was 17%, but no immediate strokes occurred in successful procedures, even though most of these patients were not eligible for transfemoral aortic valve insertion because of peripheral vascular disease.6 Clearly, based on our data,1 the presence of peripheral vascular disease added to the risk of death.1,6

Even if the issues surrounding percutaneous valve insertion remain unresolved for early versions of the devices, one important benefit is that more people who would benefit from treatment are being referred for evaluation. At Cleveland Clinic, we have already noticed that sick patients who would not previously have been referred for surgery are now being referred because of the new technology, although only about 20% of these are eventually enrolled in the PARTNER study. A further 20% undergo conventional open surgery, 20% undergo balloon valvuloplasty, and the remainder are too sick, die during evaluation, or refuse intervention.6 Indeed, none of the patients who underwent high-risk open surgery died.6

Although this new, “disruptive” technology was introduced for patients for whom surgery would pose an unacceptably high risk, it is inevitable that, with further improvements in prosthetic valves and the ways to insert them, percutaneous valve insertion will make inroads in the treatment of aortic valve stenosis.

While most disruptive technologies are cheaper than the technologies they displace, this may not be the case with percutaneous valve insertion: a standard aortic heart valve costs $2,500 to $6,000, whereas percutaneously delivered valves cost $30,000. The hospital stay may turn out to be a little shorter, which may help control the overall cost. But while the hospital stay after percutaneous insertion may be shorter than for surgical valve replacement (3–5 days vs 5–7 days), percutaneous valve insertion is currently labor-intensive and requires a team of 25 to 30 people, compared with five or six for open repair.

Percutaneous valve insertion offers selected high-risk patients one of the most beneficial treatments in cardiovascular medicine that they potentially would never have benefited from—ie, improved quality of life, and more years of life. It has great potential, but the problems of procedural safety and of access to treatment still need to be overcome.

References
  1. Svensson LG. Aortic valve stenosis and regurgitation: an overview of management. J Cardiovasc Surg 2008; 49:297–303.
  2. Svensson LG, Deglurkar I, Ung J, et al. Aortic valve repair and root preservation by remodeling, reimplantation, and tailoring: technical aspects and early outcome. J Card Surg 2007; 22:473–479.
  3. Svensson LG, Blackstone EH, Cosgrove DM. Surgical options in young adults with aortic valve disease. Curr Probl Cardiol 2003; 28:417–480.
  4. Dewey TM, Brown D, Ryan WH, Herbert MA, Prince SL, Mack MJ. Reliability of risk algorithms in predicting early and late operative outcomes in high-risk patients undergoing aortic valve replacement. J Thorac Cardiovasc Surg 2008; 135:180–187.
  5. Varadarajan P, Kapoor N, Bansal RC, Pai RG. Clinical profile and natural history of 453 nonsurgically managed patients with severe aortic stenosis. Ann Thorac Surg 2006; 82:2111–2115.
  6. Svensson LG, Dewey T, Kapadia S, et al. United States feasibility study of transcatheter insertion of a stented aortic valve via left ventricular apex. Ann Thoracic Surg 2008; 86:46–54.
  7. Singh IM, Shishehbor MH, Christofferson RD, Tuzcu EM, Kapadia SR. Percutaneous treatment of aortic valve stenosis. Cleve Clin J Med 2008; 75:805–812.
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Address: Lars G. Svensson, MD, PhD, Department of Thoracic and Cardiovascular Surgery, F24, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; email [email protected]

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Related Articles
Percutaneous treatment of aortic valve stenosis

Disruptive technologies are innovations that are quickly adopted and that change long-established practices. One example is coronary stenting; another that is emerging is percutaneous aortic valve insertion. The latter is already benefiting patients who would not be able to undergo open heart surgery for valve replacement. However, the technology is still so new that we do not yet know how to define who will benefit from it.

See related article

VALVE SURGERY CONTINUES TO IMPROVE

The first aortic valve replacement procedures, done in the 1960s, carried a mortality rate of 25% to 50%, but over time the results have improved considerably, even for very complex procedures.1–6 Indeed, for minimally invasive surgical aortic valve replacements at Cleveland Clinic, the survival rate is 99.2%, and for complex aortic valve repairs with the modified David reimplantation operation, all 201 patients who underwent the operation up to May 2008 survived hospitalization. Even in elderly patients, the mortality rate is only 1.4% for patients over age 80 undergoing primary replacement and 5.6% for reoperative replacement (Table 1).

Yet despite these excellent results, 30% to 61% of patients with severe symptomatic aortic valve stenosis do not undergo surgical aortic valve replacement because age and comorbid diseases put them at unacceptably high risk, or because they do not want it, or because they were never referred for it.

This concern about high risk is certainly justified, since age and comorbid conditions such as coronary artery disease, oxygen-dependent chronic pulmonary disease, renal disease, and peripheral vascular disease clearly have an adverse affect on outcome. For example, the risk of stroke and death is markedly higher in patients with peripheral vascular disease.1 It was because of the strong influence of comorbid disease in the elderly that we and others4,6 developed the novel approach of replacing the aortic valve with a stented valve via a catheter.

SURGICAL RISK IS HARD TO PREDICT

Decisions about which patients are at very high surgical risk or cannot undergo surgery are often somewhat subjective, based on a surgeon’s own experience.4,6 An algorithm for predicting operative outcomes, the Society for Thoracic Surgery equation score, is a reliable way to calculate the risk of death in patients in need of aortic valve replacement. Another method, the EuroScore, has been shown to be less predictive: in an audit of data for the multicenter Placement of Aortic Transcatheter Valves (PARTNER) trial currently under way to analyze results with these procedures, in 4,892 patients undergoing open surgical repair at Cleveland Clinic and considered at high risk (EuroScore > 10), the calculated expected risk of death was 26%, but the observed death rate was 10.9%—only 42% of the expected rate.

In my personal audit of the last 594 patients who underwent open surgical aortic valve replacement and were considered to be at high risk, the expected risk of death (as calculated by the EuroScore) was 27%, but the observed risk was considerably lower at 7%—only 26% of the predicted rate.

 

 

ENTER THE PERCUTANEOUS DEVICES

In this issue of the Journal, Dr. Singh and colleagues review the options for percutaneous aortic valve insertion in high-risk patients, and their potential outcomes.7 But as the authors note, much study still needs to be done regarding this technique.

In an initial feasibility study of 55 high-risk or inoperable patients undergoing transfemoral aortic valve insertion under a protocol approved by the US Food and Drug Administration (FDA), the mortality rate was 7.2% and the stroke rate was 9.2%. For the FDA-approved study of 40 patients underoing transapical valve placement, the mortality rate was 17%, but no immediate strokes occurred in successful procedures, even though most of these patients were not eligible for transfemoral aortic valve insertion because of peripheral vascular disease.6 Clearly, based on our data,1 the presence of peripheral vascular disease added to the risk of death.1,6

Even if the issues surrounding percutaneous valve insertion remain unresolved for early versions of the devices, one important benefit is that more people who would benefit from treatment are being referred for evaluation. At Cleveland Clinic, we have already noticed that sick patients who would not previously have been referred for surgery are now being referred because of the new technology, although only about 20% of these are eventually enrolled in the PARTNER study. A further 20% undergo conventional open surgery, 20% undergo balloon valvuloplasty, and the remainder are too sick, die during evaluation, or refuse intervention.6 Indeed, none of the patients who underwent high-risk open surgery died.6

Although this new, “disruptive” technology was introduced for patients for whom surgery would pose an unacceptably high risk, it is inevitable that, with further improvements in prosthetic valves and the ways to insert them, percutaneous valve insertion will make inroads in the treatment of aortic valve stenosis.

While most disruptive technologies are cheaper than the technologies they displace, this may not be the case with percutaneous valve insertion: a standard aortic heart valve costs $2,500 to $6,000, whereas percutaneously delivered valves cost $30,000. The hospital stay may turn out to be a little shorter, which may help control the overall cost. But while the hospital stay after percutaneous insertion may be shorter than for surgical valve replacement (3–5 days vs 5–7 days), percutaneous valve insertion is currently labor-intensive and requires a team of 25 to 30 people, compared with five or six for open repair.

Percutaneous valve insertion offers selected high-risk patients one of the most beneficial treatments in cardiovascular medicine that they potentially would never have benefited from—ie, improved quality of life, and more years of life. It has great potential, but the problems of procedural safety and of access to treatment still need to be overcome.

Disruptive technologies are innovations that are quickly adopted and that change long-established practices. One example is coronary stenting; another that is emerging is percutaneous aortic valve insertion. The latter is already benefiting patients who would not be able to undergo open heart surgery for valve replacement. However, the technology is still so new that we do not yet know how to define who will benefit from it.

See related article

VALVE SURGERY CONTINUES TO IMPROVE

The first aortic valve replacement procedures, done in the 1960s, carried a mortality rate of 25% to 50%, but over time the results have improved considerably, even for very complex procedures.1–6 Indeed, for minimally invasive surgical aortic valve replacements at Cleveland Clinic, the survival rate is 99.2%, and for complex aortic valve repairs with the modified David reimplantation operation, all 201 patients who underwent the operation up to May 2008 survived hospitalization. Even in elderly patients, the mortality rate is only 1.4% for patients over age 80 undergoing primary replacement and 5.6% for reoperative replacement (Table 1).

Yet despite these excellent results, 30% to 61% of patients with severe symptomatic aortic valve stenosis do not undergo surgical aortic valve replacement because age and comorbid diseases put them at unacceptably high risk, or because they do not want it, or because they were never referred for it.

This concern about high risk is certainly justified, since age and comorbid conditions such as coronary artery disease, oxygen-dependent chronic pulmonary disease, renal disease, and peripheral vascular disease clearly have an adverse affect on outcome. For example, the risk of stroke and death is markedly higher in patients with peripheral vascular disease.1 It was because of the strong influence of comorbid disease in the elderly that we and others4,6 developed the novel approach of replacing the aortic valve with a stented valve via a catheter.

SURGICAL RISK IS HARD TO PREDICT

Decisions about which patients are at very high surgical risk or cannot undergo surgery are often somewhat subjective, based on a surgeon’s own experience.4,6 An algorithm for predicting operative outcomes, the Society for Thoracic Surgery equation score, is a reliable way to calculate the risk of death in patients in need of aortic valve replacement. Another method, the EuroScore, has been shown to be less predictive: in an audit of data for the multicenter Placement of Aortic Transcatheter Valves (PARTNER) trial currently under way to analyze results with these procedures, in 4,892 patients undergoing open surgical repair at Cleveland Clinic and considered at high risk (EuroScore > 10), the calculated expected risk of death was 26%, but the observed death rate was 10.9%—only 42% of the expected rate.

In my personal audit of the last 594 patients who underwent open surgical aortic valve replacement and were considered to be at high risk, the expected risk of death (as calculated by the EuroScore) was 27%, but the observed risk was considerably lower at 7%—only 26% of the predicted rate.

 

 

ENTER THE PERCUTANEOUS DEVICES

In this issue of the Journal, Dr. Singh and colleagues review the options for percutaneous aortic valve insertion in high-risk patients, and their potential outcomes.7 But as the authors note, much study still needs to be done regarding this technique.

In an initial feasibility study of 55 high-risk or inoperable patients undergoing transfemoral aortic valve insertion under a protocol approved by the US Food and Drug Administration (FDA), the mortality rate was 7.2% and the stroke rate was 9.2%. For the FDA-approved study of 40 patients underoing transapical valve placement, the mortality rate was 17%, but no immediate strokes occurred in successful procedures, even though most of these patients were not eligible for transfemoral aortic valve insertion because of peripheral vascular disease.6 Clearly, based on our data,1 the presence of peripheral vascular disease added to the risk of death.1,6

Even if the issues surrounding percutaneous valve insertion remain unresolved for early versions of the devices, one important benefit is that more people who would benefit from treatment are being referred for evaluation. At Cleveland Clinic, we have already noticed that sick patients who would not previously have been referred for surgery are now being referred because of the new technology, although only about 20% of these are eventually enrolled in the PARTNER study. A further 20% undergo conventional open surgery, 20% undergo balloon valvuloplasty, and the remainder are too sick, die during evaluation, or refuse intervention.6 Indeed, none of the patients who underwent high-risk open surgery died.6

Although this new, “disruptive” technology was introduced for patients for whom surgery would pose an unacceptably high risk, it is inevitable that, with further improvements in prosthetic valves and the ways to insert them, percutaneous valve insertion will make inroads in the treatment of aortic valve stenosis.

While most disruptive technologies are cheaper than the technologies they displace, this may not be the case with percutaneous valve insertion: a standard aortic heart valve costs $2,500 to $6,000, whereas percutaneously delivered valves cost $30,000. The hospital stay may turn out to be a little shorter, which may help control the overall cost. But while the hospital stay after percutaneous insertion may be shorter than for surgical valve replacement (3–5 days vs 5–7 days), percutaneous valve insertion is currently labor-intensive and requires a team of 25 to 30 people, compared with five or six for open repair.

Percutaneous valve insertion offers selected high-risk patients one of the most beneficial treatments in cardiovascular medicine that they potentially would never have benefited from—ie, improved quality of life, and more years of life. It has great potential, but the problems of procedural safety and of access to treatment still need to be overcome.

References
  1. Svensson LG. Aortic valve stenosis and regurgitation: an overview of management. J Cardiovasc Surg 2008; 49:297–303.
  2. Svensson LG, Deglurkar I, Ung J, et al. Aortic valve repair and root preservation by remodeling, reimplantation, and tailoring: technical aspects and early outcome. J Card Surg 2007; 22:473–479.
  3. Svensson LG, Blackstone EH, Cosgrove DM. Surgical options in young adults with aortic valve disease. Curr Probl Cardiol 2003; 28:417–480.
  4. Dewey TM, Brown D, Ryan WH, Herbert MA, Prince SL, Mack MJ. Reliability of risk algorithms in predicting early and late operative outcomes in high-risk patients undergoing aortic valve replacement. J Thorac Cardiovasc Surg 2008; 135:180–187.
  5. Varadarajan P, Kapoor N, Bansal RC, Pai RG. Clinical profile and natural history of 453 nonsurgically managed patients with severe aortic stenosis. Ann Thorac Surg 2006; 82:2111–2115.
  6. Svensson LG, Dewey T, Kapadia S, et al. United States feasibility study of transcatheter insertion of a stented aortic valve via left ventricular apex. Ann Thoracic Surg 2008; 86:46–54.
  7. Singh IM, Shishehbor MH, Christofferson RD, Tuzcu EM, Kapadia SR. Percutaneous treatment of aortic valve stenosis. Cleve Clin J Med 2008; 75:805–812.
References
  1. Svensson LG. Aortic valve stenosis and regurgitation: an overview of management. J Cardiovasc Surg 2008; 49:297–303.
  2. Svensson LG, Deglurkar I, Ung J, et al. Aortic valve repair and root preservation by remodeling, reimplantation, and tailoring: technical aspects and early outcome. J Card Surg 2007; 22:473–479.
  3. Svensson LG, Blackstone EH, Cosgrove DM. Surgical options in young adults with aortic valve disease. Curr Probl Cardiol 2003; 28:417–480.
  4. Dewey TM, Brown D, Ryan WH, Herbert MA, Prince SL, Mack MJ. Reliability of risk algorithms in predicting early and late operative outcomes in high-risk patients undergoing aortic valve replacement. J Thorac Cardiovasc Surg 2008; 135:180–187.
  5. Varadarajan P, Kapoor N, Bansal RC, Pai RG. Clinical profile and natural history of 453 nonsurgically managed patients with severe aortic stenosis. Ann Thorac Surg 2006; 82:2111–2115.
  6. Svensson LG, Dewey T, Kapadia S, et al. United States feasibility study of transcatheter insertion of a stented aortic valve via left ventricular apex. Ann Thoracic Surg 2008; 86:46–54.
  7. Singh IM, Shishehbor MH, Christofferson RD, Tuzcu EM, Kapadia SR. Percutaneous treatment of aortic valve stenosis. Cleve Clin J Med 2008; 75:805–812.
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Evolution and results of aortic valve surgery, and a ‘disruptive’ technology
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Percutaneous treatment of aortic valve stenosis

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Article
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Percutaneous treatment of aortic valve stenosis
Author(s)
Inder M. Singh, MD, MS
Mehdi H. Shishehbor, DO, MPH
Ryan D. Christofferson, MD
E. Murat Tuzcu, MD
Samir R. Kapadia, MD

Stenosis of the aortic valve has a long, latent, asymptomatic phase, but when symptoms finally occur, clinical deterioration can be rapid. For patients with severe stenosis, the standard treatment has long been replacement of the aortic valve via open heart surgery. But many patients with severe stenosis are considered too high-risk for this procedure.

Until about 5 years ago, these patients had no other option but medical therapy or percutaneous aortic balloon valvuloplasty as a palliative measure or as a bridge to open heart surgery. But 5 years of experience with percutaneous techniques to implant prosthetic aortic valves show that this less-invasive approach may become a viable option for patients with severe symptomatic aortic valve stenosis.

In this review, we discuss current prosthetic valves and percutaneous techniques and their relative advantages and limitations and the potential future role of this new treatment option.

THE NEED FOR A LESS-INVASIVE APPROACH

Calcific aortic stenosis is the most common valvular heart disease, affecting 2% to 4% of adults over age 65 in the United States alone.1,2 The aging of our population and the lack of drug therapies to prevent, halt, or effectively slow aortic valve stenosis are leading to a greater burden of this condition.1,3,4 Already in the United States more than 50,000 surgical aortic valve replacements are performed every year for severe aortic stenosis.1,2 The associated in-hospital death rate is 8.8% in patients over age 65 years, and as high as 13% in low-volume centers.1,5

The steady increase in the number of patients requiring aortic valve replacement, the high surgical risk in patients with multiple comorbidities, the reluctance of some patients to undergo the trauma and pain associated with open heart surgery via sternotomy, and the fact that percutaneous procedures are less traumatic and offer faster recovery and fewer hospital days—all these are forces that have been driving the development of percutaneous techniques for the treatment of aortic stenosis.6–11 In addition, a recent study12 showed that 33% of patients over age 75 were deemed too high-risk for open heart surgery and thus were left untreated.12

The evolution of percutaneous aortic valve replacement

The idea of percutaneous treatment of aortic stenosis was first put into clinical practice in 1985, when Cribier performed an aortic balloon valvuloplasty.6 This was followed in 200013 by the first successful implantation of a catheter-based stent valve in a human, and in 2002 by the first successful percutaneous aortic valve replacement in a human.13–15 In the following sections, we discuss the percutaneous approaches in current use for the treatment of degenerative aortic stenosis.

AORTIC BALLOON VALVULOPLASTY

Percutaneous aortic balloon valvuloplasty, partial dilation of the stenotic aortic valve with a balloon inserted via a catheter,1,16–19 improves symptoms but has failed to show a sustained benefit on rates of mortality or morbidity.1,16–18 The restenosis rate is high, and symptoms recur in most patients within months to a year.1,16–18 Procedural complication rates are about 10%, and complication rates at the catheter access site are even higher.1,16–18 The 30-day death rate in the National Heart, Lung, and Blood Institute’s Balloon Valvuloplasty Registry, which included more than 600 patients, was 14%.18 In a retrospective study of 212 patients who underwent single or repeat percutaneous aortic balloon valvuloplasty,20 the 1-year mortality rate was 36% for the entire cohort, with a median survival of 3 years. Patients who underwent a repeat procedure (33%) had 1-year mortality rate of 42%, compared with 16% in patients who did not undergo a repeat procedure.20

Percutaneous aortic balloon valvuloplasty serves best as palliative therapy in severely symptomatic patients, and as a bridge to surgery in hemodynamically unstable adult patients.21,22 Percutaneous aortic balloon valvuloplasty is not an option in patients who are good candidates for surgical valve replacement.1

PERCUTANEOUS AORTIC VALVE REPLACEMENT: THREE TECHNIQUES

Percutaneous aortic valve replacement was first reported in 1992 using a closed-chest pig model.14 Since then, three prosthetic valves have been used in human clinical trials for this procedure: the Cribier-Edwards valve (Edwards Lifesciences Corporation, Irvine, CA), the CoreValve (CoreValve Inc, Irvine, CA), and the Edwards SAPIEN valve (Edwards Lifesciences Corporation, Irvine, CA) (Table 1). These have been implanted in humans using three different percutaneous techniques (Figure 1).

The antegrade technique

Figure 1.
In the antegrade technique, an approach that has been studied but is no longer being used, access to the femoral vein is gained and the catheter with the prosthetic aortic valve is advanced, traversing the interatrial septum and the mitral valve, and is positioned within the diseased aortic valve.15,23,24 The main advantage of this approach is that the femoral vein can accommodate the large catheter sheath and that subsequent management of the access site is by manual compression only.15,23,24 The main disadvantages are the potential for mitral valve injury and severe mitral regurgitation, and the technical challenge of delivering the aortic valve prosthesis to the correct aortic position.15,23,25–27

The retrograde technique

In the retrograde (ie, transfemoral) technique, access to the femoral artery is gained and the catheter with the prosthetic aortic valve is advanced to the stenotic aortic valve.8,11,26,28–30 This approach is faster and technically easier than the antegrade approach, but it can be associated with injury to the aortofemoral vessels and with failure of the prosthesis to cross the aortic arch or the stenotic aortic valve.11,23,30

 

 

The transapical technique

In the transapical technique, the valve delivery system is inserted via a small incision made between the ribs. The apex of the left ventricle is punctured with a needle, and the prosthetic valve is positioned within the stenotic aortic valve.27,31–33 The main advantage of this approach is that it allows more direct access to the aortic valve and eliminates the need for a large peripheral vascular access site in patients with peripheral vascular disease, small tortuous vasculature, or a history of major vascular complications or vascular repairs.31–33 Potential disadvantages are related to the left ventricular apical puncture and include adverse ventricular remodeling, left ventricular aneurysm or pseudoaneurysm, pericardial complications, pneumothorax, malignant ventricular arrhythmias, coronary artery injury, and the need for general anesthesia and chest tubes.27,31–35

Common features of the three approaches

The three percutaneous approaches have certain final steps in common.11,23,30,33 The position of final deployment of the prosthetic valve is determined by the patient’s native valvular structure and anatomy and is optimized by using fluoroscopic imaging of the native aortic valve calcification as an anatomical marker, along with guidance from supra-aortic angiography and transesophageal echocardiography.11,23,30,33 Ideally, the aortic valve prosthesis is placed at mid-position in the patient’s aortic valve, taking care to not to impinge on the coronary ostia or to impede the motion of the anterior mitral leaflet.11,23,30,33 In all three procedures, the prosthesis is then deployed by maximally inflating, rapidly deflating, and immediately withdrawing the delivery balloon. This final step is carried out during temporary high-rate right ventricular apical pacing, which produces ventricular tachycardia at 180 to 220 beats/min for up to 10 seconds.11,23,30,33 This leads to an immediate decrease in stroke volume, resulting in minimal forward flow through the aortic valve, which in turn facilitates precise positioning of the prosthetic valve.

So far, only the Cribier-Edwards valve has been deployed via all three techniques. The CoreValve has been deployed only via the retrograde technique. The Edwards SAPIEN valve has been deployed with retrograde and transapical approaches (see www.edwards.com/Products/TranscatheterValves/SapienTHV.htm and www.corevalve.com for animations depicting these techniques).

EXPERIENCE WITH THE CRIBIER-EDWARDS VALVE

The Cribier-Edwards valve has three leaflets made from equine pericardial tissue sutured inside a balloon-expandable stainless steel 14-mm stent (Table 1).11,23,33 With the use of a specially designed mechanical crimping device, the aortic valve prosthesis is mounted over a 3-cm-long balloon catheter, expandable to a diameter of 22 to 26 mm (NuMed Inc, Hopkinton, NY).11,23,30,33

After this prosthesis was tested in animal models,14,15 a trial for compassionate use in humans was begun, called the Initial Registry of Endovascular Implantation of Valves in Europe (I-REVIVE) trial. This trial was later continued as the Registry of Endovascular Critical Aortic Stenosis Treatment (RECAST) trial.23 All patients were formally evaluated by two cardio-thoracic surgeons and were deemed inappropriate for surgical aortic valve replacement.23

The success rate with the antegrade percutaneous approach was 85% (23 of 27 patients) and 57% for the retrograde approach (4 of 7 patients).11,23,30–33 Procedural limitations were migration or embolization of the prosthetic valve, failure to cross the stenotic aortic valve, and paravalvular aortic regurgitation.23 Anatomic and functional success was evidenced by improvement in aortic valve area, increase in left ventricular ejection fraction, and improved New York Heart Association functional class, all of which were sustained at up to 24 months.23

Webb et al11 reported similar results with retrograde implantation of the Cribier-Edwards valve in a cohort of 50 patients.11 The main difference between the two studies was the expected occurrence of aortofemoral complications with the retrograde approach.11,26 Procedural success increased from 76% in the first 25 patients to 96% in the second 25, and the 30-day mortality rate fell from 16% to 8%, which reflected the learning curve. Importantly, no patients needed conversion to open surgery during the first 30 days, and at a median follow-up of 359 days 35 (81%) of 43 patients who underwent successful transcatheter aortic valve replacement were still alive.11 Additionally, significant improvement was noted in left ventricular ejection fraction, mitral regurgitation, and New York Heart Association functional class, and these improvements persisted at 1 year.11

Lichtenstein et al31 and Walther et al32 successfully implanted the Cribier-Edwards valve using the transapical approach in a very high-risk elderly population with poor functional class. All patients were deemed unsuitable for standard surgical valve replacement and also for percutaneous transfemoral aortic valve implantation because of severe aorto-iliac disease. In both studies, the short-term and mid-term results were encouraging.

These experiences with the Cribier-Edwards valve showed that device- and technique-related shortcomings could be addressed. To date, more than 500 percutaneous aortic valve replacement procedures have been done with the Cribier-Edwards valve worldwide, with a greater than 95% technical success rate in the latest cohorts.36 Importantly, use of a larger (26-mm) prosthetic valve has been associated with a lower rate of prosthetic valve migration or embolization, and with a significantly lower rate of paravalvular aortic regurgitation.11,23

 

 

EXPERIENCE WITH THE COREVALVE SYSTEM

The CoreValve ReValving system is based on retrograde implantation of the CoreValve prosthesis—a self-expanding aortic valve prosthesis composed of three bovine pericardial leaflets mounted and sutured within a self-expanding 50-mm-long nitinol stent (Table 1).28–30 The inner diameter is 21 to 22 mm.28–30 This prosthesis has three distinct structural segments.28–30 The bottom portion exerts a high radial force that expands and pushes aside the calcified leaflets and avoids recoil; the central portion carries the valve, and it tapers to avoid the coronary artery ostia; and the upper portion flares to fixate and stabilize the deployed aortic valve prosthesis in the ascending aorta, thus preventing migration or embolization of the device.28–30 The main difference between the CoreValve and the Cribier-Edwards valve is that the Core-Valve is self-expanding, which theoretically permits it to conform to different aortic sizes and to anchor well in the aortic annulus.28–30 This feature allows the CoreValve to be used in patients with severe aortic insufficiency and other noncalcific aortic valvular conditions. The CoreValve has not yet been deployed via antegrade or transapical technique.

The first-generation CoreValve prosthesis was first implanted in a human recipient in 2005.29 Since then, improvements have been made, leading to the development of second- and third-generation devices. A pilot study of implantation of the first-generation CoreValve28 via the retrograde approach in elderly patients with poor functional class and severe aortic stenosis had a short-term procedural success rate of 84% (21 of 25 patients), with a significant reduction in the mean aortic valve gradient and improved functional class at 30-day follow-up.28 At 30 days, 17 (94%) of 18 patients had no or only mild aortic regurgitation.28 Procedural limitations and complications were similar to those with the Cribier-Edwards valve.

In a study of second- and third-generation devices (50 patients received a second-generation device, and 36 received a third-generation device),30 again in elderly patients with poor functional class and severe aortic stenosis, the short-term success rate of the device was 88% (76 of 86) in each group. After the procedure, the mean aortic valve gradient decreased significantly and functional class improved significantly.30 Immediate after implantation, no patient had more than moderate aortic regurgitation, and in 51 patients (66%) the aortic regurgitation remained unchanged or improved after CoreValve implantation.30 These results were maintained at 30-day follow-up.

CoreValve was approved in May 2007 for clinical use in Europe.36 Of note, CoreValve has also been used to treat severe aortic regurgitation of a degenerated bioprosthetic aortic valve in an 80-year-old man with multiple comorbidities.37

EXPERIENCE WITH THE EDWARDS SAPIEN VALVE

The Edwards SAPIEN valve is a modification of the initial Cribier-Edwards valve and is the latest percutaneous aortic valve prosthesis to enter clinical trials (Table 1). It is a trileaflet balloon-expandable stainless steel valve made from bovine pericardial tissue, available in two sizes (23 mm and 26 mm). In September 2007, it was approved for use in Europe with the RetroFlex transfemoral delivery system. The Ascendra transapical delivery system for the Edward SAPIEN valve has received approval in Europe.

The multicenter Placement of Aortic Transcatheter Valves (PARTNER) trial in North America is continuing to enroll patients, with enrollment projected to be complete by the end of 2008. The aim of this prospective randomized clinical trial is to enroll 1,040 patients in two separate treatment arms. The surgical arm of the trial is comparing the Edwards SAPIEN valve with standard surgical aortic valve replacement, with the objective of demonstrating non-inferiority. The medical management arm of the trial is comparing percutaneous valve replacement against medical therapy or balloon valvuloplasty in patients considered too high-risk for conventional surgical valve replacement.

The primary end point in both arms is death at 1 year; secondary end points focus on long-term (1-year) composite cardiovascular events, valve performance, and quality-of-life indicators. Preliminary data on the first 100 patients (74 via the transfemoral [ie, retrograde] and 26 via the transapical approach) who underwent percutaneous Edwards SAPIEN valve implantation for compassionate use showed device durability and symptom relief at up to 2 years.38 Overall procedural success was 91%, but, as with other trials, there was a steep learning curve, so that excluding the first 25 patients increased the procedural success rate to 96%.38 Aortic valve size and hemodynamics, left ventricular systolic function, mitral regurgitation, and functional class were all significantly improved. Mild aortic regurgitation was common, but none of the patients had severe aortic regurgitation. Importantly, the 15% 30-day death rate was significantly lower than the expected rate of 33%. The 6-month survival rate was 78%, but the 2-year rate was 60% in this high-risk elderly cohort.

Walther et al39 recently reported outcomes on their first 50 patients who underwent transapical implantation of the Edwards SAPIEN valve. The operators were able to implant the prosthesis in all 50 patients, but 3 required early conversion to open surgery with sternotomy. The overall survival at 30 days was 92%, but in the last 25 patients the 30-day survival rate was 96%, with a 1-year survival rate of 80%.

 

 

PUTTING THE DATA IN PERSPECTIVE

As noted in this review, a number of factors make a strong case for timely aortic valve replacement: the aging population, the increase in incidence and prevalence of aortic stenosis,1,3,4,27,40 the multiple comorbidities in older patients, and the eventually aggressive natural course of aortic stenosis.1,3,4,27,40–43 Yet current standards dictate not to proceed with standard surgical aortic valve replacement in patients who are truly asymptomatic and who have normal left ventricular systolic function,1,40 mainly because the risks of surgical valve replacement outweigh the benefits in this population.1,40 Aortic valve surgery carries a risk of early death of 15% for patients ages 80 to 84 and of 18% for patients age 85.3,9,10,12,43–45

These figures seem high when compared with death rates of 12% in recent studies of percutaneous valve replacement in similar patients.11,23,30,33 The rates become lower as the learning curve improves.11,21,23,27,30,33 Thus, as the design of aortic valve prostheses and the techniques to implant them are refined and tested for safety, the risk-benefit balance may change in favor of earlier intervention in aortic stenosis with a percutaneous approach.11,21,27,46 Some experts believe that in 10 years 10% to 30% of patients undergoing conventional valve replacement will be candidates for a percutaneous approach.

Of the techniques used to date, the retrograde approach seems most amenable to widespread acceptance, given its inherent advantage of being faster and easier.11,21,30 Limitations with the retrograde approach seen in earlier trials—challenges and complications associated with large-bore arterial vascular access, difficulty traversing the aortic arch with bulky devices, and the inability to cross the stenotic aortic valve to deploy the prosthesis even after balloon valvuloplasty11,21,30—are correctable with refinements in the devices and in technique.

New types of prosthetic aortic valves entering early human studies are improving on current devices, for example, by using collapsible, inflatable valve frames for retrievability before final deployment.

Surgical aortic valve replacement remains the gold standard treatment for patients with symptomatic aortic stenosis. And while studies of percutaneous aortic valve replacement show great promise for this less-invasive treat-men, enthusiasm about percutaneous aortic valve replacement should be tempered by an awareness of persistent limitations of this approach, such as vascular and mechanical complications and operator inexperience, which still need attention.

References
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  9. Alexander KP, Anstrom KJ, Muhlbaier LH, et al. Outcomes of cardiac surgery in patients =80 years: results from the National Cardiovascular Network. J Am Coll Cardiol 2000; 35:731–738.
  10. Mittermair RP, Muller LC. Quality of life after cardiac surgery in the elderly. J Cardiovasc Surg (Torino) 2002; 43:43–47.
  11. Webb JG, Pasupati S, Humphries K, et al. Percutaneous transarterial aortic valve replacement in selected high-risk patients with aortic stenosis. Circulation 2007; 116:755–763.
  12. Iung B, Cachier A, Baron G, et al. Decision-making in elderly patients with severe aortic stenosis: why are so many denied surgery? Eur Heart J 2005; 26:2714–2720.
  13. Bonhoeffer P, Boudjemline Y, Saliba Z, et al. Percutaneous replacement of pulmonary valve in a right-ventricle to pulmonary-artery prosthetic conduit with valve dysfunction. Lancet 2000; 356:1403–1405.
  14. Andersen HR, Knudsen LL, Hasenkam JM. Transluminal implantation of artificial heart valves. Description of a new expandable aortic valve and initial results with implantation by catheter technique in closed chest pigs. Eur Heart J 1992; 13:704–708.
  15. Cribier A, Eltchaninoff H, Bash A, et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description. Circulation 2002; 106:3006–3008.
  16. Otto CM, Mickel MC, Kennedy JW, et al. Three-year outcome after balloon aortic valvuloplasty. Insights into prognosis of valvular aortic stenosis. Circulation 1994; 89:642–650.
  17. Safian RD, Berman AD, Diver DJ, et al. Balloon aortic valvuloplasty in 170 consecutive patients. N Engl J Med 1988; 319:125–130.
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  20. Agarwal A, Kini AS, Attanti S, et al. Results of repeat balloon valvuloplasty for treatment of aortic stenosis in patients aged 59 to 104 years. Am J Cardiol 2005; 95:43–47.
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  29. Grube E, Laborde JC, Zickmann B, et al. First report on a human percutaneous transluminal implantation of a self-expanding valve prosthesis for interventional treatment of aortic valve stenosis. Catheter Cardiovasc Interv 2005; 66:465–469.
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Author and Disclosure Information

Inder M. Singh, MD, MS
Department of Cardiovascular Medicine, Cleveland Clinic

Mehdi H. Shishehbor, DO, MPH
Department of Cardiovascular Medicine, Cleveland Clinic

Ryan D. Christofferson, MD
Department of Cardiovascular Medicine, Cleveland Clinic

E. Murat Tuzcu, MD
Department of Cardiovascular Medicine, Cleveland Clinic

Samir R. Kapadia, MD
Department of Cardiovascular Medicine, Cleveland Clinic

Address: Samir Kapadia, MD, Department of Cardiovascular Medicine, F25, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

Dr. Shishehbor’s work is supported in part by the National Institutes of Health, National Institute of Child Health and Human Development, Multidisciplinary Clinical Research Career Development Programs Grant K12 HD049091.

Issue
Cleveland Clinic Journal of Medicine - 75(11)
Publications
Cleveland Clinic Journal of Medicine
Topics
Cardiology
Page Number
805-812
Sections
Reviews
Author(s)
Inder M. Singh, MD, MS
Mehdi H. Shishehbor, DO, MPH
Ryan D. Christofferson, MD
E. Murat Tuzcu, MD
Samir R. Kapadia, MD
Author(s)
Inder M. Singh, MD, MS
Mehdi H. Shishehbor, DO, MPH
Ryan D. Christofferson, MD
E. Murat Tuzcu, MD
Samir R. Kapadia, MD
Author and Disclosure Information

Inder M. Singh, MD, MS
Department of Cardiovascular Medicine, Cleveland Clinic

Mehdi H. Shishehbor, DO, MPH
Department of Cardiovascular Medicine, Cleveland Clinic

Ryan D. Christofferson, MD
Department of Cardiovascular Medicine, Cleveland Clinic

E. Murat Tuzcu, MD
Department of Cardiovascular Medicine, Cleveland Clinic

Samir R. Kapadia, MD
Department of Cardiovascular Medicine, Cleveland Clinic

Address: Samir Kapadia, MD, Department of Cardiovascular Medicine, F25, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

Dr. Shishehbor’s work is supported in part by the National Institutes of Health, National Institute of Child Health and Human Development, Multidisciplinary Clinical Research Career Development Programs Grant K12 HD049091.

Author and Disclosure Information

Inder M. Singh, MD, MS
Department of Cardiovascular Medicine, Cleveland Clinic

Mehdi H. Shishehbor, DO, MPH
Department of Cardiovascular Medicine, Cleveland Clinic

Ryan D. Christofferson, MD
Department of Cardiovascular Medicine, Cleveland Clinic

E. Murat Tuzcu, MD
Department of Cardiovascular Medicine, Cleveland Clinic

Samir R. Kapadia, MD
Department of Cardiovascular Medicine, Cleveland Clinic

Address: Samir Kapadia, MD, Department of Cardiovascular Medicine, F25, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

Dr. Shishehbor’s work is supported in part by the National Institutes of Health, National Institute of Child Health and Human Development, Multidisciplinary Clinical Research Career Development Programs Grant K12 HD049091.

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Stenosis of the aortic valve has a long, latent, asymptomatic phase, but when symptoms finally occur, clinical deterioration can be rapid. For patients with severe stenosis, the standard treatment has long been replacement of the aortic valve via open heart surgery. But many patients with severe stenosis are considered too high-risk for this procedure.

Until about 5 years ago, these patients had no other option but medical therapy or percutaneous aortic balloon valvuloplasty as a palliative measure or as a bridge to open heart surgery. But 5 years of experience with percutaneous techniques to implant prosthetic aortic valves show that this less-invasive approach may become a viable option for patients with severe symptomatic aortic valve stenosis.

In this review, we discuss current prosthetic valves and percutaneous techniques and their relative advantages and limitations and the potential future role of this new treatment option.

THE NEED FOR A LESS-INVASIVE APPROACH

Calcific aortic stenosis is the most common valvular heart disease, affecting 2% to 4% of adults over age 65 in the United States alone.1,2 The aging of our population and the lack of drug therapies to prevent, halt, or effectively slow aortic valve stenosis are leading to a greater burden of this condition.1,3,4 Already in the United States more than 50,000 surgical aortic valve replacements are performed every year for severe aortic stenosis.1,2 The associated in-hospital death rate is 8.8% in patients over age 65 years, and as high as 13% in low-volume centers.1,5

The steady increase in the number of patients requiring aortic valve replacement, the high surgical risk in patients with multiple comorbidities, the reluctance of some patients to undergo the trauma and pain associated with open heart surgery via sternotomy, and the fact that percutaneous procedures are less traumatic and offer faster recovery and fewer hospital days—all these are forces that have been driving the development of percutaneous techniques for the treatment of aortic stenosis.6–11 In addition, a recent study12 showed that 33% of patients over age 75 were deemed too high-risk for open heart surgery and thus were left untreated.12

The evolution of percutaneous aortic valve replacement

The idea of percutaneous treatment of aortic stenosis was first put into clinical practice in 1985, when Cribier performed an aortic balloon valvuloplasty.6 This was followed in 200013 by the first successful implantation of a catheter-based stent valve in a human, and in 2002 by the first successful percutaneous aortic valve replacement in a human.13–15 In the following sections, we discuss the percutaneous approaches in current use for the treatment of degenerative aortic stenosis.

AORTIC BALLOON VALVULOPLASTY

Percutaneous aortic balloon valvuloplasty, partial dilation of the stenotic aortic valve with a balloon inserted via a catheter,1,16–19 improves symptoms but has failed to show a sustained benefit on rates of mortality or morbidity.1,16–18 The restenosis rate is high, and symptoms recur in most patients within months to a year.1,16–18 Procedural complication rates are about 10%, and complication rates at the catheter access site are even higher.1,16–18 The 30-day death rate in the National Heart, Lung, and Blood Institute’s Balloon Valvuloplasty Registry, which included more than 600 patients, was 14%.18 In a retrospective study of 212 patients who underwent single or repeat percutaneous aortic balloon valvuloplasty,20 the 1-year mortality rate was 36% for the entire cohort, with a median survival of 3 years. Patients who underwent a repeat procedure (33%) had 1-year mortality rate of 42%, compared with 16% in patients who did not undergo a repeat procedure.20

Percutaneous aortic balloon valvuloplasty serves best as palliative therapy in severely symptomatic patients, and as a bridge to surgery in hemodynamically unstable adult patients.21,22 Percutaneous aortic balloon valvuloplasty is not an option in patients who are good candidates for surgical valve replacement.1

PERCUTANEOUS AORTIC VALVE REPLACEMENT: THREE TECHNIQUES

Percutaneous aortic valve replacement was first reported in 1992 using a closed-chest pig model.14 Since then, three prosthetic valves have been used in human clinical trials for this procedure: the Cribier-Edwards valve (Edwards Lifesciences Corporation, Irvine, CA), the CoreValve (CoreValve Inc, Irvine, CA), and the Edwards SAPIEN valve (Edwards Lifesciences Corporation, Irvine, CA) (Table 1). These have been implanted in humans using three different percutaneous techniques (Figure 1).

The antegrade technique

Figure 1.
In the antegrade technique, an approach that has been studied but is no longer being used, access to the femoral vein is gained and the catheter with the prosthetic aortic valve is advanced, traversing the interatrial septum and the mitral valve, and is positioned within the diseased aortic valve.15,23,24 The main advantage of this approach is that the femoral vein can accommodate the large catheter sheath and that subsequent management of the access site is by manual compression only.15,23,24 The main disadvantages are the potential for mitral valve injury and severe mitral regurgitation, and the technical challenge of delivering the aortic valve prosthesis to the correct aortic position.15,23,25–27

The retrograde technique

In the retrograde (ie, transfemoral) technique, access to the femoral artery is gained and the catheter with the prosthetic aortic valve is advanced to the stenotic aortic valve.8,11,26,28–30 This approach is faster and technically easier than the antegrade approach, but it can be associated with injury to the aortofemoral vessels and with failure of the prosthesis to cross the aortic arch or the stenotic aortic valve.11,23,30

 

 

The transapical technique

In the transapical technique, the valve delivery system is inserted via a small incision made between the ribs. The apex of the left ventricle is punctured with a needle, and the prosthetic valve is positioned within the stenotic aortic valve.27,31–33 The main advantage of this approach is that it allows more direct access to the aortic valve and eliminates the need for a large peripheral vascular access site in patients with peripheral vascular disease, small tortuous vasculature, or a history of major vascular complications or vascular repairs.31–33 Potential disadvantages are related to the left ventricular apical puncture and include adverse ventricular remodeling, left ventricular aneurysm or pseudoaneurysm, pericardial complications, pneumothorax, malignant ventricular arrhythmias, coronary artery injury, and the need for general anesthesia and chest tubes.27,31–35

Common features of the three approaches

The three percutaneous approaches have certain final steps in common.11,23,30,33 The position of final deployment of the prosthetic valve is determined by the patient’s native valvular structure and anatomy and is optimized by using fluoroscopic imaging of the native aortic valve calcification as an anatomical marker, along with guidance from supra-aortic angiography and transesophageal echocardiography.11,23,30,33 Ideally, the aortic valve prosthesis is placed at mid-position in the patient’s aortic valve, taking care to not to impinge on the coronary ostia or to impede the motion of the anterior mitral leaflet.11,23,30,33 In all three procedures, the prosthesis is then deployed by maximally inflating, rapidly deflating, and immediately withdrawing the delivery balloon. This final step is carried out during temporary high-rate right ventricular apical pacing, which produces ventricular tachycardia at 180 to 220 beats/min for up to 10 seconds.11,23,30,33 This leads to an immediate decrease in stroke volume, resulting in minimal forward flow through the aortic valve, which in turn facilitates precise positioning of the prosthetic valve.

So far, only the Cribier-Edwards valve has been deployed via all three techniques. The CoreValve has been deployed only via the retrograde technique. The Edwards SAPIEN valve has been deployed with retrograde and transapical approaches (see www.edwards.com/Products/TranscatheterValves/SapienTHV.htm and www.corevalve.com for animations depicting these techniques).

EXPERIENCE WITH THE CRIBIER-EDWARDS VALVE

The Cribier-Edwards valve has three leaflets made from equine pericardial tissue sutured inside a balloon-expandable stainless steel 14-mm stent (Table 1).11,23,33 With the use of a specially designed mechanical crimping device, the aortic valve prosthesis is mounted over a 3-cm-long balloon catheter, expandable to a diameter of 22 to 26 mm (NuMed Inc, Hopkinton, NY).11,23,30,33

After this prosthesis was tested in animal models,14,15 a trial for compassionate use in humans was begun, called the Initial Registry of Endovascular Implantation of Valves in Europe (I-REVIVE) trial. This trial was later continued as the Registry of Endovascular Critical Aortic Stenosis Treatment (RECAST) trial.23 All patients were formally evaluated by two cardio-thoracic surgeons and were deemed inappropriate for surgical aortic valve replacement.23

The success rate with the antegrade percutaneous approach was 85% (23 of 27 patients) and 57% for the retrograde approach (4 of 7 patients).11,23,30–33 Procedural limitations were migration or embolization of the prosthetic valve, failure to cross the stenotic aortic valve, and paravalvular aortic regurgitation.23 Anatomic and functional success was evidenced by improvement in aortic valve area, increase in left ventricular ejection fraction, and improved New York Heart Association functional class, all of which were sustained at up to 24 months.23

Webb et al11 reported similar results with retrograde implantation of the Cribier-Edwards valve in a cohort of 50 patients.11 The main difference between the two studies was the expected occurrence of aortofemoral complications with the retrograde approach.11,26 Procedural success increased from 76% in the first 25 patients to 96% in the second 25, and the 30-day mortality rate fell from 16% to 8%, which reflected the learning curve. Importantly, no patients needed conversion to open surgery during the first 30 days, and at a median follow-up of 359 days 35 (81%) of 43 patients who underwent successful transcatheter aortic valve replacement were still alive.11 Additionally, significant improvement was noted in left ventricular ejection fraction, mitral regurgitation, and New York Heart Association functional class, and these improvements persisted at 1 year.11

Lichtenstein et al31 and Walther et al32 successfully implanted the Cribier-Edwards valve using the transapical approach in a very high-risk elderly population with poor functional class. All patients were deemed unsuitable for standard surgical valve replacement and also for percutaneous transfemoral aortic valve implantation because of severe aorto-iliac disease. In both studies, the short-term and mid-term results were encouraging.

These experiences with the Cribier-Edwards valve showed that device- and technique-related shortcomings could be addressed. To date, more than 500 percutaneous aortic valve replacement procedures have been done with the Cribier-Edwards valve worldwide, with a greater than 95% technical success rate in the latest cohorts.36 Importantly, use of a larger (26-mm) prosthetic valve has been associated with a lower rate of prosthetic valve migration or embolization, and with a significantly lower rate of paravalvular aortic regurgitation.11,23

 

 

EXPERIENCE WITH THE COREVALVE SYSTEM

The CoreValve ReValving system is based on retrograde implantation of the CoreValve prosthesis—a self-expanding aortic valve prosthesis composed of three bovine pericardial leaflets mounted and sutured within a self-expanding 50-mm-long nitinol stent (Table 1).28–30 The inner diameter is 21 to 22 mm.28–30 This prosthesis has three distinct structural segments.28–30 The bottom portion exerts a high radial force that expands and pushes aside the calcified leaflets and avoids recoil; the central portion carries the valve, and it tapers to avoid the coronary artery ostia; and the upper portion flares to fixate and stabilize the deployed aortic valve prosthesis in the ascending aorta, thus preventing migration or embolization of the device.28–30 The main difference between the CoreValve and the Cribier-Edwards valve is that the Core-Valve is self-expanding, which theoretically permits it to conform to different aortic sizes and to anchor well in the aortic annulus.28–30 This feature allows the CoreValve to be used in patients with severe aortic insufficiency and other noncalcific aortic valvular conditions. The CoreValve has not yet been deployed via antegrade or transapical technique.

The first-generation CoreValve prosthesis was first implanted in a human recipient in 2005.29 Since then, improvements have been made, leading to the development of second- and third-generation devices. A pilot study of implantation of the first-generation CoreValve28 via the retrograde approach in elderly patients with poor functional class and severe aortic stenosis had a short-term procedural success rate of 84% (21 of 25 patients), with a significant reduction in the mean aortic valve gradient and improved functional class at 30-day follow-up.28 At 30 days, 17 (94%) of 18 patients had no or only mild aortic regurgitation.28 Procedural limitations and complications were similar to those with the Cribier-Edwards valve.

In a study of second- and third-generation devices (50 patients received a second-generation device, and 36 received a third-generation device),30 again in elderly patients with poor functional class and severe aortic stenosis, the short-term success rate of the device was 88% (76 of 86) in each group. After the procedure, the mean aortic valve gradient decreased significantly and functional class improved significantly.30 Immediate after implantation, no patient had more than moderate aortic regurgitation, and in 51 patients (66%) the aortic regurgitation remained unchanged or improved after CoreValve implantation.30 These results were maintained at 30-day follow-up.

CoreValve was approved in May 2007 for clinical use in Europe.36 Of note, CoreValve has also been used to treat severe aortic regurgitation of a degenerated bioprosthetic aortic valve in an 80-year-old man with multiple comorbidities.37

EXPERIENCE WITH THE EDWARDS SAPIEN VALVE

The Edwards SAPIEN valve is a modification of the initial Cribier-Edwards valve and is the latest percutaneous aortic valve prosthesis to enter clinical trials (Table 1). It is a trileaflet balloon-expandable stainless steel valve made from bovine pericardial tissue, available in two sizes (23 mm and 26 mm). In September 2007, it was approved for use in Europe with the RetroFlex transfemoral delivery system. The Ascendra transapical delivery system for the Edward SAPIEN valve has received approval in Europe.

The multicenter Placement of Aortic Transcatheter Valves (PARTNER) trial in North America is continuing to enroll patients, with enrollment projected to be complete by the end of 2008. The aim of this prospective randomized clinical trial is to enroll 1,040 patients in two separate treatment arms. The surgical arm of the trial is comparing the Edwards SAPIEN valve with standard surgical aortic valve replacement, with the objective of demonstrating non-inferiority. The medical management arm of the trial is comparing percutaneous valve replacement against medical therapy or balloon valvuloplasty in patients considered too high-risk for conventional surgical valve replacement.

The primary end point in both arms is death at 1 year; secondary end points focus on long-term (1-year) composite cardiovascular events, valve performance, and quality-of-life indicators. Preliminary data on the first 100 patients (74 via the transfemoral [ie, retrograde] and 26 via the transapical approach) who underwent percutaneous Edwards SAPIEN valve implantation for compassionate use showed device durability and symptom relief at up to 2 years.38 Overall procedural success was 91%, but, as with other trials, there was a steep learning curve, so that excluding the first 25 patients increased the procedural success rate to 96%.38 Aortic valve size and hemodynamics, left ventricular systolic function, mitral regurgitation, and functional class were all significantly improved. Mild aortic regurgitation was common, but none of the patients had severe aortic regurgitation. Importantly, the 15% 30-day death rate was significantly lower than the expected rate of 33%. The 6-month survival rate was 78%, but the 2-year rate was 60% in this high-risk elderly cohort.

Walther et al39 recently reported outcomes on their first 50 patients who underwent transapical implantation of the Edwards SAPIEN valve. The operators were able to implant the prosthesis in all 50 patients, but 3 required early conversion to open surgery with sternotomy. The overall survival at 30 days was 92%, but in the last 25 patients the 30-day survival rate was 96%, with a 1-year survival rate of 80%.

 

 

PUTTING THE DATA IN PERSPECTIVE

As noted in this review, a number of factors make a strong case for timely aortic valve replacement: the aging population, the increase in incidence and prevalence of aortic stenosis,1,3,4,27,40 the multiple comorbidities in older patients, and the eventually aggressive natural course of aortic stenosis.1,3,4,27,40–43 Yet current standards dictate not to proceed with standard surgical aortic valve replacement in patients who are truly asymptomatic and who have normal left ventricular systolic function,1,40 mainly because the risks of surgical valve replacement outweigh the benefits in this population.1,40 Aortic valve surgery carries a risk of early death of 15% for patients ages 80 to 84 and of 18% for patients age 85.3,9,10,12,43–45

These figures seem high when compared with death rates of 12% in recent studies of percutaneous valve replacement in similar patients.11,23,30,33 The rates become lower as the learning curve improves.11,21,23,27,30,33 Thus, as the design of aortic valve prostheses and the techniques to implant them are refined and tested for safety, the risk-benefit balance may change in favor of earlier intervention in aortic stenosis with a percutaneous approach.11,21,27,46 Some experts believe that in 10 years 10% to 30% of patients undergoing conventional valve replacement will be candidates for a percutaneous approach.

Of the techniques used to date, the retrograde approach seems most amenable to widespread acceptance, given its inherent advantage of being faster and easier.11,21,30 Limitations with the retrograde approach seen in earlier trials—challenges and complications associated with large-bore arterial vascular access, difficulty traversing the aortic arch with bulky devices, and the inability to cross the stenotic aortic valve to deploy the prosthesis even after balloon valvuloplasty11,21,30—are correctable with refinements in the devices and in technique.

New types of prosthetic aortic valves entering early human studies are improving on current devices, for example, by using collapsible, inflatable valve frames for retrievability before final deployment.

Surgical aortic valve replacement remains the gold standard treatment for patients with symptomatic aortic stenosis. And while studies of percutaneous aortic valve replacement show great promise for this less-invasive treat-men, enthusiasm about percutaneous aortic valve replacement should be tempered by an awareness of persistent limitations of this approach, such as vascular and mechanical complications and operator inexperience, which still need attention.

Stenosis of the aortic valve has a long, latent, asymptomatic phase, but when symptoms finally occur, clinical deterioration can be rapid. For patients with severe stenosis, the standard treatment has long been replacement of the aortic valve via open heart surgery. But many patients with severe stenosis are considered too high-risk for this procedure.

Until about 5 years ago, these patients had no other option but medical therapy or percutaneous aortic balloon valvuloplasty as a palliative measure or as a bridge to open heart surgery. But 5 years of experience with percutaneous techniques to implant prosthetic aortic valves show that this less-invasive approach may become a viable option for patients with severe symptomatic aortic valve stenosis.

In this review, we discuss current prosthetic valves and percutaneous techniques and their relative advantages and limitations and the potential future role of this new treatment option.

THE NEED FOR A LESS-INVASIVE APPROACH

Calcific aortic stenosis is the most common valvular heart disease, affecting 2% to 4% of adults over age 65 in the United States alone.1,2 The aging of our population and the lack of drug therapies to prevent, halt, or effectively slow aortic valve stenosis are leading to a greater burden of this condition.1,3,4 Already in the United States more than 50,000 surgical aortic valve replacements are performed every year for severe aortic stenosis.1,2 The associated in-hospital death rate is 8.8% in patients over age 65 years, and as high as 13% in low-volume centers.1,5

The steady increase in the number of patients requiring aortic valve replacement, the high surgical risk in patients with multiple comorbidities, the reluctance of some patients to undergo the trauma and pain associated with open heart surgery via sternotomy, and the fact that percutaneous procedures are less traumatic and offer faster recovery and fewer hospital days—all these are forces that have been driving the development of percutaneous techniques for the treatment of aortic stenosis.6–11 In addition, a recent study12 showed that 33% of patients over age 75 were deemed too high-risk for open heart surgery and thus were left untreated.12

The evolution of percutaneous aortic valve replacement

The idea of percutaneous treatment of aortic stenosis was first put into clinical practice in 1985, when Cribier performed an aortic balloon valvuloplasty.6 This was followed in 200013 by the first successful implantation of a catheter-based stent valve in a human, and in 2002 by the first successful percutaneous aortic valve replacement in a human.13–15 In the following sections, we discuss the percutaneous approaches in current use for the treatment of degenerative aortic stenosis.

AORTIC BALLOON VALVULOPLASTY

Percutaneous aortic balloon valvuloplasty, partial dilation of the stenotic aortic valve with a balloon inserted via a catheter,1,16–19 improves symptoms but has failed to show a sustained benefit on rates of mortality or morbidity.1,16–18 The restenosis rate is high, and symptoms recur in most patients within months to a year.1,16–18 Procedural complication rates are about 10%, and complication rates at the catheter access site are even higher.1,16–18 The 30-day death rate in the National Heart, Lung, and Blood Institute’s Balloon Valvuloplasty Registry, which included more than 600 patients, was 14%.18 In a retrospective study of 212 patients who underwent single or repeat percutaneous aortic balloon valvuloplasty,20 the 1-year mortality rate was 36% for the entire cohort, with a median survival of 3 years. Patients who underwent a repeat procedure (33%) had 1-year mortality rate of 42%, compared with 16% in patients who did not undergo a repeat procedure.20

Percutaneous aortic balloon valvuloplasty serves best as palliative therapy in severely symptomatic patients, and as a bridge to surgery in hemodynamically unstable adult patients.21,22 Percutaneous aortic balloon valvuloplasty is not an option in patients who are good candidates for surgical valve replacement.1

PERCUTANEOUS AORTIC VALVE REPLACEMENT: THREE TECHNIQUES

Percutaneous aortic valve replacement was first reported in 1992 using a closed-chest pig model.14 Since then, three prosthetic valves have been used in human clinical trials for this procedure: the Cribier-Edwards valve (Edwards Lifesciences Corporation, Irvine, CA), the CoreValve (CoreValve Inc, Irvine, CA), and the Edwards SAPIEN valve (Edwards Lifesciences Corporation, Irvine, CA) (Table 1). These have been implanted in humans using three different percutaneous techniques (Figure 1).

The antegrade technique

Figure 1.
In the antegrade technique, an approach that has been studied but is no longer being used, access to the femoral vein is gained and the catheter with the prosthetic aortic valve is advanced, traversing the interatrial septum and the mitral valve, and is positioned within the diseased aortic valve.15,23,24 The main advantage of this approach is that the femoral vein can accommodate the large catheter sheath and that subsequent management of the access site is by manual compression only.15,23,24 The main disadvantages are the potential for mitral valve injury and severe mitral regurgitation, and the technical challenge of delivering the aortic valve prosthesis to the correct aortic position.15,23,25–27

The retrograde technique

In the retrograde (ie, transfemoral) technique, access to the femoral artery is gained and the catheter with the prosthetic aortic valve is advanced to the stenotic aortic valve.8,11,26,28–30 This approach is faster and technically easier than the antegrade approach, but it can be associated with injury to the aortofemoral vessels and with failure of the prosthesis to cross the aortic arch or the stenotic aortic valve.11,23,30

 

 

The transapical technique

In the transapical technique, the valve delivery system is inserted via a small incision made between the ribs. The apex of the left ventricle is punctured with a needle, and the prosthetic valve is positioned within the stenotic aortic valve.27,31–33 The main advantage of this approach is that it allows more direct access to the aortic valve and eliminates the need for a large peripheral vascular access site in patients with peripheral vascular disease, small tortuous vasculature, or a history of major vascular complications or vascular repairs.31–33 Potential disadvantages are related to the left ventricular apical puncture and include adverse ventricular remodeling, left ventricular aneurysm or pseudoaneurysm, pericardial complications, pneumothorax, malignant ventricular arrhythmias, coronary artery injury, and the need for general anesthesia and chest tubes.27,31–35

Common features of the three approaches

The three percutaneous approaches have certain final steps in common.11,23,30,33 The position of final deployment of the prosthetic valve is determined by the patient’s native valvular structure and anatomy and is optimized by using fluoroscopic imaging of the native aortic valve calcification as an anatomical marker, along with guidance from supra-aortic angiography and transesophageal echocardiography.11,23,30,33 Ideally, the aortic valve prosthesis is placed at mid-position in the patient’s aortic valve, taking care to not to impinge on the coronary ostia or to impede the motion of the anterior mitral leaflet.11,23,30,33 In all three procedures, the prosthesis is then deployed by maximally inflating, rapidly deflating, and immediately withdrawing the delivery balloon. This final step is carried out during temporary high-rate right ventricular apical pacing, which produces ventricular tachycardia at 180 to 220 beats/min for up to 10 seconds.11,23,30,33 This leads to an immediate decrease in stroke volume, resulting in minimal forward flow through the aortic valve, which in turn facilitates precise positioning of the prosthetic valve.

So far, only the Cribier-Edwards valve has been deployed via all three techniques. The CoreValve has been deployed only via the retrograde technique. The Edwards SAPIEN valve has been deployed with retrograde and transapical approaches (see www.edwards.com/Products/TranscatheterValves/SapienTHV.htm and www.corevalve.com for animations depicting these techniques).

EXPERIENCE WITH THE CRIBIER-EDWARDS VALVE

The Cribier-Edwards valve has three leaflets made from equine pericardial tissue sutured inside a balloon-expandable stainless steel 14-mm stent (Table 1).11,23,33 With the use of a specially designed mechanical crimping device, the aortic valve prosthesis is mounted over a 3-cm-long balloon catheter, expandable to a diameter of 22 to 26 mm (NuMed Inc, Hopkinton, NY).11,23,30,33

After this prosthesis was tested in animal models,14,15 a trial for compassionate use in humans was begun, called the Initial Registry of Endovascular Implantation of Valves in Europe (I-REVIVE) trial. This trial was later continued as the Registry of Endovascular Critical Aortic Stenosis Treatment (RECAST) trial.23 All patients were formally evaluated by two cardio-thoracic surgeons and were deemed inappropriate for surgical aortic valve replacement.23

The success rate with the antegrade percutaneous approach was 85% (23 of 27 patients) and 57% for the retrograde approach (4 of 7 patients).11,23,30–33 Procedural limitations were migration or embolization of the prosthetic valve, failure to cross the stenotic aortic valve, and paravalvular aortic regurgitation.23 Anatomic and functional success was evidenced by improvement in aortic valve area, increase in left ventricular ejection fraction, and improved New York Heart Association functional class, all of which were sustained at up to 24 months.23

Webb et al11 reported similar results with retrograde implantation of the Cribier-Edwards valve in a cohort of 50 patients.11 The main difference between the two studies was the expected occurrence of aortofemoral complications with the retrograde approach.11,26 Procedural success increased from 76% in the first 25 patients to 96% in the second 25, and the 30-day mortality rate fell from 16% to 8%, which reflected the learning curve. Importantly, no patients needed conversion to open surgery during the first 30 days, and at a median follow-up of 359 days 35 (81%) of 43 patients who underwent successful transcatheter aortic valve replacement were still alive.11 Additionally, significant improvement was noted in left ventricular ejection fraction, mitral regurgitation, and New York Heart Association functional class, and these improvements persisted at 1 year.11

Lichtenstein et al31 and Walther et al32 successfully implanted the Cribier-Edwards valve using the transapical approach in a very high-risk elderly population with poor functional class. All patients were deemed unsuitable for standard surgical valve replacement and also for percutaneous transfemoral aortic valve implantation because of severe aorto-iliac disease. In both studies, the short-term and mid-term results were encouraging.

These experiences with the Cribier-Edwards valve showed that device- and technique-related shortcomings could be addressed. To date, more than 500 percutaneous aortic valve replacement procedures have been done with the Cribier-Edwards valve worldwide, with a greater than 95% technical success rate in the latest cohorts.36 Importantly, use of a larger (26-mm) prosthetic valve has been associated with a lower rate of prosthetic valve migration or embolization, and with a significantly lower rate of paravalvular aortic regurgitation.11,23

 

 

EXPERIENCE WITH THE COREVALVE SYSTEM

The CoreValve ReValving system is based on retrograde implantation of the CoreValve prosthesis—a self-expanding aortic valve prosthesis composed of three bovine pericardial leaflets mounted and sutured within a self-expanding 50-mm-long nitinol stent (Table 1).28–30 The inner diameter is 21 to 22 mm.28–30 This prosthesis has three distinct structural segments.28–30 The bottom portion exerts a high radial force that expands and pushes aside the calcified leaflets and avoids recoil; the central portion carries the valve, and it tapers to avoid the coronary artery ostia; and the upper portion flares to fixate and stabilize the deployed aortic valve prosthesis in the ascending aorta, thus preventing migration or embolization of the device.28–30 The main difference between the CoreValve and the Cribier-Edwards valve is that the Core-Valve is self-expanding, which theoretically permits it to conform to different aortic sizes and to anchor well in the aortic annulus.28–30 This feature allows the CoreValve to be used in patients with severe aortic insufficiency and other noncalcific aortic valvular conditions. The CoreValve has not yet been deployed via antegrade or transapical technique.

The first-generation CoreValve prosthesis was first implanted in a human recipient in 2005.29 Since then, improvements have been made, leading to the development of second- and third-generation devices. A pilot study of implantation of the first-generation CoreValve28 via the retrograde approach in elderly patients with poor functional class and severe aortic stenosis had a short-term procedural success rate of 84% (21 of 25 patients), with a significant reduction in the mean aortic valve gradient and improved functional class at 30-day follow-up.28 At 30 days, 17 (94%) of 18 patients had no or only mild aortic regurgitation.28 Procedural limitations and complications were similar to those with the Cribier-Edwards valve.

In a study of second- and third-generation devices (50 patients received a second-generation device, and 36 received a third-generation device),30 again in elderly patients with poor functional class and severe aortic stenosis, the short-term success rate of the device was 88% (76 of 86) in each group. After the procedure, the mean aortic valve gradient decreased significantly and functional class improved significantly.30 Immediate after implantation, no patient had more than moderate aortic regurgitation, and in 51 patients (66%) the aortic regurgitation remained unchanged or improved after CoreValve implantation.30 These results were maintained at 30-day follow-up.

CoreValve was approved in May 2007 for clinical use in Europe.36 Of note, CoreValve has also been used to treat severe aortic regurgitation of a degenerated bioprosthetic aortic valve in an 80-year-old man with multiple comorbidities.37

EXPERIENCE WITH THE EDWARDS SAPIEN VALVE

The Edwards SAPIEN valve is a modification of the initial Cribier-Edwards valve and is the latest percutaneous aortic valve prosthesis to enter clinical trials (Table 1). It is a trileaflet balloon-expandable stainless steel valve made from bovine pericardial tissue, available in two sizes (23 mm and 26 mm). In September 2007, it was approved for use in Europe with the RetroFlex transfemoral delivery system. The Ascendra transapical delivery system for the Edward SAPIEN valve has received approval in Europe.

The multicenter Placement of Aortic Transcatheter Valves (PARTNER) trial in North America is continuing to enroll patients, with enrollment projected to be complete by the end of 2008. The aim of this prospective randomized clinical trial is to enroll 1,040 patients in two separate treatment arms. The surgical arm of the trial is comparing the Edwards SAPIEN valve with standard surgical aortic valve replacement, with the objective of demonstrating non-inferiority. The medical management arm of the trial is comparing percutaneous valve replacement against medical therapy or balloon valvuloplasty in patients considered too high-risk for conventional surgical valve replacement.

The primary end point in both arms is death at 1 year; secondary end points focus on long-term (1-year) composite cardiovascular events, valve performance, and quality-of-life indicators. Preliminary data on the first 100 patients (74 via the transfemoral [ie, retrograde] and 26 via the transapical approach) who underwent percutaneous Edwards SAPIEN valve implantation for compassionate use showed device durability and symptom relief at up to 2 years.38 Overall procedural success was 91%, but, as with other trials, there was a steep learning curve, so that excluding the first 25 patients increased the procedural success rate to 96%.38 Aortic valve size and hemodynamics, left ventricular systolic function, mitral regurgitation, and functional class were all significantly improved. Mild aortic regurgitation was common, but none of the patients had severe aortic regurgitation. Importantly, the 15% 30-day death rate was significantly lower than the expected rate of 33%. The 6-month survival rate was 78%, but the 2-year rate was 60% in this high-risk elderly cohort.

Walther et al39 recently reported outcomes on their first 50 patients who underwent transapical implantation of the Edwards SAPIEN valve. The operators were able to implant the prosthesis in all 50 patients, but 3 required early conversion to open surgery with sternotomy. The overall survival at 30 days was 92%, but in the last 25 patients the 30-day survival rate was 96%, with a 1-year survival rate of 80%.

 

 

PUTTING THE DATA IN PERSPECTIVE

As noted in this review, a number of factors make a strong case for timely aortic valve replacement: the aging population, the increase in incidence and prevalence of aortic stenosis,1,3,4,27,40 the multiple comorbidities in older patients, and the eventually aggressive natural course of aortic stenosis.1,3,4,27,40–43 Yet current standards dictate not to proceed with standard surgical aortic valve replacement in patients who are truly asymptomatic and who have normal left ventricular systolic function,1,40 mainly because the risks of surgical valve replacement outweigh the benefits in this population.1,40 Aortic valve surgery carries a risk of early death of 15% for patients ages 80 to 84 and of 18% for patients age 85.3,9,10,12,43–45

These figures seem high when compared with death rates of 12% in recent studies of percutaneous valve replacement in similar patients.11,23,30,33 The rates become lower as the learning curve improves.11,21,23,27,30,33 Thus, as the design of aortic valve prostheses and the techniques to implant them are refined and tested for safety, the risk-benefit balance may change in favor of earlier intervention in aortic stenosis with a percutaneous approach.11,21,27,46 Some experts believe that in 10 years 10% to 30% of patients undergoing conventional valve replacement will be candidates for a percutaneous approach.

Of the techniques used to date, the retrograde approach seems most amenable to widespread acceptance, given its inherent advantage of being faster and easier.11,21,30 Limitations with the retrograde approach seen in earlier trials—challenges and complications associated with large-bore arterial vascular access, difficulty traversing the aortic arch with bulky devices, and the inability to cross the stenotic aortic valve to deploy the prosthesis even after balloon valvuloplasty11,21,30—are correctable with refinements in the devices and in technique.

New types of prosthetic aortic valves entering early human studies are improving on current devices, for example, by using collapsible, inflatable valve frames for retrievability before final deployment.

Surgical aortic valve replacement remains the gold standard treatment for patients with symptomatic aortic stenosis. And while studies of percutaneous aortic valve replacement show great promise for this less-invasive treat-men, enthusiasm about percutaneous aortic valve replacement should be tempered by an awareness of persistent limitations of this approach, such as vascular and mechanical complications and operator inexperience, which still need attention.

References
  1. Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation 2006; 114:e84–231.
  2. Freeman RV, Otto CM. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation 2005; 111:3316–3326.
  3. Iung B, Baron G, Butchart EG, et al. A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. Eur Heart J 2003; 24:1231–1243.
  4. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: a population-based study. Lancet 2006; 368:1005–1011.
  5. Goodney PP, O'Connor GT, Wennberg DE, Birkmeyer JD. Do hospitals with low mortality rates in coronary artery bypass also perform well in valve replacement? Ann Thorac Surg 2003; 76:1131–1137.
  6. Cribier A, Savin T, Saoudi N, Rocha P, Berland J, Letac B. Percutaneous transluminal valvuloplasty of acquired aortic stenosis in elderly patients: an alternative to valve replacement? Lancet 1986; 1:63–67.
  7. Vahanian A, Palacios IF. Percutaneous approaches to valvular disease. Circulation 2004; 109:1572–1579.
  8. Webb JG, Munt B, Makkar RR, Naqvi TZ, Dang N. Percutaneous stent-mounted valve for treatment of aortic or pulmonary valve disease. Catheter Cardiovasc Interv 2004; 63:89–93.
  9. Alexander KP, Anstrom KJ, Muhlbaier LH, et al. Outcomes of cardiac surgery in patients =80 years: results from the National Cardiovascular Network. J Am Coll Cardiol 2000; 35:731–738.
  10. Mittermair RP, Muller LC. Quality of life after cardiac surgery in the elderly. J Cardiovasc Surg (Torino) 2002; 43:43–47.
  11. Webb JG, Pasupati S, Humphries K, et al. Percutaneous transarterial aortic valve replacement in selected high-risk patients with aortic stenosis. Circulation 2007; 116:755–763.
  12. Iung B, Cachier A, Baron G, et al. Decision-making in elderly patients with severe aortic stenosis: why are so many denied surgery? Eur Heart J 2005; 26:2714–2720.
  13. Bonhoeffer P, Boudjemline Y, Saliba Z, et al. Percutaneous replacement of pulmonary valve in a right-ventricle to pulmonary-artery prosthetic conduit with valve dysfunction. Lancet 2000; 356:1403–1405.
  14. Andersen HR, Knudsen LL, Hasenkam JM. Transluminal implantation of artificial heart valves. Description of a new expandable aortic valve and initial results with implantation by catheter technique in closed chest pigs. Eur Heart J 1992; 13:704–708.
  15. Cribier A, Eltchaninoff H, Bash A, et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description. Circulation 2002; 106:3006–3008.
  16. Otto CM, Mickel MC, Kennedy JW, et al. Three-year outcome after balloon aortic valvuloplasty. Insights into prognosis of valvular aortic stenosis. Circulation 1994; 89:642–650.
  17. Safian RD, Berman AD, Diver DJ, et al. Balloon aortic valvuloplasty in 170 consecutive patients. N Engl J Med 1988; 319:125–130.
  18. Percutaneous balloon aortic valvuloplasty. Acute and 30-day follow-up results in 674 patients from the NHLBI Balloon Valvuloplasty Registry. Circulation 1991; 84:2383–2397.
  19. Safian RD, Mandell VS, Thurer RE, et al. Postmortem and intraoperative balloon valvuloplasty of calcific aortic stenosis in elderly patients: mechanisms of successful dilation. J Am Coll Cardiol 1987; 9:655–660.
  20. Agarwal A, Kini AS, Attanti S, et al. Results of repeat balloon valvuloplasty for treatment of aortic stenosis in patients aged 59 to 104 years. Am J Cardiol 2005; 95:43–47.
  21. Kapadia SR, Wazni OM, Tan WA, et al. Aortic valvuloplasty in 1990's: experience from a single center in United States. Circulation 1999; 100 18 suppl 1:1–448.
  22. Lieberman EB, Bashore TM, Hermiller JB, et al. Balloon aortic valvuloplasty in adults: failure of procedure to improve long-term survival. J Am Coll Cardiol 1995; 26:1522–1528.
  23. Cribier A, Eltchaninoff H, Tron C, et al. Treatment of calcific aortic stenosis with the percutaneous heart valve: mid-term follow-up from the initial feasibility studies: the French experience. J Am Coll Cardiol 2006; 47:1214–1223.
  24. Cribier A, Eltchaninoff H, Tron C, et al. Early experience with percutaneous transcatheter implantation of heart valve prosthesis for the treatment of end-stage inoperable patients with calcific aortic stenosis. J Am Coll Cardiol 2004; 43:698–703.
  25. Rajagopal V, Kapadia SR, Tuzcu EM. Advances in the percutaneous treatment of aortic and mitral valve disease. Minerva Cardioangiol 2007; 55:83–94.
  26. Webb JG, Chandavimol M, Thompson CR, et al. Percutaneous aortic valve implantation retrograde from the femoral artery. Circulation 2006; 113:842–850.
  27. Salemi A. Percutaneous valve interventions. Curr Opin Anaesthesiol 2007; 20:70–74.
  28. Grube E, Laborde JC, Gerckens U, et al. Percutaneous implantation of the CoreValve self-expanding valve prosthesis in high-risk patients with aortic valve disease: the Siegburg first-in-man study. Circulation 2006; 114:1616–1624.
  29. Grube E, Laborde JC, Zickmann B, et al. First report on a human percutaneous transluminal implantation of a self-expanding valve prosthesis for interventional treatment of aortic valve stenosis. Catheter Cardiovasc Interv 2005; 66:465–469.
  30. Grube E, Schuler G, Buellesfeld L, et al. Percutaneous aortic valve replacement for severe aortic stenosis in high-risk patients using the second- and current third-generation self-expanding CoreValve prosthesis: device success and 30-day clinical outcome. J Am Coll Cardiol 2007; 50:69–76.
  31. Lichtenstein SV, Cheung A, Ye J, et al. Transapical transcatheter aortic valve implantation in humans: initial clinical experience. Circulation 2006; 114:591–596.
  32. Walther T, Falk V, Borger MA, et al. Minimally invasive transapical beating heart aortic valve implantation—proof of concept. Eur J Cardiothorac Surg 2007; 31:9–15.
  33. Ye J, Cheung A, Lichtenstein SV, et al. Six-month outcome of transapical transcatheter aortic valve implantation in the initial seven patients. Eur J Cardiothorac Surg 2007; 31:16–21.
  34. Turgut T, Deeb M, Moscucci M. Left ventricular apical puncture: a procedure surviving well into the new millennium. Catheter Cardiovasc Interv 2000; 49:68–73.
  35. Zuguchi M, Shindoh C, Chida K, et al. Safety and clinical benefits of transsubxiphoidal left ventricular puncture. Catheter Cardiovasc Interv 2002; 55:58–65.
  36. Sinha AK, Kini AS, Sharma SK. Percutaneous valve replacement: a paradigm shift. Curr Opin Cardiol 2007; 22:471–477.
  37. Wenaweser P, Buellesfeld L, Gerckens U, Grube E. Percutaneous aortic valve replacement for severe aortic regurgitation in degenerated bioprosthesis: the first valve in valve procedure using the CoreValve ReValving system. Catheter Cardiovasc Interv 2007; 70:760–764.
  38. Pasupati S, Humphries K, AlAli A, et al. Balloon expandable aortic valve (BEAV) implantation. The first 100 Canadian patients. Circulation 2007; 116 suppl:357.
  39. Walther T, Falk V, Kempfert J, et al. Transapical minimally invasive aortic valve implantation; the initial 50 patients. Eur J Cardiothorac Surg 2008; 33:983–988. Epub 2008 February 21.
  40. Carabello BA. Clinical practice. Aortic stenosis. N Engl J Med 2002; 346:677–682.
  41. Pellikka PA, Nishimura RA, Bailey KR, Tajik AJ. The natural history of adults with asymptomatic, hemodynamically significant aortic stenosis. J Am Coll Cardiol 1990; 15:1012–1017.
  42. Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38:61–67.
  43. Kvidal P, Bergstrom R, Horte LG, Stahle E. Observed and relative survival after aortic valve replacement. J Am Coll Cardiol 2000; 35:747–756.
  44. Society of Thoracic Surgeons National Cardiac Surgery Database. Available at www.sts.org/documents/pdf/Spring2005STS-ExecutiveSummary.pdf. Accessed 9/11/2008.
  45. Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. N Engl J Med 2002; 346:1128–1137.
  46. Wenger NK, Weber MA, Scheidt S. Valvular heart disease at elderly age: new vistas. Am J Geriatr Cardiol 2006; 15:273–274.
References
  1. Bonow RO, Carabello BA, Kanu C, et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): developed in collaboration with the Society of Cardiovascular Anesthesiologists: endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. Circulation 2006; 114:e84–231.
  2. Freeman RV, Otto CM. Spectrum of calcific aortic valve disease: pathogenesis, disease progression, and treatment strategies. Circulation 2005; 111:3316–3326.
  3. Iung B, Baron G, Butchart EG, et al. A prospective survey of patients with valvular heart disease in Europe: The Euro Heart Survey on Valvular Heart Disease. Eur Heart J 2003; 24:1231–1243.
  4. Nkomo VT, Gardin JM, Skelton TN, Gottdiener JS, Scott CG, Enriquez-Sarano M. Burden of valvular heart diseases: a population-based study. Lancet 2006; 368:1005–1011.
  5. Goodney PP, O'Connor GT, Wennberg DE, Birkmeyer JD. Do hospitals with low mortality rates in coronary artery bypass also perform well in valve replacement? Ann Thorac Surg 2003; 76:1131–1137.
  6. Cribier A, Savin T, Saoudi N, Rocha P, Berland J, Letac B. Percutaneous transluminal valvuloplasty of acquired aortic stenosis in elderly patients: an alternative to valve replacement? Lancet 1986; 1:63–67.
  7. Vahanian A, Palacios IF. Percutaneous approaches to valvular disease. Circulation 2004; 109:1572–1579.
  8. Webb JG, Munt B, Makkar RR, Naqvi TZ, Dang N. Percutaneous stent-mounted valve for treatment of aortic or pulmonary valve disease. Catheter Cardiovasc Interv 2004; 63:89–93.
  9. Alexander KP, Anstrom KJ, Muhlbaier LH, et al. Outcomes of cardiac surgery in patients =80 years: results from the National Cardiovascular Network. J Am Coll Cardiol 2000; 35:731–738.
  10. Mittermair RP, Muller LC. Quality of life after cardiac surgery in the elderly. J Cardiovasc Surg (Torino) 2002; 43:43–47.
  11. Webb JG, Pasupati S, Humphries K, et al. Percutaneous transarterial aortic valve replacement in selected high-risk patients with aortic stenosis. Circulation 2007; 116:755–763.
  12. Iung B, Cachier A, Baron G, et al. Decision-making in elderly patients with severe aortic stenosis: why are so many denied surgery? Eur Heart J 2005; 26:2714–2720.
  13. Bonhoeffer P, Boudjemline Y, Saliba Z, et al. Percutaneous replacement of pulmonary valve in a right-ventricle to pulmonary-artery prosthetic conduit with valve dysfunction. Lancet 2000; 356:1403–1405.
  14. Andersen HR, Knudsen LL, Hasenkam JM. Transluminal implantation of artificial heart valves. Description of a new expandable aortic valve and initial results with implantation by catheter technique in closed chest pigs. Eur Heart J 1992; 13:704–708.
  15. Cribier A, Eltchaninoff H, Bash A, et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description. Circulation 2002; 106:3006–3008.
  16. Otto CM, Mickel MC, Kennedy JW, et al. Three-year outcome after balloon aortic valvuloplasty. Insights into prognosis of valvular aortic stenosis. Circulation 1994; 89:642–650.
  17. Safian RD, Berman AD, Diver DJ, et al. Balloon aortic valvuloplasty in 170 consecutive patients. N Engl J Med 1988; 319:125–130.
  18. Percutaneous balloon aortic valvuloplasty. Acute and 30-day follow-up results in 674 patients from the NHLBI Balloon Valvuloplasty Registry. Circulation 1991; 84:2383–2397.
  19. Safian RD, Mandell VS, Thurer RE, et al. Postmortem and intraoperative balloon valvuloplasty of calcific aortic stenosis in elderly patients: mechanisms of successful dilation. J Am Coll Cardiol 1987; 9:655–660.
  20. Agarwal A, Kini AS, Attanti S, et al. Results of repeat balloon valvuloplasty for treatment of aortic stenosis in patients aged 59 to 104 years. Am J Cardiol 2005; 95:43–47.
  21. Kapadia SR, Wazni OM, Tan WA, et al. Aortic valvuloplasty in 1990's: experience from a single center in United States. Circulation 1999; 100 18 suppl 1:1–448.
  22. Lieberman EB, Bashore TM, Hermiller JB, et al. Balloon aortic valvuloplasty in adults: failure of procedure to improve long-term survival. J Am Coll Cardiol 1995; 26:1522–1528.
  23. Cribier A, Eltchaninoff H, Tron C, et al. Treatment of calcific aortic stenosis with the percutaneous heart valve: mid-term follow-up from the initial feasibility studies: the French experience. J Am Coll Cardiol 2006; 47:1214–1223.
  24. Cribier A, Eltchaninoff H, Tron C, et al. Early experience with percutaneous transcatheter implantation of heart valve prosthesis for the treatment of end-stage inoperable patients with calcific aortic stenosis. J Am Coll Cardiol 2004; 43:698–703.
  25. Rajagopal V, Kapadia SR, Tuzcu EM. Advances in the percutaneous treatment of aortic and mitral valve disease. Minerva Cardioangiol 2007; 55:83–94.
  26. Webb JG, Chandavimol M, Thompson CR, et al. Percutaneous aortic valve implantation retrograde from the femoral artery. Circulation 2006; 113:842–850.
  27. Salemi A. Percutaneous valve interventions. Curr Opin Anaesthesiol 2007; 20:70–74.
  28. Grube E, Laborde JC, Gerckens U, et al. Percutaneous implantation of the CoreValve self-expanding valve prosthesis in high-risk patients with aortic valve disease: the Siegburg first-in-man study. Circulation 2006; 114:1616–1624.
  29. Grube E, Laborde JC, Zickmann B, et al. First report on a human percutaneous transluminal implantation of a self-expanding valve prosthesis for interventional treatment of aortic valve stenosis. Catheter Cardiovasc Interv 2005; 66:465–469.
  30. Grube E, Schuler G, Buellesfeld L, et al. Percutaneous aortic valve replacement for severe aortic stenosis in high-risk patients using the second- and current third-generation self-expanding CoreValve prosthesis: device success and 30-day clinical outcome. J Am Coll Cardiol 2007; 50:69–76.
  31. Lichtenstein SV, Cheung A, Ye J, et al. Transapical transcatheter aortic valve implantation in humans: initial clinical experience. Circulation 2006; 114:591–596.
  32. Walther T, Falk V, Borger MA, et al. Minimally invasive transapical beating heart aortic valve implantation—proof of concept. Eur J Cardiothorac Surg 2007; 31:9–15.
  33. Ye J, Cheung A, Lichtenstein SV, et al. Six-month outcome of transapical transcatheter aortic valve implantation in the initial seven patients. Eur J Cardiothorac Surg 2007; 31:16–21.
  34. Turgut T, Deeb M, Moscucci M. Left ventricular apical puncture: a procedure surviving well into the new millennium. Catheter Cardiovasc Interv 2000; 49:68–73.
  35. Zuguchi M, Shindoh C, Chida K, et al. Safety and clinical benefits of transsubxiphoidal left ventricular puncture. Catheter Cardiovasc Interv 2002; 55:58–65.
  36. Sinha AK, Kini AS, Sharma SK. Percutaneous valve replacement: a paradigm shift. Curr Opin Cardiol 2007; 22:471–477.
  37. Wenaweser P, Buellesfeld L, Gerckens U, Grube E. Percutaneous aortic valve replacement for severe aortic regurgitation in degenerated bioprosthesis: the first valve in valve procedure using the CoreValve ReValving system. Catheter Cardiovasc Interv 2007; 70:760–764.
  38. Pasupati S, Humphries K, AlAli A, et al. Balloon expandable aortic valve (BEAV) implantation. The first 100 Canadian patients. Circulation 2007; 116 suppl:357.
  39. Walther T, Falk V, Kempfert J, et al. Transapical minimally invasive aortic valve implantation; the initial 50 patients. Eur J Cardiothorac Surg 2008; 33:983–988. Epub 2008 February 21.
  40. Carabello BA. Clinical practice. Aortic stenosis. N Engl J Med 2002; 346:677–682.
  41. Pellikka PA, Nishimura RA, Bailey KR, Tajik AJ. The natural history of adults with asymptomatic, hemodynamically significant aortic stenosis. J Am Coll Cardiol 1990; 15:1012–1017.
  42. Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38:61–67.
  43. Kvidal P, Bergstrom R, Horte LG, Stahle E. Observed and relative survival after aortic valve replacement. J Am Coll Cardiol 2000; 35:747–756.
  44. Society of Thoracic Surgeons National Cardiac Surgery Database. Available at www.sts.org/documents/pdf/Spring2005STS-ExecutiveSummary.pdf. Accessed 9/11/2008.
  45. Birkmeyer JD, Siewers AE, Finlayson EV, et al. Hospital volume and surgical mortality in the United States. N Engl J Med 2002; 346:1128–1137.
  46. Wenger NK, Weber MA, Scheidt S. Valvular heart disease at elderly age: new vistas. Am J Geriatr Cardiol 2006; 15:273–274.
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Cleveland Clinic Journal of Medicine - 75(11)
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Cleveland Clinic Journal of Medicine - 75(11)
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Percutaneous treatment of aortic valve stenosis
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Percutaneous treatment of aortic valve stenosis
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KEY POINTS

  • Aortic stenosis is the most common valvular condition, affecting 3% of the general population; its incidence and prevalence are increasing as the population ages.
  • Many patients with severe aortic valve stenosis are considered too high-risk for standard surgical valve replacement but may be candidates for percutaneous valve replacement.
  • Of the approaches now undergoing refinement, the most promising is retrograde (ie, femoral arterial) placement of the Edwards SAPIEN valve or the CoreValve.
  • The technology is still evolving, and the learning curve is substantial, yet cautious enthusiasm about percutaneous aortic valve replacement is justified.
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Evaluation and management of pituitary incidentalomas

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Evaluation and management of pituitary incidentalomas
Author(s)
Dina Serhal, MD
Robert J. Weil, MD
Amir H. Hamrahian, MD

A 39-year-old woman is referred for evaluation of a pituitary mass, which was found on magnetic resonance imaging (MRI) performed because of persistent vertigo. The mass, measuring 1.1 by 1.0 cm, arises from the right portion of the sella turcica and does not reach the optic chiasm (Figure 1). It appears hypointense on MRI and enhances after contrast is given, suggesting it is a pituitary adenoma.

Figure 1. Coronal (A) and sagittal (B) precontrast magnetic resonance images of a 1.1 x 1.0-cm sellar mass (solid arrows) suggestive of a pituitary macroadenoma. The pituitary gland and pituitary stalk are pushed to the patient’s left by the mass (dotted arrows).
The patient has a history of migraine headaches, which have improved in the last few years. She is not taking any medications, and she says she has had no fatigue, visual problems, weight change, or breast discharge.

On physical examination she does not have any stigmata of Cushing syndrome or of acromegaly. Her blood pressure is 116/72 mm Hg and her heart rate is regular at 68 beats per minute. Her visual fields are normal as assessed by confrontation, and she has no galactorrhea.

How should this patient be evaluated?

BY DEFINITION, INCIDENTALOMAS ARE UNSUSPECTED

Pituitary “incidentalomas” are, by definition, masses that are discovered by computed tomography (CT) or MRI performed to evaluate unrelated disorders (such as head trauma), for cancer staging, or because of nonspecific symptoms such as dizziness and headache. In some series, headache was the most common reason for imaging studies that led to the discovery of pituitary incidentalomas.1

With more patients undergoing computed tomography (CT) and MRI, more incidentalomas are being discovered. Incidentally discovered pituitary adenomas accounted for 12% of the pituitary tumors in a series of 353 consecutive patients with a presumptive diagnosis of pituitary tumor at one institution over a 14-year period.2 Pituitary masses other than adenomas are discussed later in this paper.

Microadenomas are common, macroadenomas less so

Autopsy studies have revealed pituitary microadenomas (ie, < 10 mm in greatest dimension) in 3% to 27% of patients with no history of pituitary disorders. Macroadenomas (10 mm or larger), on the other hand, are found in fewer than 0.5% of people.3,4 Recently, a study of MRI in 2,000 healthy adult volunteers, age 45 to 97 years, found pituitary macroadenomas in 0.3%.5

Hall et al6 found that 10% of relatively young (< 60 years old) healthy volunteers harbored a pituitary microadenoma on pituitary MRI, but none had a macroadenoma. In a meta-analysis by Ezzat and colleagues,3 adenomas of all sizes were found in 1% to 40% of imaging or postmortem studies (for an average of 16.7%), but macroadenomas were found in only 0.16% to 0.2% of the population.

Although the natural history of pituitary incidentalomas is not well characterized, the numbers suggest that microadenomas rarely grow into macroadenomas.7 Another possibility is that most macroadenomas cause symptoms and therefore come to clinical attention, and thus are not incidentalomas per se.

THE INITIAL EVALUATION: TWO QUESTIONS

The initial approach to a patient with a pituitary incidentaloma should be guided by two questions:

  • Is the tumor hormonally active?
  • Is it causing a mass effect (ie, is it exerting pressure on adjacent structures)?

IS THE TUMOR HORMONALLY ACTIVE?

A careful history and physical examination may reveal overlooked symptoms or signs of hypersecretion of a specific hormone, which can be evaluated in detail to establish the diagnosis. However, most patients with pituitary incidentalomas have no symptoms, and for them there is no real consensus about the optimal workup strategy.

Prolactin excess

King et al8 calculated that the serum prolactin level is the single most cost-effective screening test for hormonal activity in patients with incidentally discovered pituitary microadenomas. They also suggested, however, that it may be cost-effective to measure multiple hormones in very anxious patients, since a negative test may provide reassurance and improve quality of life.

One should be careful in interpreting elevated prolactin levels in patients with pituitary incidentalomas, since a number of medications (eg, metoclopramide [Reglan], verapamil [Calan], phenothiazines) and disorders (eg, hypothyroidism, cirrhosis, renal failure) can cause mild to moderate elevations of prolactin. In general, a prolactin level of more than 200 ng/mL is almost always diagnostic of prolactinomas. In our experience, a prolactin level above 100 ng/mL is almost always due to a prolactin-secreting pituitary adenoma, except during pregnancy and in some patients who receive antipsychotics or metoclopramide. For these patients, if it is clinically safe to hold or switch medications, retesting after a drug holiday may prove useful and diagnostic.

Growth hormone excess

Growth hormone hypersecretion has been reported in patients with pituitary tumors who have no clinical stigmata of acromegaly.9,10 Moreover, acral changes may not correlate with the metabolic consequences of growth hormone excess.11 In a study by Reincke et al,12 one of 18 patients with pituitary incidentalomas and no apparent acromegalic features had a growth hormone-secreting pituitary adenoma. For this reason, looking for so-called silent growth hormone hypersecretion may be warranted in patients with pituitary tumors, especially in those with macroadenomas.9

The best initial test for growth hormone hypersecretion is the measurement of insulin-like growth factor-1 (IGF-1).13 A normal age- and sex-adjusted IGF-1 level almost always rules out acromegaly.

Further hormonal evaluation

Further hormonal evaluation should be guided by the clinical picture.

Cortisol. In a patient with excess weight gain, central obesity, proximal myopathy, and skin manifestations that suggest hypercortisolism, appropriate initial tests would be a midnight salivary cortisol level, an overnight 1-mg (low-dose) dexamethasone suppression test, or a 24-hour urinary free cortisol level.

Thyroid hormones. Patients with symptoms that suggest hyperthyroidism should have their thyroid-stimulating hormone (TSH; thyrotropin) and free thyroxine (T4) levels measured to rule out a TSH-secreting pituitary adenoma, a very rare tumor.

Gonadotropins. Screening for a gonadotropin-secreting pituitary adenoma by measuring follicle-stimulating hormone, luteinizing hormone, and gonadotropin alpha subunit is not routinely indicated, since almost all of such tumors are clinically silent and generally come to clinical attention only because of a mass effect (see below).

 

 

IS THERE A MASS EFFECT?

Pituitary macroadenomas can also cause problems via a mass effect. Examples: hypopituitarism, visual field defects (by compressing the optic chiasm), cranial neuropathy (eg, diplopia, eyelid ptosis secondary to lateral extension of the tumor into a cavernous sinus), and headache.

Hypopituitarism

Hypopituitarism can range from deficiency of one pituitary hormone to the loss of all anterior pituitary hormones (panhypopituitarism).

Hypopituitarism from a mass effect is rare in patients with microadenomas, but one or more anterior pituitary hormone deficiencies are found in more than 30% of patients with a pituitary macroadenoma.3,12,14 With some exceptions, including pituitary apoplexy, the loss of pituitary hormone secretion is slowly progressive; symptoms tend to be nonspecific and often are not noticed at first.

Increased intrasellar pressure may play a role in the pathogenesis of hypopituitarism in patients with pituitary masses.15 Blood flow through the portal vessels is decreased, possibly resulting in diminished delivery of hypo-thalamic hormones to pituitary cells or leading to variable ischemia or necrosis of the normal gland, or both.

All patients with a pituitary macroadenoma should undergo a hormonal evaluation to look for pituitary hormone deficiency.

Growth hormone, gonadotropin deficiencies. In general, pituitary hormone deficiencies from an expanding pituitary tumor tend to begin with growth hormone or the gonadotropins (luteinizing hormone and follicle-stimulating hormone), or both.

Low serum testosterone levels in men (estradiol in women) along with normal or low follicle-stimulating hormone and luteinizing hormone levels are consistent with gonadotropin deficiency in men and amenorrheic premenopausal women.

Failure of the follicle-stimulating hormone and luteinizing hormone levels to rise after menopause is also consistent with gonadotropin deficiency. The presence of regular menses almost always indicates a normal gonadotropin axis. In women with irregular menstruation, hormonal evaluation can be challenging for evaluation of the gonadotropin axis and usually is not indicated.

Patients with deficiencies of two or more pituitary axes and low IGF-1 levels can be presumed to have growth hormone deficiency and usually do not need dynamic testing. But when testing is indicated, the growth hormone axis is best evaluated by dynamic testing, using either a growth hormone-releasing hormone/ arginine stimulation test or the insulin tolerance test.

Thyroid deficiencies. As the tumor expands, deficiencies of thyrotropin and adrenocorticotropic hormone (ACTH) secretion may follow those of growth hormone and gonadotropins. In our experience, the thyrotropin axis is usually affected before the corticotropin axis.

To evaluate the thyrotropin axis, the serum thyrotropin level should be measured along with the free thyroxine level or the free thyroxine index. A low free thyroxine level with a low or normal thyrotropin level is consistent with secondary hypothyroidism. It is inappropriate to measure thyrotropin without also measuring thyroxine in a patient with pituitary disorder, since a normal thyrotropin level in a patient with hypopituitarism is not uncommon.

Adrenal insufficiency. The ACTH stimulation test or an early morning (8 am) plasma cortisol level are both reasonable initial tests to evaluate the hypothalamic-pituitary-adrenal axis. An early morning cortisol level lower than 3 μg/dL confirms adrenal insufficiency, while a value higher than 15 μg/dL makes the diagnosis highly unlikely. Cortisol levels in the range of 3 to 15 μg/dL are indeterminate and should be further evaluated by an ACTH stimulation test, which can be performed anytime during the day.

The standard-dose ACTH stimulation test uses an intravenous or intramuscular injection of 250 μg of cosyntropin (Cortrosyn; ACTH 1–24). A normal response is a plasma cortisol concentration higher than 18 μg/dL at 30 minutes.

The sensitivity of the ACTH stimulation test in detecting mild, partial adrenal insufficiency is higher if a lower dose of cosyntropin is used (1 μg intravenously). However, the low-dose test has a higher false-positive rate. In most clinical situations, the 30-minute cortisol value during a standard-dose ACTH stimulation test has a diagnostic accuracy close to that of the low-dose ACTH stimulation test.16 Patients with recent-onset ACTH deficiency (eg, in pituitary apoplexy or within 2 to 4 weeks following pituitary surgery) may have a normal response to the ACTH stimulation test, since their adrenal glands have not undergone sufficient atrophy and still respond to ACTH stimulation.

The insulin tolerance test is considered the gold standard for evaluating the hypothalamic-pituitary-adrenal axis, but it needs to be performed by an experienced clinician and is usually not needed for everyday clinical practice.

Visual field defects

Figure 2. Representative visual field loss in a patient with a pituitary macroadenoma that compresses the optic system. The right eye is on the left side of the picture, and the left eye is on the right. The dark patches indicate typical superior bitemporal visual field loss, with some small loss in the inferior temporal fields. The loss in the left eye is much greater than that in the right eye.
The optic chiasm lies about 1 cm above the pituitary fossa and can be affected by superior extension of a pituitary macroadenoma. Some patients may be unaware of the visual field defect, which progresses insidiously from the slowly growing pituitary tumor. Others might complain of progressive loss of central acuity and dimming of visual fields in the temporal area bilaterally (Figure 2).

Visual field loss generally begins in the superior temporal fields, which explains why the patient may not notice it at first. Then, with continued growth and compression, vision loss extends into the inferior temporal fields, then into the nasal fields as a late effect.

Because the patient may not notice the visual field defect, formal visual field testing is warranted if the tumor compresses or abuts the optic chiasm. While bitemporal hemianopia is the classic manifestation of chiasmal compression, variable visual field defects may occur depending on which portion of the optic apparatus is involved.

 

 

Cranial neuropathy

Abnormal eye movements, which may cause diplopia, result from extension of a pituitary tumor into one or both cavernous sinuses. Compression of the third (occulomotor, the cranial nerve most often affected), fourth (trochlear), and sixth (abducens) cranial nerves leads to eye movement deviations as well as eyelid ptosis due to third nerve dysfunction. Cranial neuropathy most commonly occurs in the setting of pituitary apoplexy (see below) but may occur without it.

Headache

Headache can be associated with pituitary tumors, but the underlying pathophysiology remains uncertain. Possible mechanisms include structural causes such as dural stretching or cavernous sinus invasion.17 Other possible mechanisms are an increase in the intrasellar pressure and tumor activity.15,18 The link between headache and tumor activity is supported by the observation that headaches resolve in some patients with acromegaly shortly after they start taking somatostatin analogues.19

Migraine may be the most common type of headache reported in patients with pituitary adenomas; however, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) has also been reported.19

Of interest, there seems to be a strong association between pituitary-associated headache and a family history of headache.19 That said, headache is a common symptom in the general population, and establishing a cause-and-effect relationship prior to surgical removal of a pituitary tumor can be challenging. Approximately 50% of patients with headache who undergo an operation for a pituitary tumor have relief after surgery; however, 35% may not have relief, and up to 15% have a worsening of their headaches.19

OUR PATIENT’S HORMONAL EVALUATION

In the patient we described earlier, hormonal evaluation revealed the following:

  • Prolactin 12.2 ng/mL (reference range 2–17.4)
  • IGF-1 189 ng/mL (114–492)
  • Thyrotropin 1.63 μU/mL (0.4–5.5)
  • Free thyroxine index 9.5 μg/L (6–11)
  • Maximum cortisol during a low-dose ACTH stimulation test 18.4 μg/dL. In short, all her test results were normal.

A formal visual field test was not performed, since the pituitary mass did not reach the optic chiasm (Figure 1).

ADENOMAS VS OTHER SELLAR MASSES

Table 1 lists a number of the sellar masses that can mimic pituitary adenomas. In a series of 1,120 patients who underwent transsphenoidal surgery done by a single surgeon over 18 years, 91% had pituitary tumors. The rest had craniopharyngiomas, meningiomas, cysts, metastases (most commonly from the breasts, lungs, and prostate), sarcoidosis, lymphocytic hypophysitis, and others.20

In some cases, it may be difficult to distinguish a nonadenomatous lesion from a nonfunctioning pituitary adenoma. However, several endocrine, radiographic, and neurologic features may help to differentiate pituitary tumors from other, less common sellar disorders.20

For instance, diabetes insipidus is extremely rare in patients with pituitary adenomas at presentation without significant suprasellar extension of the tumor. Therefore, its presence strongly suggests a nonpituitary cause such as hypophysitis, sarcoidosis, or a meta-static lesion.21

Some radiographic features that suggest sellar masses other than pituitary tumors include calcifications on CT in patients with craniopharyngiomas and meningiomas or a rapidly enlarging mass with lack of sellar enlargement (sellar remodeling), which suggests a metastatic lesion. While a dural tail sign (a linear enhanced structure or “tail” extending away from the tumor mass along the dural surface) may be seen with some meningiomas, peripheral enhancement of the dura is not specific for meningioma and may be seen with pituitary apoplexy as well.22,23

Cranial neuropathy is less common in patients with pituitary adenomas than in those with nonadenomatous masses (for example a metastasis or a meningioma), although the acute onset of cranial neuropathy often accompanies a hemorrhagic infarction of a preexisting pituitary adenoma (pituitary apoplexy).20

Figure 3. Magnetic resonance imaging of the pituitary gland. A, Coronal, nonenhanced image of a normal pituitary gland (thin arrows). B, Coronal, contrast-enhanced image from a patient with pituitary hyperplasia secondary to long-standing, untreated primary hypothyroidism (thick arrows). The enlarged pituitary gland abuts the optic chiasm superiorly (dotted arrows). A typical feature of “physiologic enlargement” is a triangular shape to the gland, with the apex pointing toward the optic apparatus.
Finally, physiologic enlargement of the pituitary gland is a common reason for referring a young woman or adolescent girl for the evaluation of a sellar mass, and its proper identification is important to prevent unnecessary surgery.24 Pituitary hyperplasia may be seen in pregnancy, in primary hypothyroidism, and in hypogonadism (Figure 3). The gland typically returns to normal size after delivery or appropriate therapy.

OUR RECOMMENDATIONS

Our approach to a patient with a pituitary incidentaloma is summarized in Figure 4.

If the tumor is hormonally active

Figure 4.
If the tumor is hormonally active, transsphenoidal surgery is usually the treatment of choice.

Prolactinoma is the exception. For this tumor, dopamine agonists can resolve symptoms and shrink the tumor in most cases. Even in patients with a visual field defect associated with a macroprolactinoma, vision usually improves within days after starting a dopamine agonist, before the tumor has observably shrunk. However, a follow-up visual field test is necessary 2 to 6 weeks after starting therapy to establish that the tumor is responding to therapy; if the tumor does not respond, surgery may be necessary.

 

 

If the tumor is hormonally inactive

If the tumor is hormonally inactive, its further evaluation depends on its size and whether there is a mass effect. In patients with a nonfunctioning pituitary macroadenoma, a comprehensive hormonal evaluation for hypopituitarism should be done. Patients with a visual field defect or cranial neuropathy should undergo surgical tumor resection. If there is no mass effect, observation may be an acceptable strategy. We, and others,1,25 recommend surgery for most patients with pituitary macroadenomas abutting the optic chiasm.

If the tumor is small

If the tumor is small (ie, a microadenoma), the risk of its growing is low. Three small studies followed such patients prospectively and found a 0 to 14% risk of tumor enlargement over a mean follow-up period of 1.8 to 6.7 years.12,25,26 While there is no consensus about how soon to follow up patients with nonfunctioning pituitary microadenomas, we obtain a follow-up MRI study in 1 year, with no further routine imaging if the tumor has remained stable, unless the patient develops symptoms or signs suggesting a mass effect.

If the tumor is large

If the tumor is large (ie, a macroadenoma), the risk of further growth is expected to be higher, since the tumor has already shown the propensity to grow. In the same three series discussed above, the risk of tumor growth for a pituitary macroadenomas was about 30% over the mean follow-up of 1.8 to 6.7 years.12,25,26

Furthermore, several recent studies have suggested a higher propensity to grow and to cause symptoms and signs than previously thought. For example, Karavitaki et al7 studied 24 patients who had nonfunctional macroadenomas and found that the 48-month probability of enlargement was 44%; of this group, 57% showed new or worsening visual field defects, and an additional 21% showed new chiasmatic compression without vision loss. Similarly, Arita and colleagues27 found that 21 (50%) of 42 nonfunctional adenomas (mean size 18.3 ± 7 mm) increased by at least 10% over an average of 32 months after the initial evaluation. Ten patients became symptomatic over a mean of about 5 years, with 4 of these 10 (9.5% of the entire cohort) suffering symptomatic pituitary apoplexy. Therefore, one may argue for surgery (especially in young patients) for pituitary macroadenomas even in the absence of mass effect.

We would obtain a follow-up MRI study at 6 months, then yearly for 5 years, and then every 2 to 3 years if the tumor is stable. Surgery would be indicated if there is evidence of tumor growth or a mass effect.

While tumor growth has been found to be independent of age in some studies,27 others have found longer tumor doubling time in patients older than 60 years.28

The risk of pituitary apoplexy

Pituitary apoplexy results from a hemorrhagic infarction of the tumor and manifests clinically as the sudden onset of severe headache, nausea, vomiting, vision loss, and cranial nerve palsies. While most cases of pituitary apoplexy are spontaneous, precipitating factors may include head injury, anticoagulant therapy, dopamine agonists, radiation therapy, or dynamic endocrine tests.29

It is important to educate patients and their families about the symptoms of pituitary apoplexy, especially patients with pituitary macroadenomas. If the condition is unrecognized and untreated, patients can develop hypotension and shock secondary to adrenal insufficiency, as well as irreversible vision loss or diplopia.

Surgery is generally recommended in cases of progressive vision loss or cranial neuropathy, preferably within 24 or 48 hours of onset if feasible, to minimize the risk of a permanent neurologic deficit.

Clinically significant pituitary apoplexy is rare in patients with pituitary microadenomas. In the study by Arita et al,27 the risk of pituitary apoplexy during 5 years of follow-up was 9.5%, and all of the tumors involved were macroadenomas. This rate is higher than in some other studies, in which the risk of apoplexy ranged from 0.4% to 7% during a mean follow-up of 2 to 6 years.1,25,30

CASE FOLLOW-UP

Since our patient had no evidence of hormonal hypersecretion or mass effect and no hypopituitarism, we asked her to return in 6 months. A repeat MRI study showed the tumor to be stable, with no evidence of growth. The patient was scheduled for a return visit in 1 year.

References
  1. Sanno N, Oyama K, Tahara S, Teramoto A, Kato Y. A survey of pituitary incidentaloma in Japan. Eur J Endocrinol 2003; 149:123–127.
  2. Gsponer J, De Tribolet N, Déruaz JP, et al. Diagnosis, treatment, and outcome of pituitary tumors and other abnormal intrasellar masses. Retrospective analysis of 353 patients. Medicine (Baltimore) 1999; 78:236–269.
  3. Ezzat S, Asa SL, Couldwell WT, et al. The prevalence of pituitary adenomas: a systematic review. Cancer 2004; 101:613–619.
  4. Molitch ME, Russell EJ. The pituitary “incidentaloma.” Ann Intern Med 1990; 112:925–931.
  5. Vernooij MW, Ikram MA, Tanghe HL, et al. Incidental findings on brain MRI in the general population. N Engl J Med 2007; 357:1821–1828.
  6. Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH. Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. Ann Intern Med 1994; 120:817–820.
  7. Karavitaki N, Collison K, Halliday J, et al. What is the natural history of nonoperated nonfunctioning pituitary adenomas? Clin Endocrinol (Oxf) 2007; 67:938–943.
  8. King JT, Justice AC, Aron DC. Management of incidental pituitary microadenomas: a cost-effectiveness analysis. J Clin Endocrinol Metab 1997; 82:3625–3632.
  9. Klibanski A, Zervas NT, Kovacs K, Ridgway EC. Clinically silent hypersecretion of growth hormone in patients with pituitary tumors. J Neurosurg 1987; 66:806–811.
  10. Trouillas J, Sassolas G, Loras B, et al. Somatotropic adenomas without acromegaly. Pathol Res Pract 1991; 187:943–949.
  11. Cryer PE, Daughaday WH. Regulation of growth hormone secretion in acromegaly. J Clin Endocrinol Metab 1969; 29:386–393.
  12. Reincke M, Allolio B, Saeger W, Menzel J, Winkelmann W. The ‘incidentaloma’ of the pituitary gland. Is neurosurgery required? JAMA 1990; 263:2772–2776.
  13. Giustina A, Barkan A, Casanueva FF, et al. Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab 2000; 85:526–529.
  14. Nammour GM, Ybarra J, Naheedy MH, Romeo JH, Aron DC. Incidental pituitary macroadenoma: a population-based study. Am J Med Sci 1997; 314:287–291.
  15. Arafah BM, Prunty D, Ybarra J, Hlavin ML, Selman WR. The dominant role of increased intrasellar pressure in the pathogenesis of hypopituitarism, hyperprolactinemia, and headaches in patients with pituitary adenomas. J Clin Endocrinol Metab 2000; 85:1789–1793.
  16. Mayenknecht J, Diederich S, Bahr V, Plockinger U, Oelkers W. Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab 1998; 83:1558–1562.
  17. Forsyth PA, Posner JB. Headaches in patients with brain tumors: a study of 111 patients. Neurology 1993; 43:1678–1683.
  18. Abe T, Matsumoto K, Kuwazawa J, Toyoda I, Sasaki K. Headache associated with pituitary adenomas. Headache 1998; 38:782–786.
  19. Levy MJ, Matharu MS, Meeran K, Powell M, Goadsby PJ. The clinical characteristics of headache in patients with pituitary tumours. Brain 2005; 128:1921–1930.
  20. Freda PU, Post KD. Differential diagnosis of sellar masses. Endocrinol Metab Clin North Am 1999; 28:81–117.
  21. Gopan T, Toms SA, Prayson RA, Suh JH, Hamrahian AH, Weil RJ. Symptomatic pituitary metastases from renal cell carcinoma. Pituitary 2007; 10:251–259.
  22. Moore AF, Grinspoon SK. A dural tale. J Clin Endocrinol Metab 2007; 92:3367–3368.
  23. Smirniotopoulos JG, Murphy FM, Rushing EJ, Rees JH, Schroeder JW. Patterns of contrast enhancement in the brain and meninges. Radiographics 2007; 27:525–551.
  24. Chanson P, Daujat F, Young J, et al. Normal pituitary hypertrophy as a frequent cause of pituitary incidentaloma: a follow-up study. J Clin Endocrinol Metab 2001; 86:3009–3015.
  25. Donovan LE, Corenblum B. The natural history of the pituitary incidentaloma. Arch Intern Med 1995; 155:181–183.
  26. Feldkamp J, Santen R, Harms E, Aulich A, Modder U, Scherbaum WA. Incidentally discovered pituitary lesions: high frequency of macroadenomas and hormone-secreting adenomas—results of a prospective study. Clin Endocrinol (Oxf) 1999; 51:109–113.
  27. Arita K, Tominaga A, Sugiyama K, et al. Natural course of incidentally found nonfunctioning pituitary adenoma, with special reference to pituitary apoplexy during follow-up examination. J Neurosurg 2006; 104:884–891.
  28. Tanaka Y, Hongo K, Tada T, Sakai K, Kakizawa Y, Kobayashi S. Growth pattern and rate in residual nonfunctioning pituitary adenomas: correlations among tumor volume doubling time, patient age, and MIB-1 index. J Neurosurg 2003; 98:359–365.
  29. Biousse V, Newman NJ, Oyesiku NM. Precipitating factors in pituitary apoplexy. J Neurol Neurosurg Psychiatry 2001; 71:542–545.
  30. Nishizawa S, Ohta S, Yokoyama T, Uemura K. Therapeutic strategy for incidentally found pituitary tumors (“pituitary incidentalomas”). Neurosurgery 1998; 43:1344–1348.
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Amir H. Hamrahian, MD
Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic; Adjunct Clinical Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

Address: Amir H. Hamrahian, MD, Department of Endocrinology, Diabetes, and Metabolism, A53, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; email [email protected]

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Amir H. Hamrahian, MD
Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic; Adjunct Clinical Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

Address: Amir H. Hamrahian, MD, Department of Endocrinology, Diabetes, and Metabolism, A53, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; email [email protected]

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Amir H. Hamrahian, MD
Department of Endocrinology, Diabetes, and Metabolism, Cleveland Clinic; Adjunct Clinical Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University

Address: Amir H. Hamrahian, MD, Department of Endocrinology, Diabetes, and Metabolism, A53, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; email [email protected]

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A 39-year-old woman is referred for evaluation of a pituitary mass, which was found on magnetic resonance imaging (MRI) performed because of persistent vertigo. The mass, measuring 1.1 by 1.0 cm, arises from the right portion of the sella turcica and does not reach the optic chiasm (Figure 1). It appears hypointense on MRI and enhances after contrast is given, suggesting it is a pituitary adenoma.

Figure 1. Coronal (A) and sagittal (B) precontrast magnetic resonance images of a 1.1 x 1.0-cm sellar mass (solid arrows) suggestive of a pituitary macroadenoma. The pituitary gland and pituitary stalk are pushed to the patient’s left by the mass (dotted arrows).
The patient has a history of migraine headaches, which have improved in the last few years. She is not taking any medications, and she says she has had no fatigue, visual problems, weight change, or breast discharge.

On physical examination she does not have any stigmata of Cushing syndrome or of acromegaly. Her blood pressure is 116/72 mm Hg and her heart rate is regular at 68 beats per minute. Her visual fields are normal as assessed by confrontation, and she has no galactorrhea.

How should this patient be evaluated?

BY DEFINITION, INCIDENTALOMAS ARE UNSUSPECTED

Pituitary “incidentalomas” are, by definition, masses that are discovered by computed tomography (CT) or MRI performed to evaluate unrelated disorders (such as head trauma), for cancer staging, or because of nonspecific symptoms such as dizziness and headache. In some series, headache was the most common reason for imaging studies that led to the discovery of pituitary incidentalomas.1

With more patients undergoing computed tomography (CT) and MRI, more incidentalomas are being discovered. Incidentally discovered pituitary adenomas accounted for 12% of the pituitary tumors in a series of 353 consecutive patients with a presumptive diagnosis of pituitary tumor at one institution over a 14-year period.2 Pituitary masses other than adenomas are discussed later in this paper.

Microadenomas are common, macroadenomas less so

Autopsy studies have revealed pituitary microadenomas (ie, < 10 mm in greatest dimension) in 3% to 27% of patients with no history of pituitary disorders. Macroadenomas (10 mm or larger), on the other hand, are found in fewer than 0.5% of people.3,4 Recently, a study of MRI in 2,000 healthy adult volunteers, age 45 to 97 years, found pituitary macroadenomas in 0.3%.5

Hall et al6 found that 10% of relatively young (< 60 years old) healthy volunteers harbored a pituitary microadenoma on pituitary MRI, but none had a macroadenoma. In a meta-analysis by Ezzat and colleagues,3 adenomas of all sizes were found in 1% to 40% of imaging or postmortem studies (for an average of 16.7%), but macroadenomas were found in only 0.16% to 0.2% of the population.

Although the natural history of pituitary incidentalomas is not well characterized, the numbers suggest that microadenomas rarely grow into macroadenomas.7 Another possibility is that most macroadenomas cause symptoms and therefore come to clinical attention, and thus are not incidentalomas per se.

THE INITIAL EVALUATION: TWO QUESTIONS

The initial approach to a patient with a pituitary incidentaloma should be guided by two questions:

  • Is the tumor hormonally active?
  • Is it causing a mass effect (ie, is it exerting pressure on adjacent structures)?

IS THE TUMOR HORMONALLY ACTIVE?

A careful history and physical examination may reveal overlooked symptoms or signs of hypersecretion of a specific hormone, which can be evaluated in detail to establish the diagnosis. However, most patients with pituitary incidentalomas have no symptoms, and for them there is no real consensus about the optimal workup strategy.

Prolactin excess

King et al8 calculated that the serum prolactin level is the single most cost-effective screening test for hormonal activity in patients with incidentally discovered pituitary microadenomas. They also suggested, however, that it may be cost-effective to measure multiple hormones in very anxious patients, since a negative test may provide reassurance and improve quality of life.

One should be careful in interpreting elevated prolactin levels in patients with pituitary incidentalomas, since a number of medications (eg, metoclopramide [Reglan], verapamil [Calan], phenothiazines) and disorders (eg, hypothyroidism, cirrhosis, renal failure) can cause mild to moderate elevations of prolactin. In general, a prolactin level of more than 200 ng/mL is almost always diagnostic of prolactinomas. In our experience, a prolactin level above 100 ng/mL is almost always due to a prolactin-secreting pituitary adenoma, except during pregnancy and in some patients who receive antipsychotics or metoclopramide. For these patients, if it is clinically safe to hold or switch medications, retesting after a drug holiday may prove useful and diagnostic.

Growth hormone excess

Growth hormone hypersecretion has been reported in patients with pituitary tumors who have no clinical stigmata of acromegaly.9,10 Moreover, acral changes may not correlate with the metabolic consequences of growth hormone excess.11 In a study by Reincke et al,12 one of 18 patients with pituitary incidentalomas and no apparent acromegalic features had a growth hormone-secreting pituitary adenoma. For this reason, looking for so-called silent growth hormone hypersecretion may be warranted in patients with pituitary tumors, especially in those with macroadenomas.9

The best initial test for growth hormone hypersecretion is the measurement of insulin-like growth factor-1 (IGF-1).13 A normal age- and sex-adjusted IGF-1 level almost always rules out acromegaly.

Further hormonal evaluation

Further hormonal evaluation should be guided by the clinical picture.

Cortisol. In a patient with excess weight gain, central obesity, proximal myopathy, and skin manifestations that suggest hypercortisolism, appropriate initial tests would be a midnight salivary cortisol level, an overnight 1-mg (low-dose) dexamethasone suppression test, or a 24-hour urinary free cortisol level.

Thyroid hormones. Patients with symptoms that suggest hyperthyroidism should have their thyroid-stimulating hormone (TSH; thyrotropin) and free thyroxine (T4) levels measured to rule out a TSH-secreting pituitary adenoma, a very rare tumor.

Gonadotropins. Screening for a gonadotropin-secreting pituitary adenoma by measuring follicle-stimulating hormone, luteinizing hormone, and gonadotropin alpha subunit is not routinely indicated, since almost all of such tumors are clinically silent and generally come to clinical attention only because of a mass effect (see below).

 

 

IS THERE A MASS EFFECT?

Pituitary macroadenomas can also cause problems via a mass effect. Examples: hypopituitarism, visual field defects (by compressing the optic chiasm), cranial neuropathy (eg, diplopia, eyelid ptosis secondary to lateral extension of the tumor into a cavernous sinus), and headache.

Hypopituitarism

Hypopituitarism can range from deficiency of one pituitary hormone to the loss of all anterior pituitary hormones (panhypopituitarism).

Hypopituitarism from a mass effect is rare in patients with microadenomas, but one or more anterior pituitary hormone deficiencies are found in more than 30% of patients with a pituitary macroadenoma.3,12,14 With some exceptions, including pituitary apoplexy, the loss of pituitary hormone secretion is slowly progressive; symptoms tend to be nonspecific and often are not noticed at first.

Increased intrasellar pressure may play a role in the pathogenesis of hypopituitarism in patients with pituitary masses.15 Blood flow through the portal vessels is decreased, possibly resulting in diminished delivery of hypo-thalamic hormones to pituitary cells or leading to variable ischemia or necrosis of the normal gland, or both.

All patients with a pituitary macroadenoma should undergo a hormonal evaluation to look for pituitary hormone deficiency.

Growth hormone, gonadotropin deficiencies. In general, pituitary hormone deficiencies from an expanding pituitary tumor tend to begin with growth hormone or the gonadotropins (luteinizing hormone and follicle-stimulating hormone), or both.

Low serum testosterone levels in men (estradiol in women) along with normal or low follicle-stimulating hormone and luteinizing hormone levels are consistent with gonadotropin deficiency in men and amenorrheic premenopausal women.

Failure of the follicle-stimulating hormone and luteinizing hormone levels to rise after menopause is also consistent with gonadotropin deficiency. The presence of regular menses almost always indicates a normal gonadotropin axis. In women with irregular menstruation, hormonal evaluation can be challenging for evaluation of the gonadotropin axis and usually is not indicated.

Patients with deficiencies of two or more pituitary axes and low IGF-1 levels can be presumed to have growth hormone deficiency and usually do not need dynamic testing. But when testing is indicated, the growth hormone axis is best evaluated by dynamic testing, using either a growth hormone-releasing hormone/ arginine stimulation test or the insulin tolerance test.

Thyroid deficiencies. As the tumor expands, deficiencies of thyrotropin and adrenocorticotropic hormone (ACTH) secretion may follow those of growth hormone and gonadotropins. In our experience, the thyrotropin axis is usually affected before the corticotropin axis.

To evaluate the thyrotropin axis, the serum thyrotropin level should be measured along with the free thyroxine level or the free thyroxine index. A low free thyroxine level with a low or normal thyrotropin level is consistent with secondary hypothyroidism. It is inappropriate to measure thyrotropin without also measuring thyroxine in a patient with pituitary disorder, since a normal thyrotropin level in a patient with hypopituitarism is not uncommon.

Adrenal insufficiency. The ACTH stimulation test or an early morning (8 am) plasma cortisol level are both reasonable initial tests to evaluate the hypothalamic-pituitary-adrenal axis. An early morning cortisol level lower than 3 μg/dL confirms adrenal insufficiency, while a value higher than 15 μg/dL makes the diagnosis highly unlikely. Cortisol levels in the range of 3 to 15 μg/dL are indeterminate and should be further evaluated by an ACTH stimulation test, which can be performed anytime during the day.

The standard-dose ACTH stimulation test uses an intravenous or intramuscular injection of 250 μg of cosyntropin (Cortrosyn; ACTH 1–24). A normal response is a plasma cortisol concentration higher than 18 μg/dL at 30 minutes.

The sensitivity of the ACTH stimulation test in detecting mild, partial adrenal insufficiency is higher if a lower dose of cosyntropin is used (1 μg intravenously). However, the low-dose test has a higher false-positive rate. In most clinical situations, the 30-minute cortisol value during a standard-dose ACTH stimulation test has a diagnostic accuracy close to that of the low-dose ACTH stimulation test.16 Patients with recent-onset ACTH deficiency (eg, in pituitary apoplexy or within 2 to 4 weeks following pituitary surgery) may have a normal response to the ACTH stimulation test, since their adrenal glands have not undergone sufficient atrophy and still respond to ACTH stimulation.

The insulin tolerance test is considered the gold standard for evaluating the hypothalamic-pituitary-adrenal axis, but it needs to be performed by an experienced clinician and is usually not needed for everyday clinical practice.

Visual field defects

Figure 2. Representative visual field loss in a patient with a pituitary macroadenoma that compresses the optic system. The right eye is on the left side of the picture, and the left eye is on the right. The dark patches indicate typical superior bitemporal visual field loss, with some small loss in the inferior temporal fields. The loss in the left eye is much greater than that in the right eye.
The optic chiasm lies about 1 cm above the pituitary fossa and can be affected by superior extension of a pituitary macroadenoma. Some patients may be unaware of the visual field defect, which progresses insidiously from the slowly growing pituitary tumor. Others might complain of progressive loss of central acuity and dimming of visual fields in the temporal area bilaterally (Figure 2).

Visual field loss generally begins in the superior temporal fields, which explains why the patient may not notice it at first. Then, with continued growth and compression, vision loss extends into the inferior temporal fields, then into the nasal fields as a late effect.

Because the patient may not notice the visual field defect, formal visual field testing is warranted if the tumor compresses or abuts the optic chiasm. While bitemporal hemianopia is the classic manifestation of chiasmal compression, variable visual field defects may occur depending on which portion of the optic apparatus is involved.

 

 

Cranial neuropathy

Abnormal eye movements, which may cause diplopia, result from extension of a pituitary tumor into one or both cavernous sinuses. Compression of the third (occulomotor, the cranial nerve most often affected), fourth (trochlear), and sixth (abducens) cranial nerves leads to eye movement deviations as well as eyelid ptosis due to third nerve dysfunction. Cranial neuropathy most commonly occurs in the setting of pituitary apoplexy (see below) but may occur without it.

Headache

Headache can be associated with pituitary tumors, but the underlying pathophysiology remains uncertain. Possible mechanisms include structural causes such as dural stretching or cavernous sinus invasion.17 Other possible mechanisms are an increase in the intrasellar pressure and tumor activity.15,18 The link between headache and tumor activity is supported by the observation that headaches resolve in some patients with acromegaly shortly after they start taking somatostatin analogues.19

Migraine may be the most common type of headache reported in patients with pituitary adenomas; however, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) has also been reported.19

Of interest, there seems to be a strong association between pituitary-associated headache and a family history of headache.19 That said, headache is a common symptom in the general population, and establishing a cause-and-effect relationship prior to surgical removal of a pituitary tumor can be challenging. Approximately 50% of patients with headache who undergo an operation for a pituitary tumor have relief after surgery; however, 35% may not have relief, and up to 15% have a worsening of their headaches.19

OUR PATIENT’S HORMONAL EVALUATION

In the patient we described earlier, hormonal evaluation revealed the following:

  • Prolactin 12.2 ng/mL (reference range 2–17.4)
  • IGF-1 189 ng/mL (114–492)
  • Thyrotropin 1.63 μU/mL (0.4–5.5)
  • Free thyroxine index 9.5 μg/L (6–11)
  • Maximum cortisol during a low-dose ACTH stimulation test 18.4 μg/dL. In short, all her test results were normal.

A formal visual field test was not performed, since the pituitary mass did not reach the optic chiasm (Figure 1).

ADENOMAS VS OTHER SELLAR MASSES

Table 1 lists a number of the sellar masses that can mimic pituitary adenomas. In a series of 1,120 patients who underwent transsphenoidal surgery done by a single surgeon over 18 years, 91% had pituitary tumors. The rest had craniopharyngiomas, meningiomas, cysts, metastases (most commonly from the breasts, lungs, and prostate), sarcoidosis, lymphocytic hypophysitis, and others.20

In some cases, it may be difficult to distinguish a nonadenomatous lesion from a nonfunctioning pituitary adenoma. However, several endocrine, radiographic, and neurologic features may help to differentiate pituitary tumors from other, less common sellar disorders.20

For instance, diabetes insipidus is extremely rare in patients with pituitary adenomas at presentation without significant suprasellar extension of the tumor. Therefore, its presence strongly suggests a nonpituitary cause such as hypophysitis, sarcoidosis, or a meta-static lesion.21

Some radiographic features that suggest sellar masses other than pituitary tumors include calcifications on CT in patients with craniopharyngiomas and meningiomas or a rapidly enlarging mass with lack of sellar enlargement (sellar remodeling), which suggests a metastatic lesion. While a dural tail sign (a linear enhanced structure or “tail” extending away from the tumor mass along the dural surface) may be seen with some meningiomas, peripheral enhancement of the dura is not specific for meningioma and may be seen with pituitary apoplexy as well.22,23

Cranial neuropathy is less common in patients with pituitary adenomas than in those with nonadenomatous masses (for example a metastasis or a meningioma), although the acute onset of cranial neuropathy often accompanies a hemorrhagic infarction of a preexisting pituitary adenoma (pituitary apoplexy).20

Figure 3. Magnetic resonance imaging of the pituitary gland. A, Coronal, nonenhanced image of a normal pituitary gland (thin arrows). B, Coronal, contrast-enhanced image from a patient with pituitary hyperplasia secondary to long-standing, untreated primary hypothyroidism (thick arrows). The enlarged pituitary gland abuts the optic chiasm superiorly (dotted arrows). A typical feature of “physiologic enlargement” is a triangular shape to the gland, with the apex pointing toward the optic apparatus.
Finally, physiologic enlargement of the pituitary gland is a common reason for referring a young woman or adolescent girl for the evaluation of a sellar mass, and its proper identification is important to prevent unnecessary surgery.24 Pituitary hyperplasia may be seen in pregnancy, in primary hypothyroidism, and in hypogonadism (Figure 3). The gland typically returns to normal size after delivery or appropriate therapy.

OUR RECOMMENDATIONS

Our approach to a patient with a pituitary incidentaloma is summarized in Figure 4.

If the tumor is hormonally active

Figure 4.
If the tumor is hormonally active, transsphenoidal surgery is usually the treatment of choice.

Prolactinoma is the exception. For this tumor, dopamine agonists can resolve symptoms and shrink the tumor in most cases. Even in patients with a visual field defect associated with a macroprolactinoma, vision usually improves within days after starting a dopamine agonist, before the tumor has observably shrunk. However, a follow-up visual field test is necessary 2 to 6 weeks after starting therapy to establish that the tumor is responding to therapy; if the tumor does not respond, surgery may be necessary.

 

 

If the tumor is hormonally inactive

If the tumor is hormonally inactive, its further evaluation depends on its size and whether there is a mass effect. In patients with a nonfunctioning pituitary macroadenoma, a comprehensive hormonal evaluation for hypopituitarism should be done. Patients with a visual field defect or cranial neuropathy should undergo surgical tumor resection. If there is no mass effect, observation may be an acceptable strategy. We, and others,1,25 recommend surgery for most patients with pituitary macroadenomas abutting the optic chiasm.

If the tumor is small

If the tumor is small (ie, a microadenoma), the risk of its growing is low. Three small studies followed such patients prospectively and found a 0 to 14% risk of tumor enlargement over a mean follow-up period of 1.8 to 6.7 years.12,25,26 While there is no consensus about how soon to follow up patients with nonfunctioning pituitary microadenomas, we obtain a follow-up MRI study in 1 year, with no further routine imaging if the tumor has remained stable, unless the patient develops symptoms or signs suggesting a mass effect.

If the tumor is large

If the tumor is large (ie, a macroadenoma), the risk of further growth is expected to be higher, since the tumor has already shown the propensity to grow. In the same three series discussed above, the risk of tumor growth for a pituitary macroadenomas was about 30% over the mean follow-up of 1.8 to 6.7 years.12,25,26

Furthermore, several recent studies have suggested a higher propensity to grow and to cause symptoms and signs than previously thought. For example, Karavitaki et al7 studied 24 patients who had nonfunctional macroadenomas and found that the 48-month probability of enlargement was 44%; of this group, 57% showed new or worsening visual field defects, and an additional 21% showed new chiasmatic compression without vision loss. Similarly, Arita and colleagues27 found that 21 (50%) of 42 nonfunctional adenomas (mean size 18.3 ± 7 mm) increased by at least 10% over an average of 32 months after the initial evaluation. Ten patients became symptomatic over a mean of about 5 years, with 4 of these 10 (9.5% of the entire cohort) suffering symptomatic pituitary apoplexy. Therefore, one may argue for surgery (especially in young patients) for pituitary macroadenomas even in the absence of mass effect.

We would obtain a follow-up MRI study at 6 months, then yearly for 5 years, and then every 2 to 3 years if the tumor is stable. Surgery would be indicated if there is evidence of tumor growth or a mass effect.

While tumor growth has been found to be independent of age in some studies,27 others have found longer tumor doubling time in patients older than 60 years.28

The risk of pituitary apoplexy

Pituitary apoplexy results from a hemorrhagic infarction of the tumor and manifests clinically as the sudden onset of severe headache, nausea, vomiting, vision loss, and cranial nerve palsies. While most cases of pituitary apoplexy are spontaneous, precipitating factors may include head injury, anticoagulant therapy, dopamine agonists, radiation therapy, or dynamic endocrine tests.29

It is important to educate patients and their families about the symptoms of pituitary apoplexy, especially patients with pituitary macroadenomas. If the condition is unrecognized and untreated, patients can develop hypotension and shock secondary to adrenal insufficiency, as well as irreversible vision loss or diplopia.

Surgery is generally recommended in cases of progressive vision loss or cranial neuropathy, preferably within 24 or 48 hours of onset if feasible, to minimize the risk of a permanent neurologic deficit.

Clinically significant pituitary apoplexy is rare in patients with pituitary microadenomas. In the study by Arita et al,27 the risk of pituitary apoplexy during 5 years of follow-up was 9.5%, and all of the tumors involved were macroadenomas. This rate is higher than in some other studies, in which the risk of apoplexy ranged from 0.4% to 7% during a mean follow-up of 2 to 6 years.1,25,30

CASE FOLLOW-UP

Since our patient had no evidence of hormonal hypersecretion or mass effect and no hypopituitarism, we asked her to return in 6 months. A repeat MRI study showed the tumor to be stable, with no evidence of growth. The patient was scheduled for a return visit in 1 year.

A 39-year-old woman is referred for evaluation of a pituitary mass, which was found on magnetic resonance imaging (MRI) performed because of persistent vertigo. The mass, measuring 1.1 by 1.0 cm, arises from the right portion of the sella turcica and does not reach the optic chiasm (Figure 1). It appears hypointense on MRI and enhances after contrast is given, suggesting it is a pituitary adenoma.

Figure 1. Coronal (A) and sagittal (B) precontrast magnetic resonance images of a 1.1 x 1.0-cm sellar mass (solid arrows) suggestive of a pituitary macroadenoma. The pituitary gland and pituitary stalk are pushed to the patient’s left by the mass (dotted arrows).
The patient has a history of migraine headaches, which have improved in the last few years. She is not taking any medications, and she says she has had no fatigue, visual problems, weight change, or breast discharge.

On physical examination she does not have any stigmata of Cushing syndrome or of acromegaly. Her blood pressure is 116/72 mm Hg and her heart rate is regular at 68 beats per minute. Her visual fields are normal as assessed by confrontation, and she has no galactorrhea.

How should this patient be evaluated?

BY DEFINITION, INCIDENTALOMAS ARE UNSUSPECTED

Pituitary “incidentalomas” are, by definition, masses that are discovered by computed tomography (CT) or MRI performed to evaluate unrelated disorders (such as head trauma), for cancer staging, or because of nonspecific symptoms such as dizziness and headache. In some series, headache was the most common reason for imaging studies that led to the discovery of pituitary incidentalomas.1

With more patients undergoing computed tomography (CT) and MRI, more incidentalomas are being discovered. Incidentally discovered pituitary adenomas accounted for 12% of the pituitary tumors in a series of 353 consecutive patients with a presumptive diagnosis of pituitary tumor at one institution over a 14-year period.2 Pituitary masses other than adenomas are discussed later in this paper.

Microadenomas are common, macroadenomas less so

Autopsy studies have revealed pituitary microadenomas (ie, < 10 mm in greatest dimension) in 3% to 27% of patients with no history of pituitary disorders. Macroadenomas (10 mm or larger), on the other hand, are found in fewer than 0.5% of people.3,4 Recently, a study of MRI in 2,000 healthy adult volunteers, age 45 to 97 years, found pituitary macroadenomas in 0.3%.5

Hall et al6 found that 10% of relatively young (< 60 years old) healthy volunteers harbored a pituitary microadenoma on pituitary MRI, but none had a macroadenoma. In a meta-analysis by Ezzat and colleagues,3 adenomas of all sizes were found in 1% to 40% of imaging or postmortem studies (for an average of 16.7%), but macroadenomas were found in only 0.16% to 0.2% of the population.

Although the natural history of pituitary incidentalomas is not well characterized, the numbers suggest that microadenomas rarely grow into macroadenomas.7 Another possibility is that most macroadenomas cause symptoms and therefore come to clinical attention, and thus are not incidentalomas per se.

THE INITIAL EVALUATION: TWO QUESTIONS

The initial approach to a patient with a pituitary incidentaloma should be guided by two questions:

  • Is the tumor hormonally active?
  • Is it causing a mass effect (ie, is it exerting pressure on adjacent structures)?

IS THE TUMOR HORMONALLY ACTIVE?

A careful history and physical examination may reveal overlooked symptoms or signs of hypersecretion of a specific hormone, which can be evaluated in detail to establish the diagnosis. However, most patients with pituitary incidentalomas have no symptoms, and for them there is no real consensus about the optimal workup strategy.

Prolactin excess

King et al8 calculated that the serum prolactin level is the single most cost-effective screening test for hormonal activity in patients with incidentally discovered pituitary microadenomas. They also suggested, however, that it may be cost-effective to measure multiple hormones in very anxious patients, since a negative test may provide reassurance and improve quality of life.

One should be careful in interpreting elevated prolactin levels in patients with pituitary incidentalomas, since a number of medications (eg, metoclopramide [Reglan], verapamil [Calan], phenothiazines) and disorders (eg, hypothyroidism, cirrhosis, renal failure) can cause mild to moderate elevations of prolactin. In general, a prolactin level of more than 200 ng/mL is almost always diagnostic of prolactinomas. In our experience, a prolactin level above 100 ng/mL is almost always due to a prolactin-secreting pituitary adenoma, except during pregnancy and in some patients who receive antipsychotics or metoclopramide. For these patients, if it is clinically safe to hold or switch medications, retesting after a drug holiday may prove useful and diagnostic.

Growth hormone excess

Growth hormone hypersecretion has been reported in patients with pituitary tumors who have no clinical stigmata of acromegaly.9,10 Moreover, acral changes may not correlate with the metabolic consequences of growth hormone excess.11 In a study by Reincke et al,12 one of 18 patients with pituitary incidentalomas and no apparent acromegalic features had a growth hormone-secreting pituitary adenoma. For this reason, looking for so-called silent growth hormone hypersecretion may be warranted in patients with pituitary tumors, especially in those with macroadenomas.9

The best initial test for growth hormone hypersecretion is the measurement of insulin-like growth factor-1 (IGF-1).13 A normal age- and sex-adjusted IGF-1 level almost always rules out acromegaly.

Further hormonal evaluation

Further hormonal evaluation should be guided by the clinical picture.

Cortisol. In a patient with excess weight gain, central obesity, proximal myopathy, and skin manifestations that suggest hypercortisolism, appropriate initial tests would be a midnight salivary cortisol level, an overnight 1-mg (low-dose) dexamethasone suppression test, or a 24-hour urinary free cortisol level.

Thyroid hormones. Patients with symptoms that suggest hyperthyroidism should have their thyroid-stimulating hormone (TSH; thyrotropin) and free thyroxine (T4) levels measured to rule out a TSH-secreting pituitary adenoma, a very rare tumor.

Gonadotropins. Screening for a gonadotropin-secreting pituitary adenoma by measuring follicle-stimulating hormone, luteinizing hormone, and gonadotropin alpha subunit is not routinely indicated, since almost all of such tumors are clinically silent and generally come to clinical attention only because of a mass effect (see below).

 

 

IS THERE A MASS EFFECT?

Pituitary macroadenomas can also cause problems via a mass effect. Examples: hypopituitarism, visual field defects (by compressing the optic chiasm), cranial neuropathy (eg, diplopia, eyelid ptosis secondary to lateral extension of the tumor into a cavernous sinus), and headache.

Hypopituitarism

Hypopituitarism can range from deficiency of one pituitary hormone to the loss of all anterior pituitary hormones (panhypopituitarism).

Hypopituitarism from a mass effect is rare in patients with microadenomas, but one or more anterior pituitary hormone deficiencies are found in more than 30% of patients with a pituitary macroadenoma.3,12,14 With some exceptions, including pituitary apoplexy, the loss of pituitary hormone secretion is slowly progressive; symptoms tend to be nonspecific and often are not noticed at first.

Increased intrasellar pressure may play a role in the pathogenesis of hypopituitarism in patients with pituitary masses.15 Blood flow through the portal vessels is decreased, possibly resulting in diminished delivery of hypo-thalamic hormones to pituitary cells or leading to variable ischemia or necrosis of the normal gland, or both.

All patients with a pituitary macroadenoma should undergo a hormonal evaluation to look for pituitary hormone deficiency.

Growth hormone, gonadotropin deficiencies. In general, pituitary hormone deficiencies from an expanding pituitary tumor tend to begin with growth hormone or the gonadotropins (luteinizing hormone and follicle-stimulating hormone), or both.

Low serum testosterone levels in men (estradiol in women) along with normal or low follicle-stimulating hormone and luteinizing hormone levels are consistent with gonadotropin deficiency in men and amenorrheic premenopausal women.

Failure of the follicle-stimulating hormone and luteinizing hormone levels to rise after menopause is also consistent with gonadotropin deficiency. The presence of regular menses almost always indicates a normal gonadotropin axis. In women with irregular menstruation, hormonal evaluation can be challenging for evaluation of the gonadotropin axis and usually is not indicated.

Patients with deficiencies of two or more pituitary axes and low IGF-1 levels can be presumed to have growth hormone deficiency and usually do not need dynamic testing. But when testing is indicated, the growth hormone axis is best evaluated by dynamic testing, using either a growth hormone-releasing hormone/ arginine stimulation test or the insulin tolerance test.

Thyroid deficiencies. As the tumor expands, deficiencies of thyrotropin and adrenocorticotropic hormone (ACTH) secretion may follow those of growth hormone and gonadotropins. In our experience, the thyrotropin axis is usually affected before the corticotropin axis.

To evaluate the thyrotropin axis, the serum thyrotropin level should be measured along with the free thyroxine level or the free thyroxine index. A low free thyroxine level with a low or normal thyrotropin level is consistent with secondary hypothyroidism. It is inappropriate to measure thyrotropin without also measuring thyroxine in a patient with pituitary disorder, since a normal thyrotropin level in a patient with hypopituitarism is not uncommon.

Adrenal insufficiency. The ACTH stimulation test or an early morning (8 am) plasma cortisol level are both reasonable initial tests to evaluate the hypothalamic-pituitary-adrenal axis. An early morning cortisol level lower than 3 μg/dL confirms adrenal insufficiency, while a value higher than 15 μg/dL makes the diagnosis highly unlikely. Cortisol levels in the range of 3 to 15 μg/dL are indeterminate and should be further evaluated by an ACTH stimulation test, which can be performed anytime during the day.

The standard-dose ACTH stimulation test uses an intravenous or intramuscular injection of 250 μg of cosyntropin (Cortrosyn; ACTH 1–24). A normal response is a plasma cortisol concentration higher than 18 μg/dL at 30 minutes.

The sensitivity of the ACTH stimulation test in detecting mild, partial adrenal insufficiency is higher if a lower dose of cosyntropin is used (1 μg intravenously). However, the low-dose test has a higher false-positive rate. In most clinical situations, the 30-minute cortisol value during a standard-dose ACTH stimulation test has a diagnostic accuracy close to that of the low-dose ACTH stimulation test.16 Patients with recent-onset ACTH deficiency (eg, in pituitary apoplexy or within 2 to 4 weeks following pituitary surgery) may have a normal response to the ACTH stimulation test, since their adrenal glands have not undergone sufficient atrophy and still respond to ACTH stimulation.

The insulin tolerance test is considered the gold standard for evaluating the hypothalamic-pituitary-adrenal axis, but it needs to be performed by an experienced clinician and is usually not needed for everyday clinical practice.

Visual field defects

Figure 2. Representative visual field loss in a patient with a pituitary macroadenoma that compresses the optic system. The right eye is on the left side of the picture, and the left eye is on the right. The dark patches indicate typical superior bitemporal visual field loss, with some small loss in the inferior temporal fields. The loss in the left eye is much greater than that in the right eye.
The optic chiasm lies about 1 cm above the pituitary fossa and can be affected by superior extension of a pituitary macroadenoma. Some patients may be unaware of the visual field defect, which progresses insidiously from the slowly growing pituitary tumor. Others might complain of progressive loss of central acuity and dimming of visual fields in the temporal area bilaterally (Figure 2).

Visual field loss generally begins in the superior temporal fields, which explains why the patient may not notice it at first. Then, with continued growth and compression, vision loss extends into the inferior temporal fields, then into the nasal fields as a late effect.

Because the patient may not notice the visual field defect, formal visual field testing is warranted if the tumor compresses or abuts the optic chiasm. While bitemporal hemianopia is the classic manifestation of chiasmal compression, variable visual field defects may occur depending on which portion of the optic apparatus is involved.

 

 

Cranial neuropathy

Abnormal eye movements, which may cause diplopia, result from extension of a pituitary tumor into one or both cavernous sinuses. Compression of the third (occulomotor, the cranial nerve most often affected), fourth (trochlear), and sixth (abducens) cranial nerves leads to eye movement deviations as well as eyelid ptosis due to third nerve dysfunction. Cranial neuropathy most commonly occurs in the setting of pituitary apoplexy (see below) but may occur without it.

Headache

Headache can be associated with pituitary tumors, but the underlying pathophysiology remains uncertain. Possible mechanisms include structural causes such as dural stretching or cavernous sinus invasion.17 Other possible mechanisms are an increase in the intrasellar pressure and tumor activity.15,18 The link between headache and tumor activity is supported by the observation that headaches resolve in some patients with acromegaly shortly after they start taking somatostatin analogues.19

Migraine may be the most common type of headache reported in patients with pituitary adenomas; however, short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) has also been reported.19

Of interest, there seems to be a strong association between pituitary-associated headache and a family history of headache.19 That said, headache is a common symptom in the general population, and establishing a cause-and-effect relationship prior to surgical removal of a pituitary tumor can be challenging. Approximately 50% of patients with headache who undergo an operation for a pituitary tumor have relief after surgery; however, 35% may not have relief, and up to 15% have a worsening of their headaches.19

OUR PATIENT’S HORMONAL EVALUATION

In the patient we described earlier, hormonal evaluation revealed the following:

  • Prolactin 12.2 ng/mL (reference range 2–17.4)
  • IGF-1 189 ng/mL (114–492)
  • Thyrotropin 1.63 μU/mL (0.4–5.5)
  • Free thyroxine index 9.5 μg/L (6–11)
  • Maximum cortisol during a low-dose ACTH stimulation test 18.4 μg/dL. In short, all her test results were normal.

A formal visual field test was not performed, since the pituitary mass did not reach the optic chiasm (Figure 1).

ADENOMAS VS OTHER SELLAR MASSES

Table 1 lists a number of the sellar masses that can mimic pituitary adenomas. In a series of 1,120 patients who underwent transsphenoidal surgery done by a single surgeon over 18 years, 91% had pituitary tumors. The rest had craniopharyngiomas, meningiomas, cysts, metastases (most commonly from the breasts, lungs, and prostate), sarcoidosis, lymphocytic hypophysitis, and others.20

In some cases, it may be difficult to distinguish a nonadenomatous lesion from a nonfunctioning pituitary adenoma. However, several endocrine, radiographic, and neurologic features may help to differentiate pituitary tumors from other, less common sellar disorders.20

For instance, diabetes insipidus is extremely rare in patients with pituitary adenomas at presentation without significant suprasellar extension of the tumor. Therefore, its presence strongly suggests a nonpituitary cause such as hypophysitis, sarcoidosis, or a meta-static lesion.21

Some radiographic features that suggest sellar masses other than pituitary tumors include calcifications on CT in patients with craniopharyngiomas and meningiomas or a rapidly enlarging mass with lack of sellar enlargement (sellar remodeling), which suggests a metastatic lesion. While a dural tail sign (a linear enhanced structure or “tail” extending away from the tumor mass along the dural surface) may be seen with some meningiomas, peripheral enhancement of the dura is not specific for meningioma and may be seen with pituitary apoplexy as well.22,23

Cranial neuropathy is less common in patients with pituitary adenomas than in those with nonadenomatous masses (for example a metastasis or a meningioma), although the acute onset of cranial neuropathy often accompanies a hemorrhagic infarction of a preexisting pituitary adenoma (pituitary apoplexy).20

Figure 3. Magnetic resonance imaging of the pituitary gland. A, Coronal, nonenhanced image of a normal pituitary gland (thin arrows). B, Coronal, contrast-enhanced image from a patient with pituitary hyperplasia secondary to long-standing, untreated primary hypothyroidism (thick arrows). The enlarged pituitary gland abuts the optic chiasm superiorly (dotted arrows). A typical feature of “physiologic enlargement” is a triangular shape to the gland, with the apex pointing toward the optic apparatus.
Finally, physiologic enlargement of the pituitary gland is a common reason for referring a young woman or adolescent girl for the evaluation of a sellar mass, and its proper identification is important to prevent unnecessary surgery.24 Pituitary hyperplasia may be seen in pregnancy, in primary hypothyroidism, and in hypogonadism (Figure 3). The gland typically returns to normal size after delivery or appropriate therapy.

OUR RECOMMENDATIONS

Our approach to a patient with a pituitary incidentaloma is summarized in Figure 4.

If the tumor is hormonally active

Figure 4.
If the tumor is hormonally active, transsphenoidal surgery is usually the treatment of choice.

Prolactinoma is the exception. For this tumor, dopamine agonists can resolve symptoms and shrink the tumor in most cases. Even in patients with a visual field defect associated with a macroprolactinoma, vision usually improves within days after starting a dopamine agonist, before the tumor has observably shrunk. However, a follow-up visual field test is necessary 2 to 6 weeks after starting therapy to establish that the tumor is responding to therapy; if the tumor does not respond, surgery may be necessary.

 

 

If the tumor is hormonally inactive

If the tumor is hormonally inactive, its further evaluation depends on its size and whether there is a mass effect. In patients with a nonfunctioning pituitary macroadenoma, a comprehensive hormonal evaluation for hypopituitarism should be done. Patients with a visual field defect or cranial neuropathy should undergo surgical tumor resection. If there is no mass effect, observation may be an acceptable strategy. We, and others,1,25 recommend surgery for most patients with pituitary macroadenomas abutting the optic chiasm.

If the tumor is small

If the tumor is small (ie, a microadenoma), the risk of its growing is low. Three small studies followed such patients prospectively and found a 0 to 14% risk of tumor enlargement over a mean follow-up period of 1.8 to 6.7 years.12,25,26 While there is no consensus about how soon to follow up patients with nonfunctioning pituitary microadenomas, we obtain a follow-up MRI study in 1 year, with no further routine imaging if the tumor has remained stable, unless the patient develops symptoms or signs suggesting a mass effect.

If the tumor is large

If the tumor is large (ie, a macroadenoma), the risk of further growth is expected to be higher, since the tumor has already shown the propensity to grow. In the same three series discussed above, the risk of tumor growth for a pituitary macroadenomas was about 30% over the mean follow-up of 1.8 to 6.7 years.12,25,26

Furthermore, several recent studies have suggested a higher propensity to grow and to cause symptoms and signs than previously thought. For example, Karavitaki et al7 studied 24 patients who had nonfunctional macroadenomas and found that the 48-month probability of enlargement was 44%; of this group, 57% showed new or worsening visual field defects, and an additional 21% showed new chiasmatic compression without vision loss. Similarly, Arita and colleagues27 found that 21 (50%) of 42 nonfunctional adenomas (mean size 18.3 ± 7 mm) increased by at least 10% over an average of 32 months after the initial evaluation. Ten patients became symptomatic over a mean of about 5 years, with 4 of these 10 (9.5% of the entire cohort) suffering symptomatic pituitary apoplexy. Therefore, one may argue for surgery (especially in young patients) for pituitary macroadenomas even in the absence of mass effect.

We would obtain a follow-up MRI study at 6 months, then yearly for 5 years, and then every 2 to 3 years if the tumor is stable. Surgery would be indicated if there is evidence of tumor growth or a mass effect.

While tumor growth has been found to be independent of age in some studies,27 others have found longer tumor doubling time in patients older than 60 years.28

The risk of pituitary apoplexy

Pituitary apoplexy results from a hemorrhagic infarction of the tumor and manifests clinically as the sudden onset of severe headache, nausea, vomiting, vision loss, and cranial nerve palsies. While most cases of pituitary apoplexy are spontaneous, precipitating factors may include head injury, anticoagulant therapy, dopamine agonists, radiation therapy, or dynamic endocrine tests.29

It is important to educate patients and their families about the symptoms of pituitary apoplexy, especially patients with pituitary macroadenomas. If the condition is unrecognized and untreated, patients can develop hypotension and shock secondary to adrenal insufficiency, as well as irreversible vision loss or diplopia.

Surgery is generally recommended in cases of progressive vision loss or cranial neuropathy, preferably within 24 or 48 hours of onset if feasible, to minimize the risk of a permanent neurologic deficit.

Clinically significant pituitary apoplexy is rare in patients with pituitary microadenomas. In the study by Arita et al,27 the risk of pituitary apoplexy during 5 years of follow-up was 9.5%, and all of the tumors involved were macroadenomas. This rate is higher than in some other studies, in which the risk of apoplexy ranged from 0.4% to 7% during a mean follow-up of 2 to 6 years.1,25,30

CASE FOLLOW-UP

Since our patient had no evidence of hormonal hypersecretion or mass effect and no hypopituitarism, we asked her to return in 6 months. A repeat MRI study showed the tumor to be stable, with no evidence of growth. The patient was scheduled for a return visit in 1 year.

References
  1. Sanno N, Oyama K, Tahara S, Teramoto A, Kato Y. A survey of pituitary incidentaloma in Japan. Eur J Endocrinol 2003; 149:123–127.
  2. Gsponer J, De Tribolet N, Déruaz JP, et al. Diagnosis, treatment, and outcome of pituitary tumors and other abnormal intrasellar masses. Retrospective analysis of 353 patients. Medicine (Baltimore) 1999; 78:236–269.
  3. Ezzat S, Asa SL, Couldwell WT, et al. The prevalence of pituitary adenomas: a systematic review. Cancer 2004; 101:613–619.
  4. Molitch ME, Russell EJ. The pituitary “incidentaloma.” Ann Intern Med 1990; 112:925–931.
  5. Vernooij MW, Ikram MA, Tanghe HL, et al. Incidental findings on brain MRI in the general population. N Engl J Med 2007; 357:1821–1828.
  6. Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH. Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. Ann Intern Med 1994; 120:817–820.
  7. Karavitaki N, Collison K, Halliday J, et al. What is the natural history of nonoperated nonfunctioning pituitary adenomas? Clin Endocrinol (Oxf) 2007; 67:938–943.
  8. King JT, Justice AC, Aron DC. Management of incidental pituitary microadenomas: a cost-effectiveness analysis. J Clin Endocrinol Metab 1997; 82:3625–3632.
  9. Klibanski A, Zervas NT, Kovacs K, Ridgway EC. Clinically silent hypersecretion of growth hormone in patients with pituitary tumors. J Neurosurg 1987; 66:806–811.
  10. Trouillas J, Sassolas G, Loras B, et al. Somatotropic adenomas without acromegaly. Pathol Res Pract 1991; 187:943–949.
  11. Cryer PE, Daughaday WH. Regulation of growth hormone secretion in acromegaly. J Clin Endocrinol Metab 1969; 29:386–393.
  12. Reincke M, Allolio B, Saeger W, Menzel J, Winkelmann W. The ‘incidentaloma’ of the pituitary gland. Is neurosurgery required? JAMA 1990; 263:2772–2776.
  13. Giustina A, Barkan A, Casanueva FF, et al. Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab 2000; 85:526–529.
  14. Nammour GM, Ybarra J, Naheedy MH, Romeo JH, Aron DC. Incidental pituitary macroadenoma: a population-based study. Am J Med Sci 1997; 314:287–291.
  15. Arafah BM, Prunty D, Ybarra J, Hlavin ML, Selman WR. The dominant role of increased intrasellar pressure in the pathogenesis of hypopituitarism, hyperprolactinemia, and headaches in patients with pituitary adenomas. J Clin Endocrinol Metab 2000; 85:1789–1793.
  16. Mayenknecht J, Diederich S, Bahr V, Plockinger U, Oelkers W. Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab 1998; 83:1558–1562.
  17. Forsyth PA, Posner JB. Headaches in patients with brain tumors: a study of 111 patients. Neurology 1993; 43:1678–1683.
  18. Abe T, Matsumoto K, Kuwazawa J, Toyoda I, Sasaki K. Headache associated with pituitary adenomas. Headache 1998; 38:782–786.
  19. Levy MJ, Matharu MS, Meeran K, Powell M, Goadsby PJ. The clinical characteristics of headache in patients with pituitary tumours. Brain 2005; 128:1921–1930.
  20. Freda PU, Post KD. Differential diagnosis of sellar masses. Endocrinol Metab Clin North Am 1999; 28:81–117.
  21. Gopan T, Toms SA, Prayson RA, Suh JH, Hamrahian AH, Weil RJ. Symptomatic pituitary metastases from renal cell carcinoma. Pituitary 2007; 10:251–259.
  22. Moore AF, Grinspoon SK. A dural tale. J Clin Endocrinol Metab 2007; 92:3367–3368.
  23. Smirniotopoulos JG, Murphy FM, Rushing EJ, Rees JH, Schroeder JW. Patterns of contrast enhancement in the brain and meninges. Radiographics 2007; 27:525–551.
  24. Chanson P, Daujat F, Young J, et al. Normal pituitary hypertrophy as a frequent cause of pituitary incidentaloma: a follow-up study. J Clin Endocrinol Metab 2001; 86:3009–3015.
  25. Donovan LE, Corenblum B. The natural history of the pituitary incidentaloma. Arch Intern Med 1995; 155:181–183.
  26. Feldkamp J, Santen R, Harms E, Aulich A, Modder U, Scherbaum WA. Incidentally discovered pituitary lesions: high frequency of macroadenomas and hormone-secreting adenomas—results of a prospective study. Clin Endocrinol (Oxf) 1999; 51:109–113.
  27. Arita K, Tominaga A, Sugiyama K, et al. Natural course of incidentally found nonfunctioning pituitary adenoma, with special reference to pituitary apoplexy during follow-up examination. J Neurosurg 2006; 104:884–891.
  28. Tanaka Y, Hongo K, Tada T, Sakai K, Kakizawa Y, Kobayashi S. Growth pattern and rate in residual nonfunctioning pituitary adenomas: correlations among tumor volume doubling time, patient age, and MIB-1 index. J Neurosurg 2003; 98:359–365.
  29. Biousse V, Newman NJ, Oyesiku NM. Precipitating factors in pituitary apoplexy. J Neurol Neurosurg Psychiatry 2001; 71:542–545.
  30. Nishizawa S, Ohta S, Yokoyama T, Uemura K. Therapeutic strategy for incidentally found pituitary tumors (“pituitary incidentalomas”). Neurosurgery 1998; 43:1344–1348.
References
  1. Sanno N, Oyama K, Tahara S, Teramoto A, Kato Y. A survey of pituitary incidentaloma in Japan. Eur J Endocrinol 2003; 149:123–127.
  2. Gsponer J, De Tribolet N, Déruaz JP, et al. Diagnosis, treatment, and outcome of pituitary tumors and other abnormal intrasellar masses. Retrospective analysis of 353 patients. Medicine (Baltimore) 1999; 78:236–269.
  3. Ezzat S, Asa SL, Couldwell WT, et al. The prevalence of pituitary adenomas: a systematic review. Cancer 2004; 101:613–619.
  4. Molitch ME, Russell EJ. The pituitary “incidentaloma.” Ann Intern Med 1990; 112:925–931.
  5. Vernooij MW, Ikram MA, Tanghe HL, et al. Incidental findings on brain MRI in the general population. N Engl J Med 2007; 357:1821–1828.
  6. Hall WA, Luciano MG, Doppman JL, Patronas NJ, Oldfield EH. Pituitary magnetic resonance imaging in normal human volunteers: occult adenomas in the general population. Ann Intern Med 1994; 120:817–820.
  7. Karavitaki N, Collison K, Halliday J, et al. What is the natural history of nonoperated nonfunctioning pituitary adenomas? Clin Endocrinol (Oxf) 2007; 67:938–943.
  8. King JT, Justice AC, Aron DC. Management of incidental pituitary microadenomas: a cost-effectiveness analysis. J Clin Endocrinol Metab 1997; 82:3625–3632.
  9. Klibanski A, Zervas NT, Kovacs K, Ridgway EC. Clinically silent hypersecretion of growth hormone in patients with pituitary tumors. J Neurosurg 1987; 66:806–811.
  10. Trouillas J, Sassolas G, Loras B, et al. Somatotropic adenomas without acromegaly. Pathol Res Pract 1991; 187:943–949.
  11. Cryer PE, Daughaday WH. Regulation of growth hormone secretion in acromegaly. J Clin Endocrinol Metab 1969; 29:386–393.
  12. Reincke M, Allolio B, Saeger W, Menzel J, Winkelmann W. The ‘incidentaloma’ of the pituitary gland. Is neurosurgery required? JAMA 1990; 263:2772–2776.
  13. Giustina A, Barkan A, Casanueva FF, et al. Criteria for cure of acromegaly: a consensus statement. J Clin Endocrinol Metab 2000; 85:526–529.
  14. Nammour GM, Ybarra J, Naheedy MH, Romeo JH, Aron DC. Incidental pituitary macroadenoma: a population-based study. Am J Med Sci 1997; 314:287–291.
  15. Arafah BM, Prunty D, Ybarra J, Hlavin ML, Selman WR. The dominant role of increased intrasellar pressure in the pathogenesis of hypopituitarism, hyperprolactinemia, and headaches in patients with pituitary adenomas. J Clin Endocrinol Metab 2000; 85:1789–1793.
  16. Mayenknecht J, Diederich S, Bahr V, Plockinger U, Oelkers W. Comparison of low and high dose corticotropin stimulation tests in patients with pituitary disease. J Clin Endocrinol Metab 1998; 83:1558–1562.
  17. Forsyth PA, Posner JB. Headaches in patients with brain tumors: a study of 111 patients. Neurology 1993; 43:1678–1683.
  18. Abe T, Matsumoto K, Kuwazawa J, Toyoda I, Sasaki K. Headache associated with pituitary adenomas. Headache 1998; 38:782–786.
  19. Levy MJ, Matharu MS, Meeran K, Powell M, Goadsby PJ. The clinical characteristics of headache in patients with pituitary tumours. Brain 2005; 128:1921–1930.
  20. Freda PU, Post KD. Differential diagnosis of sellar masses. Endocrinol Metab Clin North Am 1999; 28:81–117.
  21. Gopan T, Toms SA, Prayson RA, Suh JH, Hamrahian AH, Weil RJ. Symptomatic pituitary metastases from renal cell carcinoma. Pituitary 2007; 10:251–259.
  22. Moore AF, Grinspoon SK. A dural tale. J Clin Endocrinol Metab 2007; 92:3367–3368.
  23. Smirniotopoulos JG, Murphy FM, Rushing EJ, Rees JH, Schroeder JW. Patterns of contrast enhancement in the brain and meninges. Radiographics 2007; 27:525–551.
  24. Chanson P, Daujat F, Young J, et al. Normal pituitary hypertrophy as a frequent cause of pituitary incidentaloma: a follow-up study. J Clin Endocrinol Metab 2001; 86:3009–3015.
  25. Donovan LE, Corenblum B. The natural history of the pituitary incidentaloma. Arch Intern Med 1995; 155:181–183.
  26. Feldkamp J, Santen R, Harms E, Aulich A, Modder U, Scherbaum WA. Incidentally discovered pituitary lesions: high frequency of macroadenomas and hormone-secreting adenomas—results of a prospective study. Clin Endocrinol (Oxf) 1999; 51:109–113.
  27. Arita K, Tominaga A, Sugiyama K, et al. Natural course of incidentally found nonfunctioning pituitary adenoma, with special reference to pituitary apoplexy during follow-up examination. J Neurosurg 2006; 104:884–891.
  28. Tanaka Y, Hongo K, Tada T, Sakai K, Kakizawa Y, Kobayashi S. Growth pattern and rate in residual nonfunctioning pituitary adenomas: correlations among tumor volume doubling time, patient age, and MIB-1 index. J Neurosurg 2003; 98:359–365.
  29. Biousse V, Newman NJ, Oyesiku NM. Precipitating factors in pituitary apoplexy. J Neurol Neurosurg Psychiatry 2001; 71:542–545.
  30. Nishizawa S, Ohta S, Yokoyama T, Uemura K. Therapeutic strategy for incidentally found pituitary tumors (“pituitary incidentalomas”). Neurosurgery 1998; 43:1344–1348.
Issue
Cleveland Clinic Journal of Medicine - 75(11)
Issue
Cleveland Clinic Journal of Medicine - 75(11)
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Page Number
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Evaluation and management of pituitary incidentalomas
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Evaluation and management of pituitary incidentalomas
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KEY POINTS

 

  • Two key questions that must be answered when a pituitary incidentaloma is discovered are whether it is hormonally active and whether it is causing a mass effect (eg, a visual field defect due to pressure on the optic chiasm).
  • Incidentalomas that are not hormonally active and that are not causing a mass effect can generally be managed by watchful waiting.
  • Hormonally active prolactin-secreting tumors can be treated with dopamine agonists. Other hormonally active tumors and those that are causing a mass effect should be surgically removed.
  • The risks of further tumor growth and of pituitary apoplexy are higher in tumors that are larger when discovered.
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A young pregnant woman with shortness of breath

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A young pregnant woman with shortness of breath
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Dwayne A. Perkins, MD
Craig Nielsen, MD
Michael Faulx, MD

A 21-year-old woman who is 12 weeks pregnant according to the date of her last menstrual period comes to the emergency department with shortness of breath and chest pain.

One week ago she began experiencing pre-syncope and shortness of breath on minimal exertion and then even at rest on most days. The shortness of breath worsened throughout the week, eventually limiting her daily activities to such a degree that she restricted herself to bed rest.

Her chest pain started today while she was sitting in church, without any apparent provocation. It is right-sided, sharp, and focal, and it does not radiate. At the same time, her shortness of breath was more severe than before, so she immediately came to the emergency department.

This is her third pregnancy; she has had one live birth and one abortion. Her last pregnancy was full-term, with routine prenatal care and no complications. However, so far during this pregnancy, she has had no prenatal care, she has not taken prenatal vitamins, and she has been unable to maintain adequate nutrition because of persistent emesis, which began early in her pregnancy and continues to occur as often as two or three times daily. She has lost 20 pounds over the past 12 weeks.

She says she has no close contacts who are sick, and she has had no fever, diarrhea, dysuria, urinary frequency or urgency, palpitations, swelling of the legs or feet, blurry vision, or increase in neck girth. She says she does not smoke or use alcohol or illicit substances. Her only previous surgery was laser-assisted in situ keratoplasty (LASIK) eye surgery in 1998. She is allergic to seafood only. She has not eaten at any new places recently. She is up to date with her childhood vaccinations. She has no family history of hypercoagulability or venous thrombotic events.

PHYSICAL EXAMINATION

She is breathing rapidly—as fast as 45 breaths per minute. Her temperature is 37.2°C (98.9°F), blood pressure 95/60 mm Hg, oxygen saturation 100% while on 10 L of oxygen using a nonrebreather mask, pulse 102 beats per minute, and weight 55.9 kg (123.2 pounds). She appears alert, oriented, and comfortable, with a thin body habitus. She has no jugular venous distention, neck mass, or thyromegaly. Her lungs are clear to auscultation, with no wheezes or rales. The cardiovascular examination is normal. She has a regular heart rate and rhythm, normal S1 and S2 sounds, and no rubs, clicks, or murmurs. Pulses in the extremities are normal, and she has no peripheral edema. The neurologic examination is normal.

Electrocardiography shows sinus tachycardia with first-degree atrioventricular block.

DIFFERENTIAL DIAGNOSIS

1. At this point, which is the most probable cause of her symptoms?

  • Pulmonary embolism
  • Peripartum cardiomyopathy
  • Acute coronary syndrome
  • Aortic dissection
  • Expected physiologic changes of pregnancy

Pulmonary embolism would be the most probable diagnosis, given the patient’s pregnancy, shortness of breath, and tachycardia and the pleuritic quality of her chest pain.

Peripartum cardiomyopathy is also a possible cause, as it may present with profound shortness of breath and markedly decreased cardiac function. But it is much less likely in this patient because she is early in her pregnancy, and peripartum cardiomyopathy usually is seen during the last month of gestation or the first months after delivery.

Acute coronary syndrome is unlikely, given her young age and the lack of significant risk factors or a supporting history.

Aortic dissection is unlikely in view of her medical history.

Physiologic changes of pregnancy. Many pregnant women experience a sensation of not being able to catch their breath or expand their lungs fully, as the diaphragm is limited by the gravid abdomen. They also present with dyspnea, fatigue, reduced exercise capacity, peripheral edema, or volume overload.1 However, these changes tend to occur gradually and worsen over time. This patient’s degree of shortness of breath and its sudden onset do not seem like normal physiologic changes of pregnancy.

Other possible causes of dyspnea in a pregnant woman include asthma, pleural empyema, pneumonia, and severe anemia. Asthma should be considered in anyone with a history of wheezing, cough, and dyspnea. Fever and sputum production would support a diagnosis of pneumonia or empyema. In addition, maternal heart disease (eg, endocarditis, pulmonary hypertension) complicates 0.2% to 3% of pregnancies.1

CASE CONTINUED

The emergency department staff decide to evaluate the patient for heart failure and pulmonary embolism.

Bedside echocardiography reveals an ejection fraction of 55% (normal range 50%–75%), normal heart function and size, and no valvular abnormalities.

Chest radiography is normal.

Lower-extremity duplex ultrasonography is negative for deep-vein thrombosis.

The D-dimer level is 380 ng/mL (normal range < 500 ng/mL).

The medical intensive care unit is consulted about the patient’s continued tachypnea and the possible need for intubation. A ventilation-perfusion scan is performed to screen for pulmonary embolism, and it is negative.

An obstetric team performs Doppler ultrasonography at the bedside; a fetal heartbeat can be heard, thus confirming a viable pregnancy.

The patient has normal serum levels of the cardiac enzymes troponin T and creatine kinase-MB fraction, thus all but ruling out myocardial ischemia.

The patient is admitted to the hospital the next day, and a cardiology consult is obtained.

 

 

RULING OUT PULMONARY EMBOLISM

2. Has pulmonary embolism been definitively ruled out at this point?

  • Yes
  • No

The answer is no. The negative ventilation-perfusion scan and normal D-dimer test in this patient are not enough to rule out pulmonary embolism. The diagnosis of pulmonary embolism should be based on the clinician’s estimation of the pretest probability of pulmonary embolism (which is based on presenting signs and symptoms), as well as on a variety of tests, including spiral computed tomography (CT), ventilation-perfusion lung scanning, and serum D-dimer testing. Signs and symptoms that may guide the clinician are chest pain (present in 70% of patients with pulmonary embolism), tachypnea (70%), cough (40%), shortness of breath (25%), and tachycardia (33%).2 A history of pregnancy, malignancy, immobility, or recent surgery may also increase the pretest probability of pulmonary embolism. In many cases, one’s clinical suspicion is highly predictive and is useful in diagnosing pulmonary embolism.

The accuracy of the tests varies widely, depending on the pretest probability of pulmonary embolism. For instance, in a patient with a high pretest probability but a low-probability ventilation-perfusion scan, the true probability of pulmonary embolism is 40%, but in a patient with a low pretest probability and a low-probability scan, the probability is only 4%.

The Wells criteria can be used to calculate the pretest probability of pulmonary embolism. Given this patient’s tachycardia and clinical presentation, her pretest probability according to the Wells criteria indicates increased risk. However, because her D-dimer test, lower-extremity Doppler test, and ventilation-perfusion scan were normal, pulmonary embolism is less likely.3

However, if one’s clinical suspicion is high enough, further investigation of pulmonary embolism would proceed despite the encouraging test results.

CASE CONTINUED

Our patient’s initial laboratory test results are listed in Table 1.

The cardiology consult team notes that her beta human chorionic gonadotropin (beta-hCG) level is much higher than would be expected at 12 weeks of pregnancy, and so they are concerned about the possibility of a molar pregnancy. In addition, her level of thyroid-stimulating hormone (TSH, or thyrotropin) is markedly low.

HYPERTHYROIDISM IN PREGNANCY

3. Which of the following would not explain this patient’s markedly low TSH level?

  • Graves disease
  • Molar pregnancy
  • TSH-secreting pituitary adenoma
  • Gestational transient thyrotoxicosis
  • Twin pregnancy

Hyperthyroidism (also called thyrotoxicosis) has many causes, including but not limited to Graves disease, pituitary adenoma, struma ovarii (teratoma), hCG-secreting hydatidiform mole, and thyroid carcinoma (which is rare).4 In most of these disorders, the TSH level is low while the levels of thyroxine (T4), triiodothyronine (T3), or both are high.

Symptoms of hyperthyroidism are the effect of elevated T4 and T3 levels on the target organs themselves. Common symptoms include fever, tachycardia, tremor, stare, sweating, and lid lag. Other symptoms include nervousness, delirium, hypersensitivity to heat, flushing, palpitations, fatigue, weight loss, dyspnea, weakness, increased appetite, swelling of the legs, nausea, vomiting, diarrhea, goiter, tremor, atrial fibrillation, and cardiac failure.4 In its extreme form, called thyroid storm, thyrotoxicosis can be life-threatening. The likelihood of an impending thyroid storm can be assessed by clinical variables such as the patient’s temperature and heart rate and whether he or she has heart failure or gastrointestinal manifestations.5

Graves disease, the most common cause of hyperthyroidism in pregnancy, is due to stimulation of TSH receptors by antibodies against these receptors. Graves disease is possible in this patient, but a subsequent TSH receptor antibody test is negative.

Pituitary adenomas are one of the few causes of hyperthyroidism in which the TSH level is high, not low. Therefore, this is the correct answer.

Gestational transient thyrotoxicosis is a nonautoimmune condition that results in transient hyperthyroidism of variable severity.6 Usually, it occurs in otherwise normal pregnancies without complications, but the initial manifestation is hyper- emesis.6 It can be differentiated from Graves disease by the absence of TSH receptor antibodies and by no history of thyroid disorder.7 Common symptoms of gestational transient thyrotoxicosis include weight loss (or failure to gain weight), tachycardia, and fatigue.

The reason for the transient rise in T4 may be that beta-hCG is structurally similar to TSH (and also to luteinizing hormone and follicle-stimulating hormone), so that it has mild thyroid-stimulating effects.7 Sustained high levels of beta-hCG may in time give rise to the manifestations of thyrotoxicosis.

Molar pregnancy also can cause hyper-thyroidism via elevated levels of beta-hCG. However, twin pregnancy is more common and can produce sustained levels of beta-hCG above 100,000 IU/L. In most cases of twin pregnancy, the TSH level is decreased and the T4 level transiently elevated.6 The elevated beta-hCG and the subsequent thyrotropic manifestations are thought to be directly related, and symptoms resolve when beta-hCG levels go down.6

In most cases of hyperthyroidism in pregnancy, the acute condition can be managed by a short (≤ 2-month) course of a beta-blocker. In rare cases, propylthiouracil treatment may be required. Gestational transient thyrotoxicosis is not associated with detrimental outcomes.

Case continued

Our patient’s TSH level is low and her free T4 and T3 levels are elevated. Her high beta-hCG level may be stimulating the thyroid gland and may account for the low TSH value, as well as for her tachycardia, emesis, shortness of breath, and weight loss.

After an obstetric consult, it is determined that our patient has a viable pregnancy. However, further investigation with transvaginal ultrasonography reveals that she has two viable, single-placenta, intrauterine gestations, separated by a thin chorionic membrane.

Beta-hCG and free T4 levels are significantly higher in twin pregnancies than in single pregnancies, especially in the early stages.6 In our patient, the twin pregnancy led to the elevated beta-hCG, which eventually manifested as thyrotoxicosis, which caused the shortness of breath, hyperemesis, weight loss, tachycardia, and nausea.

Shortness of breath in patients with thyrotoxicosis is well recognized but not well explained. It may be caused by decreased lung compliance, engorged capillaries in the lung, or left ventricular failure, as well as by chest pain due to increased myocardial demand or coronary artery vasospasm.4 The dyspnea is present at rest and during exertion, and the high metabolic rate is thought to lead to an inappropriate response of the ventilatory system.3,8

 

 

WHAT TREATMENT?

4. How would you treat this patient at this point?

  • No drug therapy, just supportive care
  • Propranolol (Inderal)
  • Levothyroxine
  • Propylthiouracil

Several types of drugs are used to manage hyperthyroidism.

Antithyroid drugs such as propylthiouracil, methimazole (Northyx, Tapazole), and carbimazole block thyroid hormone synthesis by inhibiting thyroid peroxidase. Propylthiouracil also blocks peripheral conversion of T4 to T3. Side effects of these agents include abnormal sense of taste, pruritus, urticaria, agranulocytosis, and hepatotoxicity.4

Usually, hyperthyroidism is treated with propylthiouracil at the smallest effective dose. This has been proven to be safe to the fetus and mother during pregnancy.9 Propylthiouracil and the other drugs in its class cross the placenta, but propylthiouracil crosses at one-quarter the rate of the other two.9

Beta-blockers are effective in the acute phase of thyrotoxicosis against tachycardia, hypertension, and atrial fibrillation. They also decrease conversion of T4 to T3, which is an added benefit. Beta-blockers can be tapered as thyroid hormone levels decrease.

A short course of a short-acting beta-blocker would be an option for our patient and would decrease her symptoms, although she does not have the typical markedly elevated T4 or T3 levels. In the long term, a beta-blocker would present a fetal risk, but short courses can be tolerated without incident.9

Radioactive iodine 131 is used in patients with Graves disease. 131Iodine therapy is safe for most adults, but in pregnancy its use is contraindicated. Fetal thyroid tissue is thought to be present after 10 weeks of gestation and could be damaged by the use of radioactive iodine. Another warning with the use of radioactive iodine is that patients should avoid close contact with other adults for a few days after treatment, and should avoid close contact with children and pregnant women for 2 to 3 weeks after treatment because of the risk of exposure to radiation emanating from the thyroid gland.

Levothyroxine is a treatment for hypothyroidism, not hyperthyroidism.

CASE CONTINUED

Our patient is treated with propranolol and monitored for several days in the hospital, during which her symptoms markedly improve. She is discharged without complications.

TAKE-HOME POINTS

The evaluation of shortness of breath in adult patients can be difficult, given the many possible causes. It is especially challenging in pregnant patients, since normal physiologic changes of pregnancy may produce these symptoms.

In many instances, cardiomyopathy must be suspected if a pregnant patient complains of shortness of breath. However, it is not the only possible cause.

References
  1. Dobbenga-Rhodes YA, Prive AM. Assessment and evaluation of the woman with cardiac disease during pregnancy. J Perinat Neonatal Nurs 2006; 20:295–302.
  2. Carman TL, Deitcher SR. Advances in diagnosing and excluding pulmonary embolism: spiral CT and D-dimer measurement. Cleve Clin J Med 2002; 69:721–729.
  3. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients’ probability of pulmonary embolism: increasing the model’s utility with the SimpliRED D-dimer. Thromb Haemost 2000; 83:416–420.
  4. Nayak B, Burman K. Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin North Am 2006; 35:663–686.
  5. Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin North Am 1993; 22:263–277.
  6. Grün JP, Meuris S, De Nayer P, Glinoer D. The thyrotrophic role of human chorionic gonadotrophin (hCG) in the early stages of twin (versus single) pregnancies. Clin Endocrinol (Oxf) 1997; 46:719–725.
  7. Glinoer D, De Nayer P, Robyn C, Lejeune B, Kinthaert J, Meuris S. Serum levels of intact human chorionic gonadotropin (HCG) and its free alpha and beta subunits, in relation to maternal thyroid stimulation during normal pregnancy. J Endocrinol Invest 1993; 16:881–888.
  8. Small D, Gibbons W, Levy RD, de Lucas P, Gregory W, Cosio MG. Exertional dyspnea and ventilation in hyper-thyroidism. Chest 1992; 101:1268–1273.
  9. Atkins P, Cohen SB, Phillips BJ. Drug therapy for hyper-thyroidism in pregnancy: safety issues for mother and fetus. Drug Saf 2000; 23:229–244.
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Craig Nielsen, MD
Department of Internal Medicine, and Director, Internal Medicine Residency Program, Cleveland Clinic

Michael Faulx, MD
Department of Cardiovascular Medicine, Cleveland Clinic

Address: Craig Nielsen, MD, Department of Internal Medicine, E13, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

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Michael Faulx, MD
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Craig Nielsen, MD
Department of Internal Medicine, and Director, Internal Medicine Residency Program, Cleveland Clinic

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Department of Cardiovascular Medicine, Cleveland Clinic

Address: Craig Nielsen, MD, Department of Internal Medicine, E13, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

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Department of Internal Medicine, and Director, Internal Medicine Residency Program, Cleveland Clinic

Michael Faulx, MD
Department of Cardiovascular Medicine, Cleveland Clinic

Address: Craig Nielsen, MD, Department of Internal Medicine, E13, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]

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Related Articles
Hyperthyroidism or thyrotoxicosis?

A 21-year-old woman who is 12 weeks pregnant according to the date of her last menstrual period comes to the emergency department with shortness of breath and chest pain.

One week ago she began experiencing pre-syncope and shortness of breath on minimal exertion and then even at rest on most days. The shortness of breath worsened throughout the week, eventually limiting her daily activities to such a degree that she restricted herself to bed rest.

Her chest pain started today while she was sitting in church, without any apparent provocation. It is right-sided, sharp, and focal, and it does not radiate. At the same time, her shortness of breath was more severe than before, so she immediately came to the emergency department.

This is her third pregnancy; she has had one live birth and one abortion. Her last pregnancy was full-term, with routine prenatal care and no complications. However, so far during this pregnancy, she has had no prenatal care, she has not taken prenatal vitamins, and she has been unable to maintain adequate nutrition because of persistent emesis, which began early in her pregnancy and continues to occur as often as two or three times daily. She has lost 20 pounds over the past 12 weeks.

She says she has no close contacts who are sick, and she has had no fever, diarrhea, dysuria, urinary frequency or urgency, palpitations, swelling of the legs or feet, blurry vision, or increase in neck girth. She says she does not smoke or use alcohol or illicit substances. Her only previous surgery was laser-assisted in situ keratoplasty (LASIK) eye surgery in 1998. She is allergic to seafood only. She has not eaten at any new places recently. She is up to date with her childhood vaccinations. She has no family history of hypercoagulability or venous thrombotic events.

PHYSICAL EXAMINATION

She is breathing rapidly—as fast as 45 breaths per minute. Her temperature is 37.2°C (98.9°F), blood pressure 95/60 mm Hg, oxygen saturation 100% while on 10 L of oxygen using a nonrebreather mask, pulse 102 beats per minute, and weight 55.9 kg (123.2 pounds). She appears alert, oriented, and comfortable, with a thin body habitus. She has no jugular venous distention, neck mass, or thyromegaly. Her lungs are clear to auscultation, with no wheezes or rales. The cardiovascular examination is normal. She has a regular heart rate and rhythm, normal S1 and S2 sounds, and no rubs, clicks, or murmurs. Pulses in the extremities are normal, and she has no peripheral edema. The neurologic examination is normal.

Electrocardiography shows sinus tachycardia with first-degree atrioventricular block.

DIFFERENTIAL DIAGNOSIS

1. At this point, which is the most probable cause of her symptoms?

  • Pulmonary embolism
  • Peripartum cardiomyopathy
  • Acute coronary syndrome
  • Aortic dissection
  • Expected physiologic changes of pregnancy

Pulmonary embolism would be the most probable diagnosis, given the patient’s pregnancy, shortness of breath, and tachycardia and the pleuritic quality of her chest pain.

Peripartum cardiomyopathy is also a possible cause, as it may present with profound shortness of breath and markedly decreased cardiac function. But it is much less likely in this patient because she is early in her pregnancy, and peripartum cardiomyopathy usually is seen during the last month of gestation or the first months after delivery.

Acute coronary syndrome is unlikely, given her young age and the lack of significant risk factors or a supporting history.

Aortic dissection is unlikely in view of her medical history.

Physiologic changes of pregnancy. Many pregnant women experience a sensation of not being able to catch their breath or expand their lungs fully, as the diaphragm is limited by the gravid abdomen. They also present with dyspnea, fatigue, reduced exercise capacity, peripheral edema, or volume overload.1 However, these changes tend to occur gradually and worsen over time. This patient’s degree of shortness of breath and its sudden onset do not seem like normal physiologic changes of pregnancy.

Other possible causes of dyspnea in a pregnant woman include asthma, pleural empyema, pneumonia, and severe anemia. Asthma should be considered in anyone with a history of wheezing, cough, and dyspnea. Fever and sputum production would support a diagnosis of pneumonia or empyema. In addition, maternal heart disease (eg, endocarditis, pulmonary hypertension) complicates 0.2% to 3% of pregnancies.1

CASE CONTINUED

The emergency department staff decide to evaluate the patient for heart failure and pulmonary embolism.

Bedside echocardiography reveals an ejection fraction of 55% (normal range 50%–75%), normal heart function and size, and no valvular abnormalities.

Chest radiography is normal.

Lower-extremity duplex ultrasonography is negative for deep-vein thrombosis.

The D-dimer level is 380 ng/mL (normal range < 500 ng/mL).

The medical intensive care unit is consulted about the patient’s continued tachypnea and the possible need for intubation. A ventilation-perfusion scan is performed to screen for pulmonary embolism, and it is negative.

An obstetric team performs Doppler ultrasonography at the bedside; a fetal heartbeat can be heard, thus confirming a viable pregnancy.

The patient has normal serum levels of the cardiac enzymes troponin T and creatine kinase-MB fraction, thus all but ruling out myocardial ischemia.

The patient is admitted to the hospital the next day, and a cardiology consult is obtained.

 

 

RULING OUT PULMONARY EMBOLISM

2. Has pulmonary embolism been definitively ruled out at this point?

  • Yes
  • No

The answer is no. The negative ventilation-perfusion scan and normal D-dimer test in this patient are not enough to rule out pulmonary embolism. The diagnosis of pulmonary embolism should be based on the clinician’s estimation of the pretest probability of pulmonary embolism (which is based on presenting signs and symptoms), as well as on a variety of tests, including spiral computed tomography (CT), ventilation-perfusion lung scanning, and serum D-dimer testing. Signs and symptoms that may guide the clinician are chest pain (present in 70% of patients with pulmonary embolism), tachypnea (70%), cough (40%), shortness of breath (25%), and tachycardia (33%).2 A history of pregnancy, malignancy, immobility, or recent surgery may also increase the pretest probability of pulmonary embolism. In many cases, one’s clinical suspicion is highly predictive and is useful in diagnosing pulmonary embolism.

The accuracy of the tests varies widely, depending on the pretest probability of pulmonary embolism. For instance, in a patient with a high pretest probability but a low-probability ventilation-perfusion scan, the true probability of pulmonary embolism is 40%, but in a patient with a low pretest probability and a low-probability scan, the probability is only 4%.

The Wells criteria can be used to calculate the pretest probability of pulmonary embolism. Given this patient’s tachycardia and clinical presentation, her pretest probability according to the Wells criteria indicates increased risk. However, because her D-dimer test, lower-extremity Doppler test, and ventilation-perfusion scan were normal, pulmonary embolism is less likely.3

However, if one’s clinical suspicion is high enough, further investigation of pulmonary embolism would proceed despite the encouraging test results.

CASE CONTINUED

Our patient’s initial laboratory test results are listed in Table 1.

The cardiology consult team notes that her beta human chorionic gonadotropin (beta-hCG) level is much higher than would be expected at 12 weeks of pregnancy, and so they are concerned about the possibility of a molar pregnancy. In addition, her level of thyroid-stimulating hormone (TSH, or thyrotropin) is markedly low.

HYPERTHYROIDISM IN PREGNANCY

3. Which of the following would not explain this patient’s markedly low TSH level?

  • Graves disease
  • Molar pregnancy
  • TSH-secreting pituitary adenoma
  • Gestational transient thyrotoxicosis
  • Twin pregnancy

Hyperthyroidism (also called thyrotoxicosis) has many causes, including but not limited to Graves disease, pituitary adenoma, struma ovarii (teratoma), hCG-secreting hydatidiform mole, and thyroid carcinoma (which is rare).4 In most of these disorders, the TSH level is low while the levels of thyroxine (T4), triiodothyronine (T3), or both are high.

Symptoms of hyperthyroidism are the effect of elevated T4 and T3 levels on the target organs themselves. Common symptoms include fever, tachycardia, tremor, stare, sweating, and lid lag. Other symptoms include nervousness, delirium, hypersensitivity to heat, flushing, palpitations, fatigue, weight loss, dyspnea, weakness, increased appetite, swelling of the legs, nausea, vomiting, diarrhea, goiter, tremor, atrial fibrillation, and cardiac failure.4 In its extreme form, called thyroid storm, thyrotoxicosis can be life-threatening. The likelihood of an impending thyroid storm can be assessed by clinical variables such as the patient’s temperature and heart rate and whether he or she has heart failure or gastrointestinal manifestations.5

Graves disease, the most common cause of hyperthyroidism in pregnancy, is due to stimulation of TSH receptors by antibodies against these receptors. Graves disease is possible in this patient, but a subsequent TSH receptor antibody test is negative.

Pituitary adenomas are one of the few causes of hyperthyroidism in which the TSH level is high, not low. Therefore, this is the correct answer.

Gestational transient thyrotoxicosis is a nonautoimmune condition that results in transient hyperthyroidism of variable severity.6 Usually, it occurs in otherwise normal pregnancies without complications, but the initial manifestation is hyper- emesis.6 It can be differentiated from Graves disease by the absence of TSH receptor antibodies and by no history of thyroid disorder.7 Common symptoms of gestational transient thyrotoxicosis include weight loss (or failure to gain weight), tachycardia, and fatigue.

The reason for the transient rise in T4 may be that beta-hCG is structurally similar to TSH (and also to luteinizing hormone and follicle-stimulating hormone), so that it has mild thyroid-stimulating effects.7 Sustained high levels of beta-hCG may in time give rise to the manifestations of thyrotoxicosis.

Molar pregnancy also can cause hyper-thyroidism via elevated levels of beta-hCG. However, twin pregnancy is more common and can produce sustained levels of beta-hCG above 100,000 IU/L. In most cases of twin pregnancy, the TSH level is decreased and the T4 level transiently elevated.6 The elevated beta-hCG and the subsequent thyrotropic manifestations are thought to be directly related, and symptoms resolve when beta-hCG levels go down.6

In most cases of hyperthyroidism in pregnancy, the acute condition can be managed by a short (≤ 2-month) course of a beta-blocker. In rare cases, propylthiouracil treatment may be required. Gestational transient thyrotoxicosis is not associated with detrimental outcomes.

Case continued

Our patient’s TSH level is low and her free T4 and T3 levels are elevated. Her high beta-hCG level may be stimulating the thyroid gland and may account for the low TSH value, as well as for her tachycardia, emesis, shortness of breath, and weight loss.

After an obstetric consult, it is determined that our patient has a viable pregnancy. However, further investigation with transvaginal ultrasonography reveals that she has two viable, single-placenta, intrauterine gestations, separated by a thin chorionic membrane.

Beta-hCG and free T4 levels are significantly higher in twin pregnancies than in single pregnancies, especially in the early stages.6 In our patient, the twin pregnancy led to the elevated beta-hCG, which eventually manifested as thyrotoxicosis, which caused the shortness of breath, hyperemesis, weight loss, tachycardia, and nausea.

Shortness of breath in patients with thyrotoxicosis is well recognized but not well explained. It may be caused by decreased lung compliance, engorged capillaries in the lung, or left ventricular failure, as well as by chest pain due to increased myocardial demand or coronary artery vasospasm.4 The dyspnea is present at rest and during exertion, and the high metabolic rate is thought to lead to an inappropriate response of the ventilatory system.3,8

 

 

WHAT TREATMENT?

4. How would you treat this patient at this point?

  • No drug therapy, just supportive care
  • Propranolol (Inderal)
  • Levothyroxine
  • Propylthiouracil

Several types of drugs are used to manage hyperthyroidism.

Antithyroid drugs such as propylthiouracil, methimazole (Northyx, Tapazole), and carbimazole block thyroid hormone synthesis by inhibiting thyroid peroxidase. Propylthiouracil also blocks peripheral conversion of T4 to T3. Side effects of these agents include abnormal sense of taste, pruritus, urticaria, agranulocytosis, and hepatotoxicity.4

Usually, hyperthyroidism is treated with propylthiouracil at the smallest effective dose. This has been proven to be safe to the fetus and mother during pregnancy.9 Propylthiouracil and the other drugs in its class cross the placenta, but propylthiouracil crosses at one-quarter the rate of the other two.9

Beta-blockers are effective in the acute phase of thyrotoxicosis against tachycardia, hypertension, and atrial fibrillation. They also decrease conversion of T4 to T3, which is an added benefit. Beta-blockers can be tapered as thyroid hormone levels decrease.

A short course of a short-acting beta-blocker would be an option for our patient and would decrease her symptoms, although she does not have the typical markedly elevated T4 or T3 levels. In the long term, a beta-blocker would present a fetal risk, but short courses can be tolerated without incident.9

Radioactive iodine 131 is used in patients with Graves disease. 131Iodine therapy is safe for most adults, but in pregnancy its use is contraindicated. Fetal thyroid tissue is thought to be present after 10 weeks of gestation and could be damaged by the use of radioactive iodine. Another warning with the use of radioactive iodine is that patients should avoid close contact with other adults for a few days after treatment, and should avoid close contact with children and pregnant women for 2 to 3 weeks after treatment because of the risk of exposure to radiation emanating from the thyroid gland.

Levothyroxine is a treatment for hypothyroidism, not hyperthyroidism.

CASE CONTINUED

Our patient is treated with propranolol and monitored for several days in the hospital, during which her symptoms markedly improve. She is discharged without complications.

TAKE-HOME POINTS

The evaluation of shortness of breath in adult patients can be difficult, given the many possible causes. It is especially challenging in pregnant patients, since normal physiologic changes of pregnancy may produce these symptoms.

In many instances, cardiomyopathy must be suspected if a pregnant patient complains of shortness of breath. However, it is not the only possible cause.

A 21-year-old woman who is 12 weeks pregnant according to the date of her last menstrual period comes to the emergency department with shortness of breath and chest pain.

One week ago she began experiencing pre-syncope and shortness of breath on minimal exertion and then even at rest on most days. The shortness of breath worsened throughout the week, eventually limiting her daily activities to such a degree that she restricted herself to bed rest.

Her chest pain started today while she was sitting in church, without any apparent provocation. It is right-sided, sharp, and focal, and it does not radiate. At the same time, her shortness of breath was more severe than before, so she immediately came to the emergency department.

This is her third pregnancy; she has had one live birth and one abortion. Her last pregnancy was full-term, with routine prenatal care and no complications. However, so far during this pregnancy, she has had no prenatal care, she has not taken prenatal vitamins, and she has been unable to maintain adequate nutrition because of persistent emesis, which began early in her pregnancy and continues to occur as often as two or three times daily. She has lost 20 pounds over the past 12 weeks.

She says she has no close contacts who are sick, and she has had no fever, diarrhea, dysuria, urinary frequency or urgency, palpitations, swelling of the legs or feet, blurry vision, or increase in neck girth. She says she does not smoke or use alcohol or illicit substances. Her only previous surgery was laser-assisted in situ keratoplasty (LASIK) eye surgery in 1998. She is allergic to seafood only. She has not eaten at any new places recently. She is up to date with her childhood vaccinations. She has no family history of hypercoagulability or venous thrombotic events.

PHYSICAL EXAMINATION

She is breathing rapidly—as fast as 45 breaths per minute. Her temperature is 37.2°C (98.9°F), blood pressure 95/60 mm Hg, oxygen saturation 100% while on 10 L of oxygen using a nonrebreather mask, pulse 102 beats per minute, and weight 55.9 kg (123.2 pounds). She appears alert, oriented, and comfortable, with a thin body habitus. She has no jugular venous distention, neck mass, or thyromegaly. Her lungs are clear to auscultation, with no wheezes or rales. The cardiovascular examination is normal. She has a regular heart rate and rhythm, normal S1 and S2 sounds, and no rubs, clicks, or murmurs. Pulses in the extremities are normal, and she has no peripheral edema. The neurologic examination is normal.

Electrocardiography shows sinus tachycardia with first-degree atrioventricular block.

DIFFERENTIAL DIAGNOSIS

1. At this point, which is the most probable cause of her symptoms?

  • Pulmonary embolism
  • Peripartum cardiomyopathy
  • Acute coronary syndrome
  • Aortic dissection
  • Expected physiologic changes of pregnancy

Pulmonary embolism would be the most probable diagnosis, given the patient’s pregnancy, shortness of breath, and tachycardia and the pleuritic quality of her chest pain.

Peripartum cardiomyopathy is also a possible cause, as it may present with profound shortness of breath and markedly decreased cardiac function. But it is much less likely in this patient because she is early in her pregnancy, and peripartum cardiomyopathy usually is seen during the last month of gestation or the first months after delivery.

Acute coronary syndrome is unlikely, given her young age and the lack of significant risk factors or a supporting history.

Aortic dissection is unlikely in view of her medical history.

Physiologic changes of pregnancy. Many pregnant women experience a sensation of not being able to catch their breath or expand their lungs fully, as the diaphragm is limited by the gravid abdomen. They also present with dyspnea, fatigue, reduced exercise capacity, peripheral edema, or volume overload.1 However, these changes tend to occur gradually and worsen over time. This patient’s degree of shortness of breath and its sudden onset do not seem like normal physiologic changes of pregnancy.

Other possible causes of dyspnea in a pregnant woman include asthma, pleural empyema, pneumonia, and severe anemia. Asthma should be considered in anyone with a history of wheezing, cough, and dyspnea. Fever and sputum production would support a diagnosis of pneumonia or empyema. In addition, maternal heart disease (eg, endocarditis, pulmonary hypertension) complicates 0.2% to 3% of pregnancies.1

CASE CONTINUED

The emergency department staff decide to evaluate the patient for heart failure and pulmonary embolism.

Bedside echocardiography reveals an ejection fraction of 55% (normal range 50%–75%), normal heart function and size, and no valvular abnormalities.

Chest radiography is normal.

Lower-extremity duplex ultrasonography is negative for deep-vein thrombosis.

The D-dimer level is 380 ng/mL (normal range < 500 ng/mL).

The medical intensive care unit is consulted about the patient’s continued tachypnea and the possible need for intubation. A ventilation-perfusion scan is performed to screen for pulmonary embolism, and it is negative.

An obstetric team performs Doppler ultrasonography at the bedside; a fetal heartbeat can be heard, thus confirming a viable pregnancy.

The patient has normal serum levels of the cardiac enzymes troponin T and creatine kinase-MB fraction, thus all but ruling out myocardial ischemia.

The patient is admitted to the hospital the next day, and a cardiology consult is obtained.

 

 

RULING OUT PULMONARY EMBOLISM

2. Has pulmonary embolism been definitively ruled out at this point?

  • Yes
  • No

The answer is no. The negative ventilation-perfusion scan and normal D-dimer test in this patient are not enough to rule out pulmonary embolism. The diagnosis of pulmonary embolism should be based on the clinician’s estimation of the pretest probability of pulmonary embolism (which is based on presenting signs and symptoms), as well as on a variety of tests, including spiral computed tomography (CT), ventilation-perfusion lung scanning, and serum D-dimer testing. Signs and symptoms that may guide the clinician are chest pain (present in 70% of patients with pulmonary embolism), tachypnea (70%), cough (40%), shortness of breath (25%), and tachycardia (33%).2 A history of pregnancy, malignancy, immobility, or recent surgery may also increase the pretest probability of pulmonary embolism. In many cases, one’s clinical suspicion is highly predictive and is useful in diagnosing pulmonary embolism.

The accuracy of the tests varies widely, depending on the pretest probability of pulmonary embolism. For instance, in a patient with a high pretest probability but a low-probability ventilation-perfusion scan, the true probability of pulmonary embolism is 40%, but in a patient with a low pretest probability and a low-probability scan, the probability is only 4%.

The Wells criteria can be used to calculate the pretest probability of pulmonary embolism. Given this patient’s tachycardia and clinical presentation, her pretest probability according to the Wells criteria indicates increased risk. However, because her D-dimer test, lower-extremity Doppler test, and ventilation-perfusion scan were normal, pulmonary embolism is less likely.3

However, if one’s clinical suspicion is high enough, further investigation of pulmonary embolism would proceed despite the encouraging test results.

CASE CONTINUED

Our patient’s initial laboratory test results are listed in Table 1.

The cardiology consult team notes that her beta human chorionic gonadotropin (beta-hCG) level is much higher than would be expected at 12 weeks of pregnancy, and so they are concerned about the possibility of a molar pregnancy. In addition, her level of thyroid-stimulating hormone (TSH, or thyrotropin) is markedly low.

HYPERTHYROIDISM IN PREGNANCY

3. Which of the following would not explain this patient’s markedly low TSH level?

  • Graves disease
  • Molar pregnancy
  • TSH-secreting pituitary adenoma
  • Gestational transient thyrotoxicosis
  • Twin pregnancy

Hyperthyroidism (also called thyrotoxicosis) has many causes, including but not limited to Graves disease, pituitary adenoma, struma ovarii (teratoma), hCG-secreting hydatidiform mole, and thyroid carcinoma (which is rare).4 In most of these disorders, the TSH level is low while the levels of thyroxine (T4), triiodothyronine (T3), or both are high.

Symptoms of hyperthyroidism are the effect of elevated T4 and T3 levels on the target organs themselves. Common symptoms include fever, tachycardia, tremor, stare, sweating, and lid lag. Other symptoms include nervousness, delirium, hypersensitivity to heat, flushing, palpitations, fatigue, weight loss, dyspnea, weakness, increased appetite, swelling of the legs, nausea, vomiting, diarrhea, goiter, tremor, atrial fibrillation, and cardiac failure.4 In its extreme form, called thyroid storm, thyrotoxicosis can be life-threatening. The likelihood of an impending thyroid storm can be assessed by clinical variables such as the patient’s temperature and heart rate and whether he or she has heart failure or gastrointestinal manifestations.5

Graves disease, the most common cause of hyperthyroidism in pregnancy, is due to stimulation of TSH receptors by antibodies against these receptors. Graves disease is possible in this patient, but a subsequent TSH receptor antibody test is negative.

Pituitary adenomas are one of the few causes of hyperthyroidism in which the TSH level is high, not low. Therefore, this is the correct answer.

Gestational transient thyrotoxicosis is a nonautoimmune condition that results in transient hyperthyroidism of variable severity.6 Usually, it occurs in otherwise normal pregnancies without complications, but the initial manifestation is hyper- emesis.6 It can be differentiated from Graves disease by the absence of TSH receptor antibodies and by no history of thyroid disorder.7 Common symptoms of gestational transient thyrotoxicosis include weight loss (or failure to gain weight), tachycardia, and fatigue.

The reason for the transient rise in T4 may be that beta-hCG is structurally similar to TSH (and also to luteinizing hormone and follicle-stimulating hormone), so that it has mild thyroid-stimulating effects.7 Sustained high levels of beta-hCG may in time give rise to the manifestations of thyrotoxicosis.

Molar pregnancy also can cause hyper-thyroidism via elevated levels of beta-hCG. However, twin pregnancy is more common and can produce sustained levels of beta-hCG above 100,000 IU/L. In most cases of twin pregnancy, the TSH level is decreased and the T4 level transiently elevated.6 The elevated beta-hCG and the subsequent thyrotropic manifestations are thought to be directly related, and symptoms resolve when beta-hCG levels go down.6

In most cases of hyperthyroidism in pregnancy, the acute condition can be managed by a short (≤ 2-month) course of a beta-blocker. In rare cases, propylthiouracil treatment may be required. Gestational transient thyrotoxicosis is not associated with detrimental outcomes.

Case continued

Our patient’s TSH level is low and her free T4 and T3 levels are elevated. Her high beta-hCG level may be stimulating the thyroid gland and may account for the low TSH value, as well as for her tachycardia, emesis, shortness of breath, and weight loss.

After an obstetric consult, it is determined that our patient has a viable pregnancy. However, further investigation with transvaginal ultrasonography reveals that she has two viable, single-placenta, intrauterine gestations, separated by a thin chorionic membrane.

Beta-hCG and free T4 levels are significantly higher in twin pregnancies than in single pregnancies, especially in the early stages.6 In our patient, the twin pregnancy led to the elevated beta-hCG, which eventually manifested as thyrotoxicosis, which caused the shortness of breath, hyperemesis, weight loss, tachycardia, and nausea.

Shortness of breath in patients with thyrotoxicosis is well recognized but not well explained. It may be caused by decreased lung compliance, engorged capillaries in the lung, or left ventricular failure, as well as by chest pain due to increased myocardial demand or coronary artery vasospasm.4 The dyspnea is present at rest and during exertion, and the high metabolic rate is thought to lead to an inappropriate response of the ventilatory system.3,8

 

 

WHAT TREATMENT?

4. How would you treat this patient at this point?

  • No drug therapy, just supportive care
  • Propranolol (Inderal)
  • Levothyroxine
  • Propylthiouracil

Several types of drugs are used to manage hyperthyroidism.

Antithyroid drugs such as propylthiouracil, methimazole (Northyx, Tapazole), and carbimazole block thyroid hormone synthesis by inhibiting thyroid peroxidase. Propylthiouracil also blocks peripheral conversion of T4 to T3. Side effects of these agents include abnormal sense of taste, pruritus, urticaria, agranulocytosis, and hepatotoxicity.4

Usually, hyperthyroidism is treated with propylthiouracil at the smallest effective dose. This has been proven to be safe to the fetus and mother during pregnancy.9 Propylthiouracil and the other drugs in its class cross the placenta, but propylthiouracil crosses at one-quarter the rate of the other two.9

Beta-blockers are effective in the acute phase of thyrotoxicosis against tachycardia, hypertension, and atrial fibrillation. They also decrease conversion of T4 to T3, which is an added benefit. Beta-blockers can be tapered as thyroid hormone levels decrease.

A short course of a short-acting beta-blocker would be an option for our patient and would decrease her symptoms, although she does not have the typical markedly elevated T4 or T3 levels. In the long term, a beta-blocker would present a fetal risk, but short courses can be tolerated without incident.9

Radioactive iodine 131 is used in patients with Graves disease. 131Iodine therapy is safe for most adults, but in pregnancy its use is contraindicated. Fetal thyroid tissue is thought to be present after 10 weeks of gestation and could be damaged by the use of radioactive iodine. Another warning with the use of radioactive iodine is that patients should avoid close contact with other adults for a few days after treatment, and should avoid close contact with children and pregnant women for 2 to 3 weeks after treatment because of the risk of exposure to radiation emanating from the thyroid gland.

Levothyroxine is a treatment for hypothyroidism, not hyperthyroidism.

CASE CONTINUED

Our patient is treated with propranolol and monitored for several days in the hospital, during which her symptoms markedly improve. She is discharged without complications.

TAKE-HOME POINTS

The evaluation of shortness of breath in adult patients can be difficult, given the many possible causes. It is especially challenging in pregnant patients, since normal physiologic changes of pregnancy may produce these symptoms.

In many instances, cardiomyopathy must be suspected if a pregnant patient complains of shortness of breath. However, it is not the only possible cause.

References
  1. Dobbenga-Rhodes YA, Prive AM. Assessment and evaluation of the woman with cardiac disease during pregnancy. J Perinat Neonatal Nurs 2006; 20:295–302.
  2. Carman TL, Deitcher SR. Advances in diagnosing and excluding pulmonary embolism: spiral CT and D-dimer measurement. Cleve Clin J Med 2002; 69:721–729.
  3. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients’ probability of pulmonary embolism: increasing the model’s utility with the SimpliRED D-dimer. Thromb Haemost 2000; 83:416–420.
  4. Nayak B, Burman K. Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin North Am 2006; 35:663–686.
  5. Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin North Am 1993; 22:263–277.
  6. Grün JP, Meuris S, De Nayer P, Glinoer D. The thyrotrophic role of human chorionic gonadotrophin (hCG) in the early stages of twin (versus single) pregnancies. Clin Endocrinol (Oxf) 1997; 46:719–725.
  7. Glinoer D, De Nayer P, Robyn C, Lejeune B, Kinthaert J, Meuris S. Serum levels of intact human chorionic gonadotropin (HCG) and its free alpha and beta subunits, in relation to maternal thyroid stimulation during normal pregnancy. J Endocrinol Invest 1993; 16:881–888.
  8. Small D, Gibbons W, Levy RD, de Lucas P, Gregory W, Cosio MG. Exertional dyspnea and ventilation in hyper-thyroidism. Chest 1992; 101:1268–1273.
  9. Atkins P, Cohen SB, Phillips BJ. Drug therapy for hyper-thyroidism in pregnancy: safety issues for mother and fetus. Drug Saf 2000; 23:229–244.
References
  1. Dobbenga-Rhodes YA, Prive AM. Assessment and evaluation of the woman with cardiac disease during pregnancy. J Perinat Neonatal Nurs 2006; 20:295–302.
  2. Carman TL, Deitcher SR. Advances in diagnosing and excluding pulmonary embolism: spiral CT and D-dimer measurement. Cleve Clin J Med 2002; 69:721–729.
  3. Wells PS, Anderson DR, Rodger M, et al. Derivation of a simple clinical model to categorize patients’ probability of pulmonary embolism: increasing the model’s utility with the SimpliRED D-dimer. Thromb Haemost 2000; 83:416–420.
  4. Nayak B, Burman K. Thyrotoxicosis and thyroid storm. Endocrinol Metab Clin North Am 2006; 35:663–686.
  5. Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin North Am 1993; 22:263–277.
  6. Grün JP, Meuris S, De Nayer P, Glinoer D. The thyrotrophic role of human chorionic gonadotrophin (hCG) in the early stages of twin (versus single) pregnancies. Clin Endocrinol (Oxf) 1997; 46:719–725.
  7. Glinoer D, De Nayer P, Robyn C, Lejeune B, Kinthaert J, Meuris S. Serum levels of intact human chorionic gonadotropin (HCG) and its free alpha and beta subunits, in relation to maternal thyroid stimulation during normal pregnancy. J Endocrinol Invest 1993; 16:881–888.
  8. Small D, Gibbons W, Levy RD, de Lucas P, Gregory W, Cosio MG. Exertional dyspnea and ventilation in hyper-thyroidism. Chest 1992; 101:1268–1273.
  9. Atkins P, Cohen SB, Phillips BJ. Drug therapy for hyper-thyroidism in pregnancy: safety issues for mother and fetus. Drug Saf 2000; 23:229–244.
Issue
Cleveland Clinic Journal of Medicine - 75(11)
Issue
Cleveland Clinic Journal of Medicine - 75(11)
Page Number
788-792
Page Number
788-792
Publications
Cleveland Clinic Journal of Medicine
Publications
Cleveland Clinic Journal of Medicine
Topics
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Emergency Medicine
Cardiology
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Endocrinology
Article Type
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A young pregnant woman with shortness of breath
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Skin manifestations of diabetes

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Skin manifestations of diabetes
Author(s)
Simone Van Hattem, MD
Aart H. Bootsma, MD, PhD
H. Bing Thio, MD, PhD

Almost all diabetic patients eventually develop skin complications from the long-term effects of diabetes mellitus on the microcirculation and on skin collagen. Cutaneous infections are more common in type 2 diabetes, whereas autoimmune-related lesions are more common in type 1. Patients who have had diabetes for many years tend to develop the most devastating skin problems. However, problems can also develop in the short term, as insulins and oral hypoglycemic drugs can also have dermal side effects. Furthermore, diabetes-related cutaneous lesions may also serve as a port of entry for secondary infection.

This review aims to guide the clinician to the correct diagnosis of cutaneous manifestations associated with type 1 (Table 1) and type 2 (Table 2) diabetes mellitus, to recognize cutaneous side effects of glucose-lowering drugs, and to aid the treatment of diabetic skin disease. The classification and treatment of the diabetic foot are not within the scope of this review.

MANIFESTATIONS ASSOCIATED WITH TYPE 1 DIABETES

Periungual telangiectasia

The lesions of periungual telangiectasia, appearing as red, dilated, capillary veins, are easily visible with the naked eye and are the result of a loss of capillary loops and dilation of the remaining capillaries. A prevalence up to 49% has been described in all diabetic patients.1 Connective tissue diseases may also involve periungual telangiectases, although these lesions are morphologically different. In diabetes, periungual telangiectasia is often associated with nail fold erythema, accompanied by fingertip tenderness and “ragged” cuticles.2

Necrobiosis lipoidica

Figure 1. General appearance of necrobiosis lipoidica, consisting of nonscaling plaques in the pretibial region of the legs.
Necrobiosis lipoidica diabeticorum (Figure 1) appears in 0.3% to 1.6% of diabetic patients. Its origin is unknown. The fully developed clinical appearance is diagnostic: nonscaling plaques with a yellow atrophic center, surface telangiectases, and an erythematous or violaceous border that may be raised. The pretibial region is the area typically affected. Ulceration occurs in up to 35% of cases. Women are affected more often than men. Patients with type 1 diabetes develop necrobiosis lipoidica at an earlier mean age than those with type 2 and those without diabetes. The yellow aspect in the central area of the lesions is most likely due to thinning of the dermis, making subcutaneous fat more visible.3–5

Metabolic control has no proven effect on the course of this condition,6 although Cohen et al7 reported that tight glucose control reduced the incidence in diabetic patients. Treatment includes application of a topical steroid with or without occlusion; intralesional steroids at the active border; or, in the rare severe or extensive case, systemic steroids.6,7 In some resistant cases, aspirin, chloroquine (Aralen), and cyclosporine (Sandimmune, Neoral) have been used with some success.3,8,9

Bullosis diabeticorum

Bullosis diabeticorum develops in approximately 0.5% of diabetic patients, but more often in those with type 1 diabetes, and more often in men and in patients with long-standing diabetes with peripheral neuropathy. It presents as asymptomatic bullae containing sterile fluid on a noninflamed base, usually arising spontaneously on the dorsa and sides of the lower legs and feet, sometimes on the hands or the forearms. The cause is unknown, and it is a diagnosis of exclusion. The differential diagnosis includes epidermolysis bullosa acquisita, porphyria cutanea tarda, bullous pemphigoid, bullous impetigo, coma blisters, and erythema multiforme.

Treatment is symptomatic and conservative. In case of discomfort, the bullae can be aspirated (leaving the blister roof intact), or compresses can be used. Topical antibiotics may be required to prevent secondary infection.3 Most lesions resolve in 2 to 3 weeks without residual scarring.5,6

Vitiligo

Vitiligo vulgaris, or skin depigmentation, occurs more often in type 1 diabetic patients. From 1% to 7% of all diabetic patients have vitiligo vs 0.2% to 1% of the general population. The mechanism behind the association has not been elucidated, although some have suggested polyglandular autoimmune syndrome (PAS), a rare immune endocrinopathy characterized by the coexistence of at least two endocrine gland insufficiencies that are based on autoimmune mechanisms. PAS type 2 is more common (estimated prevalence of 1:20,000), occurs mainly in the third or fourth decade, and is characterized by adrenal failure, autoimmune thyroid disease, or type 1 diabetes. Adrenal failure may precede other endocrinopathies. Vitiligo and gonadal failure occur more frequently in PAS type 1 than in PAS type 2, whereas immunogastritis, pernicious anemia, and alopecia areata are the main features of PAS type 2. In contrast to PAS type 1, family members of PAS type 2 patients are often affected as well. PAS type 2 is believed to be polygenic, with an autosomal dominant pattern of inheritance.10

Treatment of vitiligo is unsatisfactory in general. Patients should be advised to avoid the sun and to use broad-spectrum sunscreens. For localized vitiligo, topical corticosteroids are preferred, whereas for generalized vitiligo ultraviolet B light treatment is most effective. Cosmetic treatment is an option for improved well-being.11

Oral lichen planus

Figure 2. Lichen ruber planus typically presents on the skin as flat, polygonal, erythematous lesions of the lower legs, and also on the wrists and the dorsal areas of the feet.
The association between diabetes and lichen planus (Figure 2), especially oral lichen planus, has been the subject of much research. However, most studies have examined the prevalence of diabetes mellitus in patients with lichen planus, rather than the reverse. Also, many reports do not differentiate between the types of diabetes. Petrou-Amerikanou et al12 reported a significantly higher prevalence of oral lichen planus in type 1 diabetic patients vs a control population, but not in type 2 diabetic patients.

Clinically, lichen planus presents as polygonal erythematous flat lesions. Most often affected are the wrists, the dorsa of the feet, and the lower legs. Oral lichen planus presents as white stripes in a reticular pattern.

Clinical and histopathologic differentiation of these lesions from lichenoid reactions to drugs (eg, nonsteroidal anti-inflammatory drugs, antihypertensive drugs) may be difficult, although numerous eosinophils, parakeratosis, and perivascular inflammation around the mid and deep dermal plexuses, are seen in lichenoid drug reactions, but generally not in lichen planus.13

Treatment consists of topical corticosteroids or topical cyclosporine, or both.6

 

 

SKIN MANIFESTATIONS ASSOCIATED WITH TYPE 2 DIABETES

Yellow nails

Elderly type 2 diabetic patients tend to have yellow nails. A prevalence of 40% to 50% in patients with type 2 diabetes has been reported,14 but occasionally yellow nails are also found in normal elderly people and in patients with onychomycosis. The yellow discoloration in diabetes is most evident on the distal end of the hallux nail. It probably represents end-products of glycosylation, similar to the yellow color in diabetic skin, although this has not yet been confirmed.15

Diabetic thick skin

Diabetes mellitus is generally associated with a thickening of the skin,2 measurable via ultrasonography,16 and this thickening may increase with age in all diabetic patients, unlike normally aging skin.

Diabetic thick skin occurs in three forms. First is the general asymptomatic but measurable thickening. Second is a clinically apparent thickening of the skin involving the fingers and hands. Third is diabetic scleredema, an infrequent syndrome in which the dermis of the upper back becomes markedly thickened.2,6

Thickening of the skin on the dorsum of the hands occurs in 20% to 30% of all diabetic patients, regardless of the type of diabetes.17 Manifestations range from pebbled knuckles to diabetic hand syndrome.2 Pebbled knuckles (or Huntley papules) are multiple minute papules, grouped on the extensor side of the fingers, on the knuckles, or on the periungual surface.18 The prevalence of diabetic hand syndrome varies from 8% to 50%.19 It begins with stiffness of the metacarpophalangeal and proximal interphalangeal joints and progresses to limit joint mobility.20,21 Dupuytren contracture (or palmar fascial thickening) may further complicate diabetic hand syndrome.5,22

Scleredema diabeticorum is characterized by remarkable thickening of the skin of the posterior neck and upper back, occasionally extending to the deltoid and lumbar regions. A peau d’orange appearance of the skin can occur, often with decreased sensitivity to pain and touch.

Scleredema occurs in 2.5% to 14% of people with diabetes6 and is sometimes confused with scleredema of Buschke, a rare disorder in which areas of dermal thickening occur, mostly on the face, arms, and hands, often after an upper respiratory infection. It clears spontaneously in months or years. Women are affected more often than men. These characteristics differentiate scleredema of Buschke from scleredema diabeticorum, which almost exclusively occurs in long-standing diabetes, is usually permanent, is not related to previous infection, and is limited to the posterior neck and upper back. No effective treatment is known for scleredema diabeticorum.23

Skin tags or acrochordons

Skin tags are small, pedunculated, soft, often pigmented lesions occurring on the eyelids, the neck, and the axillae. A few studies have reported an association between multiple skin tags and diabetes, and between skin tags and insulin resistance.24–27 Crook28 found that skin tags were associated with the typical atherogenic lipid profile seen in insulin-resistant states: elevated triglycerides and low levels of high-density-lipoprotein cholesterol. In a large study of patients with skin tags,24 over 25% had diabetes and 8% had impaired glucose tolerance.24

Treatment is not necessary, but skin tags can be removed with grade 1 scissors, cryotherapy, or electrodessication.28 Skin tags may be regarded as a sign of impaired glucose tolerance, diabetes, and increased cardiovascular risk.28,29

Diabetic dermopathy

Diabetic dermopathy (ie, shin spots and pigmented pretibial papules) affects 7% to 70% of all diabetic patients. It is not specific for diabetes: 20% of nondiabetic people show similar lesions. Men are affected more often than women, and the mean age is 50 years.

Shin spots present as multiple, bilateral, asymmetrical, annular or irregular red papules or plaques on the extensor surface of the lower legs and may precede abnormal glucose metabolism. The clinician usually sees only the end result: atrophic, scarred, hyperpigmented, finely scaled macules. Lesions may also be found on the forearms, thighs, and lateral malleoli. Several studies found severe microvascular complications in patients with diabetic dermopathy, indicating a close association with a high risk of accelerated diabetes complications.

Treatment is not very effective; however, some lesions resolve spontaneously.6,30

Acanthosis nigricans

Figure 3. The velvety, hyperpigmented plaques of acanthosis nigricans occur usually in body folds and are thought to be related to high levels of circulating insulin.
Acanthosis nigricans (Figure 3) presents as hyperpigmented, velvety plaques in body folds. The dark color is due to thickening of keratin-containing superficial epithelium.31 It is traditionally classified as benign in insulin-resistant states. However, it can occur as a sign of paraneoplasm (particularly in stomach cancer), as an adverse effect of certain drugs (eg, nicotinic acid, corticosteroids), and in various endocrinopathies (eg, acromegaly, Cushing syndrome, leprechaunism). Even in the insulin-resistant diabetic patient, an underlying pathologic condition should be excluded.

The pathogenesis is most likely related to high levels of circulating insulin, which binds to insulin-like growth factor receptors to stimulate the growth of keratinocytes and dermal fibroblasts.

Although the lesions are generally asymptomatic, they can be painful, malodorous, or macerated.3 The most effective treatment is lifestyle alteration. Weight reduction and exercise can reduce insulin resistance. Acanthosis nigricans is reversible with weight reduction if it is seen as a complication of obesity. If the lesions are asymptomatic, they need no treatment. Ointments containing salicylic or retinoic acid can be used to reduce thicker lesions in areas of maceration in order to decrease odor and promote comfort. Systemic isotretinoin (Accutane) improves acanthosis nigricans, but it recurs when the drug is discontinued.3,5,6,32

Acquired perforating dermatosis

Acquired perforating dermatosis is seen in patients with kidney failure, type 2 diabetes, or type 1 diabetes. A prevalence of up to 10% has been reported in dialysis patients.33,34

The characteristic lesions are 2- to 10-mm, pruritic, dome-shaped papules and nodules with a hyperkeratotic plug. They occur mainly on the limbs, the trunk, and the dorsal surface of the hands, and to a lesser extent on the face. The Koebner phenomenon (also called isomorphic effect) may also occur.

Histologic study shows a hyperplastic epidermis with marked spongiosis directly over the plug. The contents of the plug itself are collagen, elastic fibers, nuclear debris, and polymorphonuclear leukocytes. These leukocytes have been implicated in the pathogenesis of acquired perforating dermatosis.6,17

The lesions are chronic but may heal after months if trauma and scratching are avoided. Further treatments include topical keratolytics, psoralen-ultraviolet A light, ultraviolet B light, topical and systemic retinoids, topical and intralesional steroids, oral antihistamines, and cryotherapy.6

 

 

Calciphylaxis

Calciphylaxis is a small-vessel vasculopathy accompanied by mural calcification with intimal proliferation, fibrosis, and thrombosis. It occurs mostly in patients with renal failure and causes a spectrum of end-organ damage due to ischemia. The reported prevalence is 1% to 4% in the dialysis population.

Damage is seen in the epidermal and the subcutaneous tissues. First, redness and tenderness evolve in a small area, which may be surrounded by ecchymosis or pallor, and eventually ischemia leads to the development of subcutaneous nodules and poor-healing, necrotizing skin ulcers. These ulcers serve as a port of entry for infectious agents.

Calciphylaxis has a predilection for vascular regions with thicker subcutaneous adipose tissue, such as the breasts, abdomen, and thighs. In renal failure patients, those who are women, white, obese, or diabetic (especially those with type 2 diabetes) are considered at risk.

Histologic features are medial wall calcification and fibrous expansion in capillaries, venules, arterioles, and small arteries of dermis and subcutaneous fat. Calciphylaxis should not be considered a small-vessel variant of Mönckeberg calcification, which is a medial wall calcification of medium and large vessels. Mönckeberg calcification has been described in patients with diabetes, renal failure, or vitamin D intoxification.

The outcome of calciphylaxis is poor because of impaired wound-healing and infection of the skin with progression to sepsis. Extremely aggressive treatment with analgesics is required for ischemic pain. Furthermore, weight reduction and aggressive control of blood sugar levels seem prudent.35

Eruptive xanthoma

Eruptive xanthoma presents as crops of small (1- to 2-mm) yellow papules with an erythematous halo; these papules may be pruritic and tender. They occur in less than 0.1% of diabetic patients.36 Areas of predilection are extensor surfaces and the buttocks.20

The key histologic feature is the formation of foam cells in the superficial dermis that are mixed with a lymphocytic and neutrophilic infiltrate.

Eruptive xanthomas appear in association with elevated levels of triglyceride-rich lipoproteins. The lipid changes appear in association with familial hypertriglyceridemia and diabetes mellitus, resulting in hypertriglyceridemia from a lack of lipoprotein lipase activity and impaired clearance of chylomicrons and very-low-density lipoproteins. These eruptive xanthomas tend to resolve with control of carbohydrate and lipid metabolism.5,6,17

Granuloma annulare: Not linked to diabetes

Although many have tried to prove an association between localized granuloma annulare and diabetes, no association has been clearly established, and the association between generalized (disseminated) granuloma annulare and diabetes is controversial.21

The cause is not known. The lesions are oval or ring-shaped, with a raised border of skin-colored or erythematous papules. The size varies from millimeters to centimeters. The dorsa of the hands and arms are the areas usually affected. Histologically, the epidermis usually appears normal, whereas the upper and mid dermis show focal degeneration of collagen, palisaded histiocytes around collagen bundles, and abundant mucin.

Localized lesions often resolve spontaneously, whereas the generalized form has a more protracted course which, in rare cases, resolves spontaneously. Sporadic therapeutic success has been reported with topical, systemic, and intralesional steroids; isotretinoin; chlorambucil (Leukeran); cryotherapy; chlorpropamide (Diabinese); chloroquine; potassium iodide/nicotinamide; dapsone; antimalarials; and psoralen-ultraviolet A light.5,6,20

CUTANEOUS INFECTIONS

Skin infections occur in 20% to 50% of diabetic patients (more often in those with type 2 diabetes) and are often associated with poor glycemic control (Table 3). Poor microcirculation, peripheral vascular disease, peripheral neuropathy, and decreased immune response have been implicated in the increased susceptibility to infection.

Candidal infection

A candidal infection (moniliasis) can be an early sign of undiagnosed diabetes. Perlèche is a classic sign of diabetes in children, and localized candidal infection of the female genitalia has a strong association with diabetes. This infection appears as erythema with scaling and typical satellite papules and pustules. Paronychia is another sign.

It is important to remember that in men, Candida balanitis, balanoposthitis, and intertrigo can be presenting signs of diabetes.

Candidal infections improve with adequate metabolic control and treatment with topical midazoles or nystatin (Mycostatin).5,37

Infections with dermatophytes

Common superficial infections are caused by Trichophyton rubrum, T mentagrophytes, and Epidermophyton floccosum. In diabetic patients, onychomycosis or tinea pedis needs to be monitored for and treated, as it can be a port of entry for infection. This is especially true for patients with neurovascular complications and intertrigo.

Signs of T rubrum infection are noninflamed, white, powdery scaling or skin creases on the palms and soles, often with nail involvement. T mentagrophytes-associated intertrigo or interdigital infection presents as maceration and superficial scaling with an active red border. Treatments of choice are drying the local area and applying one of the newer topical imidazole antifungal agents.5,37

 

 

Bacterial infections

Pyodermic infections such as impetigo, folliculitis, carbuncles, furunculosis, ecthyma, and erysipelas can be more severe and widespread in diabetic patients. Therapy consists of adequate diabetic control and, if necessary, adequate systemic antibiotic therapy; deeper infections require intravenous antibiotics.

Erythrasma, caused by Corynebacterium minutissimum, occurs with increased frequency in obese diabetic patients, but it is often missed. Intertriginous areas are the main affected site. Sweat, friction, and maceration play a role in the development. Erythrasma presents as shiny, hyperpigmented patches with an active border. With the Wood’s lamp, a characteristic coral fluorescence is seen. Treatment consists of topical or systemic erythromycin, or both. Prevention of sweating, friction, and maceration can limit the chances of developing this infection.5,6,37

Rare infections

Poor metabolic control and ketoacidosis may set the stage for severe infections by otherwise nonpathogenic microorganisms, such as mucormycosis by Phycomycetes and anaerobic cellulitis by Clostridium species. Treatment consists of metabolic control, aggressive debride ment of devitalized tissue, and intravenous antimicrobial therapy.37

In older diabetic patients, malignant otitis externa, often caused by Pseudomonas aeruginosa, can be fatal. This invasive infection may spread from the external auditory canal to the base of the skull, the meninges, and the brain itself. Treatment consists of irrigation and drainage of the ear canal, antibiotics, and sometimes debridement. A cure rate of more than 90% can be achieved using parenteral or oral quinolones.3

CUTANEOUS REACTIONS TO INSULIN

Impurities in insulin preparations, the presence of cow or pig proteins, the insulin molecule itself, preservatives, or additives cause allergic reactions. The use of human recombinant insulin has decreased the incidence of insulin allergy, so that now it is reported in fewer than 1% of diabetic patients treated with insulin.6

Allergic reactions to insulin can be classified as immediate-local, generalized, delayed, or biphasic.

Immediate-local reactions reach maximum intensity in 15 to 30 minutes and usually subside within 1 hour. Clinically, one finds erythema, which may become urticarial. This reaction probably is mediated by immunoglobulin E (IgE).

Generalized reactions. Immediate reactions may progress to generalized erythema and urticaria. Anaphylaxis is unusual.

Delayed hypersensitivity reactions are the most common. They usually appear about 2 weeks after the start of insulin therapy as an itchy nodule at the site of injection, 4 to 24 hours after injection.

Biphasic, or dual, reactions are rare events and consist of an immediate and a delayed local reaction, often with a generalized illness resembling serum sickness. They are considered Arthus-immune complex reactions.6

Other complications of insulin injections

Other local cutaneous complications include keloids, hyperkeratotic papules, purpura, and localized pigmentation.

The treatment of choice for localized immediate allergic reactions is a change of insulin to a more purified product.17 Other tools to manage allergic reactions are antihistamines, the addition of glucocorticoids to insulin, discontinuation of therapy, desensitization therapy, or a change in the insulin delivery system.5,6

The most important immunologic problem is IgE-mediated anaphylaxis, which can be managed by temporary reduction in dose or by insulin desensitization. Serum sickness responds to corticosteroid therapy.38

Insulin therapy may also cause lipoatrophy and lipohypertrophy that can coexist in the same patient. Lipoatrophy presents as circumscribed, depressed areas of skin at the insulin injection site 6 to 24 months after the start of therapy. Children and obese women are affected most often. It may be caused by lipolytic components in the insulin preparation or by an inflammatory process mediated by the immune complex. Other theories involve cryotrauma from refrigerated insulin, mechanical trauma due to the angle of injection, surface alcohol contamination, or local hyperproduction of tumor necrosis factor alpha from macrophages induced by injected insulin. Since the introduction of purified recombinant human insulin, lipoatrophy has become rare.37,39 Duration of the presence of an insulin depot has been implicated as well. That is why Murao et al40 suggested substituting rapid-acting insulin.

Lipohypertrophy clinically resembles lipoma and presents as soft dermal nodules at the site of frequent injections. Lipohypertrophy is regarded as a local response to the lipogenic action of insulin and can be prevented by rotation of the injection site.5,17,37

SKIN EFFECTS OF INSULIN ANALOGUES

Cutaneous side effects are not often described in insulin analogues, but there have been case reports. A case of IgE-mediated anaphylaxis41 and one case of vitiligo42 were described with insulin lispro. One case of allergy was described with insulin glargine.43 Although insulin detemir is well tolerated in general, several cases of local injection site reactions have been reported.44,45 Treatment depends on the extent of the reaction and can include desensitization, changing the type of insulin, rotating the injection site, or a combination of these.41–45

 

 

SKIN EFFECTS OF ORAL HYPOGLYCEMIC AGENTS

First-generation sulfonylureas

Figure 4. (Left) Erythema exsudativum multiforme and (above) erythema nodosum in diabetic patients taking a first-generation sulfonylurea.
Most cutaneous reactions to oral hypoglycemic drugs have been reported with first-generation sulfonylureas (eg, chlorpropamide, tolbutamide [Orinase]). Between 1% and 5% of patients taking first-generation sulfonylureas develop cutaneous reactions within the first 2 months of treatment. Maculopapular eruptions are the most common reaction and often disappear with discontinuation of the medication. Other cutaneous reactions are generalized erythema, urticaria, lichenoid eruptions, erythema exsudativum multiforme (Figure 4), exfoliative dermatitis, erythema nodosum (Figure 4), and photosensitivity reactions. Even if a photo-patch test is negative in a patient with a photosensitivity reaction, the oral glucose-lowering drug should be switched.

In 10% to 30% of patients using chlorpropamide, an alcohol flush is induced, consisting of redness and warmth, headache, tachycardia, and occasionally dyspnea, starting about 15 minutes after alcohol consumption. Usually, the symptoms disappear after an hour. This reaction pattern seems to be inherited in an autosomal-dominant pattern.6,37

Second-generation sulfonylureas

Second-generation sulfonylureas such as glipizide (Glucotrol) and glimepiride (Amaryl) have also been associated with cutaneous reactions. The most frequent reactions associated with glipizide are photosensitivity, rash, urticaria, and pruritus. These are reported less often with glimepiride. Deerochanawong46 reported patients with skin rash after the use of glimepiride. A case of lichenoid drug eruption was described by Noakes.47

Other oral hypoglycemic drugs

Metformin (Glucophage), a biguanide-derivative antihyperglycemic drug, is the first-choice oral drug in type 2 diabetic patients. Dermal side effects reported include psoriatiform drug eruption,48 erythema exsudativum multiforme,49 and leukocytoclastic vasculitis.50,51Litt’s Drug Eruption Manual gives the risk of photosensitivity reaction to metformin as 1% to 10%52 but cites no reference for this statement. Erythema, exanthema, pruritus, and urticaria have also been reported as side effects of metformin.52

Acarbose (Precose) is minimally absorbed from the gut: only about 1% of a dose reaches the bloodstream,53 and thus it seldom causes adverse effects. Kono et al54 reported a case of acarbose-induced generalized erythema multiforme confirmed by a challenge test. The drug-induced lymphocyte stimulation test and patch test for acarbose were negative. Ahr et al55 reported that acarbose labeled with carbon 14 was poorly absorbed when given orally, but that up to 35% of this formulation of acarbose was absorbed after degradation by digestive enzymes, intestinal microorganisms, or both. Because the drug-induced lymphocyte stimulation test and the patch test were negative in the patient described by Kono et al,54 it is possible that the degradation products of acarbose induced the allergic reaction after absorption. Poszepczynska-Guigné et al56 described the first case of acute generalized exanthematous pustulosis induced after administration of acarbose.

Thiazolidinediones. Edema has been reported as an adverse cutaneous effect of rosiglitazone (Avandia) and pioglitazone (Actos).52

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  43. Durand-Gonzalez KN, Guillausseau N, Pecquet C, Gayno JP. Glargine insulin is not an alternative in insulin allergy. Diabetes Care 2003; 26:2216.
  44. Blumer IR. Severe injection site reaction to insulin detemir. Diabetes Care 2006; 29:946.
  45. Darmon P, Castera V, Koeppel MC, Petitjean C, Dutour A. Type III allergy to insulin detemir. Diabetes Care 2005; 28:2980.
  46. Deerochanawong C, Chandraprasert S. Glimepiride in type 2 diabetes mellitus Thai patients. J Med Assoc Thai 2001; 84:1221–1228.
  47. Noakes R. Lichenoid drug eruption as a result of the recently released sulfonylurea glimepiride. Australas J Dermatol 2003; 44:302–303.
  48. Koca R, Altinyazar HC, Yenidünya S, Tekin NS. Psoriasiform [sic] drug eruption associated with metformin hydrochloride: a case report. Dermatol Online J 2003; 9:11. http://dermatology.cdlib.org/93/case_reports/metformin/koca.html. Accessed July 30, 2008.
  49. Burger DE, Goyal S. Erythema multiforme from metformin. Ann Pharmacother 2004; 38:1537.
  50. Klapholz L, Leitersdorf E, Weinrauch L. Leucocytoclastic vasculitis and pneumonitis induced by metformin. BMJ (Clin Res Ed) 1986; 293:483.
  51. Ben Salem C, Hmouda H, Slim R, Denguezli M, Belajouza C, Bouraoui K. Rare case of metformin-induced leucocytoclastic vasculitis. Ann Pharmacother 2006; 40:1685–1687.
  52. Litt JZ. Litt’s Drug Eruption Reference Manual. London: Taylor and Francis, 2001.
  53. Balfour JA, McTavish D. Acarbose: an update of its pharmacology and therapeutic use in diabetes mellitus. Drugs 1993; 46:1024–1054. Erratum in: Drugs 1994; 48:929.
  54. Kono T, Hayami M, Kobayashi H, Ishii M, Taniguchi S. Acarbose-induced generalized erythema multiforme. Lancet 1999; 354:396–397.
  55. Ahr HJ, Boberg M, Krause HP, et al. Pharmacokinetics of acarbose. Part 1: Absorption, concentration in plasma, metabolism, and excretion after single administration of 14C acarbose to rats, dogs and man. Arzneimittelforschung 1989; 39:1254–1260.
  56. Poszepczynska-Guigné E, Viguier M, Assier H, Pinquier L, Hochedez P, Dubertret L. Acute generalized exanthematous pustulosis induced by drugs with low-digestive absorption: acarbose and nystatin. Ann Dermatol Venereol 2003; 130:439–442.
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Aart H. Bootsma, MD, PhD
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands

H. Bing Thio, MD, PhD
Department of Dermatology, Erasmus Medical Center, Rotterdam, Netherlands

Address: H. Bing Thio, MD, PhD, Department of Dermatology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, Netherlands; e-mail [email protected]

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Cleveland Clinic Journal of Medicine - 75(11)
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Type 2 Diabetes ICYMI
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Aart H. Bootsma, MD, PhD
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H. Bing Thio, MD, PhD
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Simone Van Hattem, MD
Department of Dermatology, Amphia Hospital, Breda, Netherlands, and Department of Dermatology, Erasmus Medical Center, Rotterdam, Netherlands

Aart H. Bootsma, MD, PhD
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands

H. Bing Thio, MD, PhD
Department of Dermatology, Erasmus Medical Center, Rotterdam, Netherlands

Address: H. Bing Thio, MD, PhD, Department of Dermatology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, Netherlands; e-mail [email protected]

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Department of Dermatology, Amphia Hospital, Breda, Netherlands, and Department of Dermatology, Erasmus Medical Center, Rotterdam, Netherlands

Aart H. Bootsma, MD, PhD
Department of Internal Medicine, Erasmus Medical Center, Rotterdam, Netherlands

H. Bing Thio, MD, PhD
Department of Dermatology, Erasmus Medical Center, Rotterdam, Netherlands

Address: H. Bing Thio, MD, PhD, Department of Dermatology, Erasmus Medical Center, PO Box 2040, 3000 CA Rotterdam, Netherlands; e-mail [email protected]

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Almost all diabetic patients eventually develop skin complications from the long-term effects of diabetes mellitus on the microcirculation and on skin collagen. Cutaneous infections are more common in type 2 diabetes, whereas autoimmune-related lesions are more common in type 1. Patients who have had diabetes for many years tend to develop the most devastating skin problems. However, problems can also develop in the short term, as insulins and oral hypoglycemic drugs can also have dermal side effects. Furthermore, diabetes-related cutaneous lesions may also serve as a port of entry for secondary infection.

This review aims to guide the clinician to the correct diagnosis of cutaneous manifestations associated with type 1 (Table 1) and type 2 (Table 2) diabetes mellitus, to recognize cutaneous side effects of glucose-lowering drugs, and to aid the treatment of diabetic skin disease. The classification and treatment of the diabetic foot are not within the scope of this review.

MANIFESTATIONS ASSOCIATED WITH TYPE 1 DIABETES

Periungual telangiectasia

The lesions of periungual telangiectasia, appearing as red, dilated, capillary veins, are easily visible with the naked eye and are the result of a loss of capillary loops and dilation of the remaining capillaries. A prevalence up to 49% has been described in all diabetic patients.1 Connective tissue diseases may also involve periungual telangiectases, although these lesions are morphologically different. In diabetes, periungual telangiectasia is often associated with nail fold erythema, accompanied by fingertip tenderness and “ragged” cuticles.2

Necrobiosis lipoidica

Figure 1. General appearance of necrobiosis lipoidica, consisting of nonscaling plaques in the pretibial region of the legs.
Necrobiosis lipoidica diabeticorum (Figure 1) appears in 0.3% to 1.6% of diabetic patients. Its origin is unknown. The fully developed clinical appearance is diagnostic: nonscaling plaques with a yellow atrophic center, surface telangiectases, and an erythematous or violaceous border that may be raised. The pretibial region is the area typically affected. Ulceration occurs in up to 35% of cases. Women are affected more often than men. Patients with type 1 diabetes develop necrobiosis lipoidica at an earlier mean age than those with type 2 and those without diabetes. The yellow aspect in the central area of the lesions is most likely due to thinning of the dermis, making subcutaneous fat more visible.3–5

Metabolic control has no proven effect on the course of this condition,6 although Cohen et al7 reported that tight glucose control reduced the incidence in diabetic patients. Treatment includes application of a topical steroid with or without occlusion; intralesional steroids at the active border; or, in the rare severe or extensive case, systemic steroids.6,7 In some resistant cases, aspirin, chloroquine (Aralen), and cyclosporine (Sandimmune, Neoral) have been used with some success.3,8,9

Bullosis diabeticorum

Bullosis diabeticorum develops in approximately 0.5% of diabetic patients, but more often in those with type 1 diabetes, and more often in men and in patients with long-standing diabetes with peripheral neuropathy. It presents as asymptomatic bullae containing sterile fluid on a noninflamed base, usually arising spontaneously on the dorsa and sides of the lower legs and feet, sometimes on the hands or the forearms. The cause is unknown, and it is a diagnosis of exclusion. The differential diagnosis includes epidermolysis bullosa acquisita, porphyria cutanea tarda, bullous pemphigoid, bullous impetigo, coma blisters, and erythema multiforme.

Treatment is symptomatic and conservative. In case of discomfort, the bullae can be aspirated (leaving the blister roof intact), or compresses can be used. Topical antibiotics may be required to prevent secondary infection.3 Most lesions resolve in 2 to 3 weeks without residual scarring.5,6

Vitiligo

Vitiligo vulgaris, or skin depigmentation, occurs more often in type 1 diabetic patients. From 1% to 7% of all diabetic patients have vitiligo vs 0.2% to 1% of the general population. The mechanism behind the association has not been elucidated, although some have suggested polyglandular autoimmune syndrome (PAS), a rare immune endocrinopathy characterized by the coexistence of at least two endocrine gland insufficiencies that are based on autoimmune mechanisms. PAS type 2 is more common (estimated prevalence of 1:20,000), occurs mainly in the third or fourth decade, and is characterized by adrenal failure, autoimmune thyroid disease, or type 1 diabetes. Adrenal failure may precede other endocrinopathies. Vitiligo and gonadal failure occur more frequently in PAS type 1 than in PAS type 2, whereas immunogastritis, pernicious anemia, and alopecia areata are the main features of PAS type 2. In contrast to PAS type 1, family members of PAS type 2 patients are often affected as well. PAS type 2 is believed to be polygenic, with an autosomal dominant pattern of inheritance.10

Treatment of vitiligo is unsatisfactory in general. Patients should be advised to avoid the sun and to use broad-spectrum sunscreens. For localized vitiligo, topical corticosteroids are preferred, whereas for generalized vitiligo ultraviolet B light treatment is most effective. Cosmetic treatment is an option for improved well-being.11

Oral lichen planus

Figure 2. Lichen ruber planus typically presents on the skin as flat, polygonal, erythematous lesions of the lower legs, and also on the wrists and the dorsal areas of the feet.
The association between diabetes and lichen planus (Figure 2), especially oral lichen planus, has been the subject of much research. However, most studies have examined the prevalence of diabetes mellitus in patients with lichen planus, rather than the reverse. Also, many reports do not differentiate between the types of diabetes. Petrou-Amerikanou et al12 reported a significantly higher prevalence of oral lichen planus in type 1 diabetic patients vs a control population, but not in type 2 diabetic patients.

Clinically, lichen planus presents as polygonal erythematous flat lesions. Most often affected are the wrists, the dorsa of the feet, and the lower legs. Oral lichen planus presents as white stripes in a reticular pattern.

Clinical and histopathologic differentiation of these lesions from lichenoid reactions to drugs (eg, nonsteroidal anti-inflammatory drugs, antihypertensive drugs) may be difficult, although numerous eosinophils, parakeratosis, and perivascular inflammation around the mid and deep dermal plexuses, are seen in lichenoid drug reactions, but generally not in lichen planus.13

Treatment consists of topical corticosteroids or topical cyclosporine, or both.6

 

 

SKIN MANIFESTATIONS ASSOCIATED WITH TYPE 2 DIABETES

Yellow nails

Elderly type 2 diabetic patients tend to have yellow nails. A prevalence of 40% to 50% in patients with type 2 diabetes has been reported,14 but occasionally yellow nails are also found in normal elderly people and in patients with onychomycosis. The yellow discoloration in diabetes is most evident on the distal end of the hallux nail. It probably represents end-products of glycosylation, similar to the yellow color in diabetic skin, although this has not yet been confirmed.15

Diabetic thick skin

Diabetes mellitus is generally associated with a thickening of the skin,2 measurable via ultrasonography,16 and this thickening may increase with age in all diabetic patients, unlike normally aging skin.

Diabetic thick skin occurs in three forms. First is the general asymptomatic but measurable thickening. Second is a clinically apparent thickening of the skin involving the fingers and hands. Third is diabetic scleredema, an infrequent syndrome in which the dermis of the upper back becomes markedly thickened.2,6

Thickening of the skin on the dorsum of the hands occurs in 20% to 30% of all diabetic patients, regardless of the type of diabetes.17 Manifestations range from pebbled knuckles to diabetic hand syndrome.2 Pebbled knuckles (or Huntley papules) are multiple minute papules, grouped on the extensor side of the fingers, on the knuckles, or on the periungual surface.18 The prevalence of diabetic hand syndrome varies from 8% to 50%.19 It begins with stiffness of the metacarpophalangeal and proximal interphalangeal joints and progresses to limit joint mobility.20,21 Dupuytren contracture (or palmar fascial thickening) may further complicate diabetic hand syndrome.5,22

Scleredema diabeticorum is characterized by remarkable thickening of the skin of the posterior neck and upper back, occasionally extending to the deltoid and lumbar regions. A peau d’orange appearance of the skin can occur, often with decreased sensitivity to pain and touch.

Scleredema occurs in 2.5% to 14% of people with diabetes6 and is sometimes confused with scleredema of Buschke, a rare disorder in which areas of dermal thickening occur, mostly on the face, arms, and hands, often after an upper respiratory infection. It clears spontaneously in months or years. Women are affected more often than men. These characteristics differentiate scleredema of Buschke from scleredema diabeticorum, which almost exclusively occurs in long-standing diabetes, is usually permanent, is not related to previous infection, and is limited to the posterior neck and upper back. No effective treatment is known for scleredema diabeticorum.23

Skin tags or acrochordons

Skin tags are small, pedunculated, soft, often pigmented lesions occurring on the eyelids, the neck, and the axillae. A few studies have reported an association between multiple skin tags and diabetes, and between skin tags and insulin resistance.24–27 Crook28 found that skin tags were associated with the typical atherogenic lipid profile seen in insulin-resistant states: elevated triglycerides and low levels of high-density-lipoprotein cholesterol. In a large study of patients with skin tags,24 over 25% had diabetes and 8% had impaired glucose tolerance.24

Treatment is not necessary, but skin tags can be removed with grade 1 scissors, cryotherapy, or electrodessication.28 Skin tags may be regarded as a sign of impaired glucose tolerance, diabetes, and increased cardiovascular risk.28,29

Diabetic dermopathy

Diabetic dermopathy (ie, shin spots and pigmented pretibial papules) affects 7% to 70% of all diabetic patients. It is not specific for diabetes: 20% of nondiabetic people show similar lesions. Men are affected more often than women, and the mean age is 50 years.

Shin spots present as multiple, bilateral, asymmetrical, annular or irregular red papules or plaques on the extensor surface of the lower legs and may precede abnormal glucose metabolism. The clinician usually sees only the end result: atrophic, scarred, hyperpigmented, finely scaled macules. Lesions may also be found on the forearms, thighs, and lateral malleoli. Several studies found severe microvascular complications in patients with diabetic dermopathy, indicating a close association with a high risk of accelerated diabetes complications.

Treatment is not very effective; however, some lesions resolve spontaneously.6,30

Acanthosis nigricans

Figure 3. The velvety, hyperpigmented plaques of acanthosis nigricans occur usually in body folds and are thought to be related to high levels of circulating insulin.
Acanthosis nigricans (Figure 3) presents as hyperpigmented, velvety plaques in body folds. The dark color is due to thickening of keratin-containing superficial epithelium.31 It is traditionally classified as benign in insulin-resistant states. However, it can occur as a sign of paraneoplasm (particularly in stomach cancer), as an adverse effect of certain drugs (eg, nicotinic acid, corticosteroids), and in various endocrinopathies (eg, acromegaly, Cushing syndrome, leprechaunism). Even in the insulin-resistant diabetic patient, an underlying pathologic condition should be excluded.

The pathogenesis is most likely related to high levels of circulating insulin, which binds to insulin-like growth factor receptors to stimulate the growth of keratinocytes and dermal fibroblasts.

Although the lesions are generally asymptomatic, they can be painful, malodorous, or macerated.3 The most effective treatment is lifestyle alteration. Weight reduction and exercise can reduce insulin resistance. Acanthosis nigricans is reversible with weight reduction if it is seen as a complication of obesity. If the lesions are asymptomatic, they need no treatment. Ointments containing salicylic or retinoic acid can be used to reduce thicker lesions in areas of maceration in order to decrease odor and promote comfort. Systemic isotretinoin (Accutane) improves acanthosis nigricans, but it recurs when the drug is discontinued.3,5,6,32

Acquired perforating dermatosis

Acquired perforating dermatosis is seen in patients with kidney failure, type 2 diabetes, or type 1 diabetes. A prevalence of up to 10% has been reported in dialysis patients.33,34

The characteristic lesions are 2- to 10-mm, pruritic, dome-shaped papules and nodules with a hyperkeratotic plug. They occur mainly on the limbs, the trunk, and the dorsal surface of the hands, and to a lesser extent on the face. The Koebner phenomenon (also called isomorphic effect) may also occur.

Histologic study shows a hyperplastic epidermis with marked spongiosis directly over the plug. The contents of the plug itself are collagen, elastic fibers, nuclear debris, and polymorphonuclear leukocytes. These leukocytes have been implicated in the pathogenesis of acquired perforating dermatosis.6,17

The lesions are chronic but may heal after months if trauma and scratching are avoided. Further treatments include topical keratolytics, psoralen-ultraviolet A light, ultraviolet B light, topical and systemic retinoids, topical and intralesional steroids, oral antihistamines, and cryotherapy.6

 

 

Calciphylaxis

Calciphylaxis is a small-vessel vasculopathy accompanied by mural calcification with intimal proliferation, fibrosis, and thrombosis. It occurs mostly in patients with renal failure and causes a spectrum of end-organ damage due to ischemia. The reported prevalence is 1% to 4% in the dialysis population.

Damage is seen in the epidermal and the subcutaneous tissues. First, redness and tenderness evolve in a small area, which may be surrounded by ecchymosis or pallor, and eventually ischemia leads to the development of subcutaneous nodules and poor-healing, necrotizing skin ulcers. These ulcers serve as a port of entry for infectious agents.

Calciphylaxis has a predilection for vascular regions with thicker subcutaneous adipose tissue, such as the breasts, abdomen, and thighs. In renal failure patients, those who are women, white, obese, or diabetic (especially those with type 2 diabetes) are considered at risk.

Histologic features are medial wall calcification and fibrous expansion in capillaries, venules, arterioles, and small arteries of dermis and subcutaneous fat. Calciphylaxis should not be considered a small-vessel variant of Mönckeberg calcification, which is a medial wall calcification of medium and large vessels. Mönckeberg calcification has been described in patients with diabetes, renal failure, or vitamin D intoxification.

The outcome of calciphylaxis is poor because of impaired wound-healing and infection of the skin with progression to sepsis. Extremely aggressive treatment with analgesics is required for ischemic pain. Furthermore, weight reduction and aggressive control of blood sugar levels seem prudent.35

Eruptive xanthoma

Eruptive xanthoma presents as crops of small (1- to 2-mm) yellow papules with an erythematous halo; these papules may be pruritic and tender. They occur in less than 0.1% of diabetic patients.36 Areas of predilection are extensor surfaces and the buttocks.20

The key histologic feature is the formation of foam cells in the superficial dermis that are mixed with a lymphocytic and neutrophilic infiltrate.

Eruptive xanthomas appear in association with elevated levels of triglyceride-rich lipoproteins. The lipid changes appear in association with familial hypertriglyceridemia and diabetes mellitus, resulting in hypertriglyceridemia from a lack of lipoprotein lipase activity and impaired clearance of chylomicrons and very-low-density lipoproteins. These eruptive xanthomas tend to resolve with control of carbohydrate and lipid metabolism.5,6,17

Granuloma annulare: Not linked to diabetes

Although many have tried to prove an association between localized granuloma annulare and diabetes, no association has been clearly established, and the association between generalized (disseminated) granuloma annulare and diabetes is controversial.21

The cause is not known. The lesions are oval or ring-shaped, with a raised border of skin-colored or erythematous papules. The size varies from millimeters to centimeters. The dorsa of the hands and arms are the areas usually affected. Histologically, the epidermis usually appears normal, whereas the upper and mid dermis show focal degeneration of collagen, palisaded histiocytes around collagen bundles, and abundant mucin.

Localized lesions often resolve spontaneously, whereas the generalized form has a more protracted course which, in rare cases, resolves spontaneously. Sporadic therapeutic success has been reported with topical, systemic, and intralesional steroids; isotretinoin; chlorambucil (Leukeran); cryotherapy; chlorpropamide (Diabinese); chloroquine; potassium iodide/nicotinamide; dapsone; antimalarials; and psoralen-ultraviolet A light.5,6,20

CUTANEOUS INFECTIONS

Skin infections occur in 20% to 50% of diabetic patients (more often in those with type 2 diabetes) and are often associated with poor glycemic control (Table 3). Poor microcirculation, peripheral vascular disease, peripheral neuropathy, and decreased immune response have been implicated in the increased susceptibility to infection.

Candidal infection

A candidal infection (moniliasis) can be an early sign of undiagnosed diabetes. Perlèche is a classic sign of diabetes in children, and localized candidal infection of the female genitalia has a strong association with diabetes. This infection appears as erythema with scaling and typical satellite papules and pustules. Paronychia is another sign.

It is important to remember that in men, Candida balanitis, balanoposthitis, and intertrigo can be presenting signs of diabetes.

Candidal infections improve with adequate metabolic control and treatment with topical midazoles or nystatin (Mycostatin).5,37

Infections with dermatophytes

Common superficial infections are caused by Trichophyton rubrum, T mentagrophytes, and Epidermophyton floccosum. In diabetic patients, onychomycosis or tinea pedis needs to be monitored for and treated, as it can be a port of entry for infection. This is especially true for patients with neurovascular complications and intertrigo.

Signs of T rubrum infection are noninflamed, white, powdery scaling or skin creases on the palms and soles, often with nail involvement. T mentagrophytes-associated intertrigo or interdigital infection presents as maceration and superficial scaling with an active red border. Treatments of choice are drying the local area and applying one of the newer topical imidazole antifungal agents.5,37

 

 

Bacterial infections

Pyodermic infections such as impetigo, folliculitis, carbuncles, furunculosis, ecthyma, and erysipelas can be more severe and widespread in diabetic patients. Therapy consists of adequate diabetic control and, if necessary, adequate systemic antibiotic therapy; deeper infections require intravenous antibiotics.

Erythrasma, caused by Corynebacterium minutissimum, occurs with increased frequency in obese diabetic patients, but it is often missed. Intertriginous areas are the main affected site. Sweat, friction, and maceration play a role in the development. Erythrasma presents as shiny, hyperpigmented patches with an active border. With the Wood’s lamp, a characteristic coral fluorescence is seen. Treatment consists of topical or systemic erythromycin, or both. Prevention of sweating, friction, and maceration can limit the chances of developing this infection.5,6,37

Rare infections

Poor metabolic control and ketoacidosis may set the stage for severe infections by otherwise nonpathogenic microorganisms, such as mucormycosis by Phycomycetes and anaerobic cellulitis by Clostridium species. Treatment consists of metabolic control, aggressive debride ment of devitalized tissue, and intravenous antimicrobial therapy.37

In older diabetic patients, malignant otitis externa, often caused by Pseudomonas aeruginosa, can be fatal. This invasive infection may spread from the external auditory canal to the base of the skull, the meninges, and the brain itself. Treatment consists of irrigation and drainage of the ear canal, antibiotics, and sometimes debridement. A cure rate of more than 90% can be achieved using parenteral or oral quinolones.3

CUTANEOUS REACTIONS TO INSULIN

Impurities in insulin preparations, the presence of cow or pig proteins, the insulin molecule itself, preservatives, or additives cause allergic reactions. The use of human recombinant insulin has decreased the incidence of insulin allergy, so that now it is reported in fewer than 1% of diabetic patients treated with insulin.6

Allergic reactions to insulin can be classified as immediate-local, generalized, delayed, or biphasic.

Immediate-local reactions reach maximum intensity in 15 to 30 minutes and usually subside within 1 hour. Clinically, one finds erythema, which may become urticarial. This reaction probably is mediated by immunoglobulin E (IgE).

Generalized reactions. Immediate reactions may progress to generalized erythema and urticaria. Anaphylaxis is unusual.

Delayed hypersensitivity reactions are the most common. They usually appear about 2 weeks after the start of insulin therapy as an itchy nodule at the site of injection, 4 to 24 hours after injection.

Biphasic, or dual, reactions are rare events and consist of an immediate and a delayed local reaction, often with a generalized illness resembling serum sickness. They are considered Arthus-immune complex reactions.6

Other complications of insulin injections

Other local cutaneous complications include keloids, hyperkeratotic papules, purpura, and localized pigmentation.

The treatment of choice for localized immediate allergic reactions is a change of insulin to a more purified product.17 Other tools to manage allergic reactions are antihistamines, the addition of glucocorticoids to insulin, discontinuation of therapy, desensitization therapy, or a change in the insulin delivery system.5,6

The most important immunologic problem is IgE-mediated anaphylaxis, which can be managed by temporary reduction in dose or by insulin desensitization. Serum sickness responds to corticosteroid therapy.38

Insulin therapy may also cause lipoatrophy and lipohypertrophy that can coexist in the same patient. Lipoatrophy presents as circumscribed, depressed areas of skin at the insulin injection site 6 to 24 months after the start of therapy. Children and obese women are affected most often. It may be caused by lipolytic components in the insulin preparation or by an inflammatory process mediated by the immune complex. Other theories involve cryotrauma from refrigerated insulin, mechanical trauma due to the angle of injection, surface alcohol contamination, or local hyperproduction of tumor necrosis factor alpha from macrophages induced by injected insulin. Since the introduction of purified recombinant human insulin, lipoatrophy has become rare.37,39 Duration of the presence of an insulin depot has been implicated as well. That is why Murao et al40 suggested substituting rapid-acting insulin.

Lipohypertrophy clinically resembles lipoma and presents as soft dermal nodules at the site of frequent injections. Lipohypertrophy is regarded as a local response to the lipogenic action of insulin and can be prevented by rotation of the injection site.5,17,37

SKIN EFFECTS OF INSULIN ANALOGUES

Cutaneous side effects are not often described in insulin analogues, but there have been case reports. A case of IgE-mediated anaphylaxis41 and one case of vitiligo42 were described with insulin lispro. One case of allergy was described with insulin glargine.43 Although insulin detemir is well tolerated in general, several cases of local injection site reactions have been reported.44,45 Treatment depends on the extent of the reaction and can include desensitization, changing the type of insulin, rotating the injection site, or a combination of these.41–45

 

 

SKIN EFFECTS OF ORAL HYPOGLYCEMIC AGENTS

First-generation sulfonylureas

Figure 4. (Left) Erythema exsudativum multiforme and (above) erythema nodosum in diabetic patients taking a first-generation sulfonylurea.
Most cutaneous reactions to oral hypoglycemic drugs have been reported with first-generation sulfonylureas (eg, chlorpropamide, tolbutamide [Orinase]). Between 1% and 5% of patients taking first-generation sulfonylureas develop cutaneous reactions within the first 2 months of treatment. Maculopapular eruptions are the most common reaction and often disappear with discontinuation of the medication. Other cutaneous reactions are generalized erythema, urticaria, lichenoid eruptions, erythema exsudativum multiforme (Figure 4), exfoliative dermatitis, erythema nodosum (Figure 4), and photosensitivity reactions. Even if a photo-patch test is negative in a patient with a photosensitivity reaction, the oral glucose-lowering drug should be switched.

In 10% to 30% of patients using chlorpropamide, an alcohol flush is induced, consisting of redness and warmth, headache, tachycardia, and occasionally dyspnea, starting about 15 minutes after alcohol consumption. Usually, the symptoms disappear after an hour. This reaction pattern seems to be inherited in an autosomal-dominant pattern.6,37

Second-generation sulfonylureas

Second-generation sulfonylureas such as glipizide (Glucotrol) and glimepiride (Amaryl) have also been associated with cutaneous reactions. The most frequent reactions associated with glipizide are photosensitivity, rash, urticaria, and pruritus. These are reported less often with glimepiride. Deerochanawong46 reported patients with skin rash after the use of glimepiride. A case of lichenoid drug eruption was described by Noakes.47

Other oral hypoglycemic drugs

Metformin (Glucophage), a biguanide-derivative antihyperglycemic drug, is the first-choice oral drug in type 2 diabetic patients. Dermal side effects reported include psoriatiform drug eruption,48 erythema exsudativum multiforme,49 and leukocytoclastic vasculitis.50,51Litt’s Drug Eruption Manual gives the risk of photosensitivity reaction to metformin as 1% to 10%52 but cites no reference for this statement. Erythema, exanthema, pruritus, and urticaria have also been reported as side effects of metformin.52

Acarbose (Precose) is minimally absorbed from the gut: only about 1% of a dose reaches the bloodstream,53 and thus it seldom causes adverse effects. Kono et al54 reported a case of acarbose-induced generalized erythema multiforme confirmed by a challenge test. The drug-induced lymphocyte stimulation test and patch test for acarbose were negative. Ahr et al55 reported that acarbose labeled with carbon 14 was poorly absorbed when given orally, but that up to 35% of this formulation of acarbose was absorbed after degradation by digestive enzymes, intestinal microorganisms, or both. Because the drug-induced lymphocyte stimulation test and the patch test were negative in the patient described by Kono et al,54 it is possible that the degradation products of acarbose induced the allergic reaction after absorption. Poszepczynska-Guigné et al56 described the first case of acute generalized exanthematous pustulosis induced after administration of acarbose.

Thiazolidinediones. Edema has been reported as an adverse cutaneous effect of rosiglitazone (Avandia) and pioglitazone (Actos).52

Almost all diabetic patients eventually develop skin complications from the long-term effects of diabetes mellitus on the microcirculation and on skin collagen. Cutaneous infections are more common in type 2 diabetes, whereas autoimmune-related lesions are more common in type 1. Patients who have had diabetes for many years tend to develop the most devastating skin problems. However, problems can also develop in the short term, as insulins and oral hypoglycemic drugs can also have dermal side effects. Furthermore, diabetes-related cutaneous lesions may also serve as a port of entry for secondary infection.

This review aims to guide the clinician to the correct diagnosis of cutaneous manifestations associated with type 1 (Table 1) and type 2 (Table 2) diabetes mellitus, to recognize cutaneous side effects of glucose-lowering drugs, and to aid the treatment of diabetic skin disease. The classification and treatment of the diabetic foot are not within the scope of this review.

MANIFESTATIONS ASSOCIATED WITH TYPE 1 DIABETES

Periungual telangiectasia

The lesions of periungual telangiectasia, appearing as red, dilated, capillary veins, are easily visible with the naked eye and are the result of a loss of capillary loops and dilation of the remaining capillaries. A prevalence up to 49% has been described in all diabetic patients.1 Connective tissue diseases may also involve periungual telangiectases, although these lesions are morphologically different. In diabetes, periungual telangiectasia is often associated with nail fold erythema, accompanied by fingertip tenderness and “ragged” cuticles.2

Necrobiosis lipoidica

Figure 1. General appearance of necrobiosis lipoidica, consisting of nonscaling plaques in the pretibial region of the legs.
Necrobiosis lipoidica diabeticorum (Figure 1) appears in 0.3% to 1.6% of diabetic patients. Its origin is unknown. The fully developed clinical appearance is diagnostic: nonscaling plaques with a yellow atrophic center, surface telangiectases, and an erythematous or violaceous border that may be raised. The pretibial region is the area typically affected. Ulceration occurs in up to 35% of cases. Women are affected more often than men. Patients with type 1 diabetes develop necrobiosis lipoidica at an earlier mean age than those with type 2 and those without diabetes. The yellow aspect in the central area of the lesions is most likely due to thinning of the dermis, making subcutaneous fat more visible.3–5

Metabolic control has no proven effect on the course of this condition,6 although Cohen et al7 reported that tight glucose control reduced the incidence in diabetic patients. Treatment includes application of a topical steroid with or without occlusion; intralesional steroids at the active border; or, in the rare severe or extensive case, systemic steroids.6,7 In some resistant cases, aspirin, chloroquine (Aralen), and cyclosporine (Sandimmune, Neoral) have been used with some success.3,8,9

Bullosis diabeticorum

Bullosis diabeticorum develops in approximately 0.5% of diabetic patients, but more often in those with type 1 diabetes, and more often in men and in patients with long-standing diabetes with peripheral neuropathy. It presents as asymptomatic bullae containing sterile fluid on a noninflamed base, usually arising spontaneously on the dorsa and sides of the lower legs and feet, sometimes on the hands or the forearms. The cause is unknown, and it is a diagnosis of exclusion. The differential diagnosis includes epidermolysis bullosa acquisita, porphyria cutanea tarda, bullous pemphigoid, bullous impetigo, coma blisters, and erythema multiforme.

Treatment is symptomatic and conservative. In case of discomfort, the bullae can be aspirated (leaving the blister roof intact), or compresses can be used. Topical antibiotics may be required to prevent secondary infection.3 Most lesions resolve in 2 to 3 weeks without residual scarring.5,6

Vitiligo

Vitiligo vulgaris, or skin depigmentation, occurs more often in type 1 diabetic patients. From 1% to 7% of all diabetic patients have vitiligo vs 0.2% to 1% of the general population. The mechanism behind the association has not been elucidated, although some have suggested polyglandular autoimmune syndrome (PAS), a rare immune endocrinopathy characterized by the coexistence of at least two endocrine gland insufficiencies that are based on autoimmune mechanisms. PAS type 2 is more common (estimated prevalence of 1:20,000), occurs mainly in the third or fourth decade, and is characterized by adrenal failure, autoimmune thyroid disease, or type 1 diabetes. Adrenal failure may precede other endocrinopathies. Vitiligo and gonadal failure occur more frequently in PAS type 1 than in PAS type 2, whereas immunogastritis, pernicious anemia, and alopecia areata are the main features of PAS type 2. In contrast to PAS type 1, family members of PAS type 2 patients are often affected as well. PAS type 2 is believed to be polygenic, with an autosomal dominant pattern of inheritance.10

Treatment of vitiligo is unsatisfactory in general. Patients should be advised to avoid the sun and to use broad-spectrum sunscreens. For localized vitiligo, topical corticosteroids are preferred, whereas for generalized vitiligo ultraviolet B light treatment is most effective. Cosmetic treatment is an option for improved well-being.11

Oral lichen planus

Figure 2. Lichen ruber planus typically presents on the skin as flat, polygonal, erythematous lesions of the lower legs, and also on the wrists and the dorsal areas of the feet.
The association between diabetes and lichen planus (Figure 2), especially oral lichen planus, has been the subject of much research. However, most studies have examined the prevalence of diabetes mellitus in patients with lichen planus, rather than the reverse. Also, many reports do not differentiate between the types of diabetes. Petrou-Amerikanou et al12 reported a significantly higher prevalence of oral lichen planus in type 1 diabetic patients vs a control population, but not in type 2 diabetic patients.

Clinically, lichen planus presents as polygonal erythematous flat lesions. Most often affected are the wrists, the dorsa of the feet, and the lower legs. Oral lichen planus presents as white stripes in a reticular pattern.

Clinical and histopathologic differentiation of these lesions from lichenoid reactions to drugs (eg, nonsteroidal anti-inflammatory drugs, antihypertensive drugs) may be difficult, although numerous eosinophils, parakeratosis, and perivascular inflammation around the mid and deep dermal plexuses, are seen in lichenoid drug reactions, but generally not in lichen planus.13

Treatment consists of topical corticosteroids or topical cyclosporine, or both.6

 

 

SKIN MANIFESTATIONS ASSOCIATED WITH TYPE 2 DIABETES

Yellow nails

Elderly type 2 diabetic patients tend to have yellow nails. A prevalence of 40% to 50% in patients with type 2 diabetes has been reported,14 but occasionally yellow nails are also found in normal elderly people and in patients with onychomycosis. The yellow discoloration in diabetes is most evident on the distal end of the hallux nail. It probably represents end-products of glycosylation, similar to the yellow color in diabetic skin, although this has not yet been confirmed.15

Diabetic thick skin

Diabetes mellitus is generally associated with a thickening of the skin,2 measurable via ultrasonography,16 and this thickening may increase with age in all diabetic patients, unlike normally aging skin.

Diabetic thick skin occurs in three forms. First is the general asymptomatic but measurable thickening. Second is a clinically apparent thickening of the skin involving the fingers and hands. Third is diabetic scleredema, an infrequent syndrome in which the dermis of the upper back becomes markedly thickened.2,6

Thickening of the skin on the dorsum of the hands occurs in 20% to 30% of all diabetic patients, regardless of the type of diabetes.17 Manifestations range from pebbled knuckles to diabetic hand syndrome.2 Pebbled knuckles (or Huntley papules) are multiple minute papules, grouped on the extensor side of the fingers, on the knuckles, or on the periungual surface.18 The prevalence of diabetic hand syndrome varies from 8% to 50%.19 It begins with stiffness of the metacarpophalangeal and proximal interphalangeal joints and progresses to limit joint mobility.20,21 Dupuytren contracture (or palmar fascial thickening) may further complicate diabetic hand syndrome.5,22

Scleredema diabeticorum is characterized by remarkable thickening of the skin of the posterior neck and upper back, occasionally extending to the deltoid and lumbar regions. A peau d’orange appearance of the skin can occur, often with decreased sensitivity to pain and touch.

Scleredema occurs in 2.5% to 14% of people with diabetes6 and is sometimes confused with scleredema of Buschke, a rare disorder in which areas of dermal thickening occur, mostly on the face, arms, and hands, often after an upper respiratory infection. It clears spontaneously in months or years. Women are affected more often than men. These characteristics differentiate scleredema of Buschke from scleredema diabeticorum, which almost exclusively occurs in long-standing diabetes, is usually permanent, is not related to previous infection, and is limited to the posterior neck and upper back. No effective treatment is known for scleredema diabeticorum.23

Skin tags or acrochordons

Skin tags are small, pedunculated, soft, often pigmented lesions occurring on the eyelids, the neck, and the axillae. A few studies have reported an association between multiple skin tags and diabetes, and between skin tags and insulin resistance.24–27 Crook28 found that skin tags were associated with the typical atherogenic lipid profile seen in insulin-resistant states: elevated triglycerides and low levels of high-density-lipoprotein cholesterol. In a large study of patients with skin tags,24 over 25% had diabetes and 8% had impaired glucose tolerance.24

Treatment is not necessary, but skin tags can be removed with grade 1 scissors, cryotherapy, or electrodessication.28 Skin tags may be regarded as a sign of impaired glucose tolerance, diabetes, and increased cardiovascular risk.28,29

Diabetic dermopathy

Diabetic dermopathy (ie, shin spots and pigmented pretibial papules) affects 7% to 70% of all diabetic patients. It is not specific for diabetes: 20% of nondiabetic people show similar lesions. Men are affected more often than women, and the mean age is 50 years.

Shin spots present as multiple, bilateral, asymmetrical, annular or irregular red papules or plaques on the extensor surface of the lower legs and may precede abnormal glucose metabolism. The clinician usually sees only the end result: atrophic, scarred, hyperpigmented, finely scaled macules. Lesions may also be found on the forearms, thighs, and lateral malleoli. Several studies found severe microvascular complications in patients with diabetic dermopathy, indicating a close association with a high risk of accelerated diabetes complications.

Treatment is not very effective; however, some lesions resolve spontaneously.6,30

Acanthosis nigricans

Figure 3. The velvety, hyperpigmented plaques of acanthosis nigricans occur usually in body folds and are thought to be related to high levels of circulating insulin.
Acanthosis nigricans (Figure 3) presents as hyperpigmented, velvety plaques in body folds. The dark color is due to thickening of keratin-containing superficial epithelium.31 It is traditionally classified as benign in insulin-resistant states. However, it can occur as a sign of paraneoplasm (particularly in stomach cancer), as an adverse effect of certain drugs (eg, nicotinic acid, corticosteroids), and in various endocrinopathies (eg, acromegaly, Cushing syndrome, leprechaunism). Even in the insulin-resistant diabetic patient, an underlying pathologic condition should be excluded.

The pathogenesis is most likely related to high levels of circulating insulin, which binds to insulin-like growth factor receptors to stimulate the growth of keratinocytes and dermal fibroblasts.

Although the lesions are generally asymptomatic, they can be painful, malodorous, or macerated.3 The most effective treatment is lifestyle alteration. Weight reduction and exercise can reduce insulin resistance. Acanthosis nigricans is reversible with weight reduction if it is seen as a complication of obesity. If the lesions are asymptomatic, they need no treatment. Ointments containing salicylic or retinoic acid can be used to reduce thicker lesions in areas of maceration in order to decrease odor and promote comfort. Systemic isotretinoin (Accutane) improves acanthosis nigricans, but it recurs when the drug is discontinued.3,5,6,32

Acquired perforating dermatosis

Acquired perforating dermatosis is seen in patients with kidney failure, type 2 diabetes, or type 1 diabetes. A prevalence of up to 10% has been reported in dialysis patients.33,34

The characteristic lesions are 2- to 10-mm, pruritic, dome-shaped papules and nodules with a hyperkeratotic plug. They occur mainly on the limbs, the trunk, and the dorsal surface of the hands, and to a lesser extent on the face. The Koebner phenomenon (also called isomorphic effect) may also occur.

Histologic study shows a hyperplastic epidermis with marked spongiosis directly over the plug. The contents of the plug itself are collagen, elastic fibers, nuclear debris, and polymorphonuclear leukocytes. These leukocytes have been implicated in the pathogenesis of acquired perforating dermatosis.6,17

The lesions are chronic but may heal after months if trauma and scratching are avoided. Further treatments include topical keratolytics, psoralen-ultraviolet A light, ultraviolet B light, topical and systemic retinoids, topical and intralesional steroids, oral antihistamines, and cryotherapy.6

 

 

Calciphylaxis

Calciphylaxis is a small-vessel vasculopathy accompanied by mural calcification with intimal proliferation, fibrosis, and thrombosis. It occurs mostly in patients with renal failure and causes a spectrum of end-organ damage due to ischemia. The reported prevalence is 1% to 4% in the dialysis population.

Damage is seen in the epidermal and the subcutaneous tissues. First, redness and tenderness evolve in a small area, which may be surrounded by ecchymosis or pallor, and eventually ischemia leads to the development of subcutaneous nodules and poor-healing, necrotizing skin ulcers. These ulcers serve as a port of entry for infectious agents.

Calciphylaxis has a predilection for vascular regions with thicker subcutaneous adipose tissue, such as the breasts, abdomen, and thighs. In renal failure patients, those who are women, white, obese, or diabetic (especially those with type 2 diabetes) are considered at risk.

Histologic features are medial wall calcification and fibrous expansion in capillaries, venules, arterioles, and small arteries of dermis and subcutaneous fat. Calciphylaxis should not be considered a small-vessel variant of Mönckeberg calcification, which is a medial wall calcification of medium and large vessels. Mönckeberg calcification has been described in patients with diabetes, renal failure, or vitamin D intoxification.

The outcome of calciphylaxis is poor because of impaired wound-healing and infection of the skin with progression to sepsis. Extremely aggressive treatment with analgesics is required for ischemic pain. Furthermore, weight reduction and aggressive control of blood sugar levels seem prudent.35

Eruptive xanthoma

Eruptive xanthoma presents as crops of small (1- to 2-mm) yellow papules with an erythematous halo; these papules may be pruritic and tender. They occur in less than 0.1% of diabetic patients.36 Areas of predilection are extensor surfaces and the buttocks.20

The key histologic feature is the formation of foam cells in the superficial dermis that are mixed with a lymphocytic and neutrophilic infiltrate.

Eruptive xanthomas appear in association with elevated levels of triglyceride-rich lipoproteins. The lipid changes appear in association with familial hypertriglyceridemia and diabetes mellitus, resulting in hypertriglyceridemia from a lack of lipoprotein lipase activity and impaired clearance of chylomicrons and very-low-density lipoproteins. These eruptive xanthomas tend to resolve with control of carbohydrate and lipid metabolism.5,6,17

Granuloma annulare: Not linked to diabetes

Although many have tried to prove an association between localized granuloma annulare and diabetes, no association has been clearly established, and the association between generalized (disseminated) granuloma annulare and diabetes is controversial.21

The cause is not known. The lesions are oval or ring-shaped, with a raised border of skin-colored or erythematous papules. The size varies from millimeters to centimeters. The dorsa of the hands and arms are the areas usually affected. Histologically, the epidermis usually appears normal, whereas the upper and mid dermis show focal degeneration of collagen, palisaded histiocytes around collagen bundles, and abundant mucin.

Localized lesions often resolve spontaneously, whereas the generalized form has a more protracted course which, in rare cases, resolves spontaneously. Sporadic therapeutic success has been reported with topical, systemic, and intralesional steroids; isotretinoin; chlorambucil (Leukeran); cryotherapy; chlorpropamide (Diabinese); chloroquine; potassium iodide/nicotinamide; dapsone; antimalarials; and psoralen-ultraviolet A light.5,6,20

CUTANEOUS INFECTIONS

Skin infections occur in 20% to 50% of diabetic patients (more often in those with type 2 diabetes) and are often associated with poor glycemic control (Table 3). Poor microcirculation, peripheral vascular disease, peripheral neuropathy, and decreased immune response have been implicated in the increased susceptibility to infection.

Candidal infection

A candidal infection (moniliasis) can be an early sign of undiagnosed diabetes. Perlèche is a classic sign of diabetes in children, and localized candidal infection of the female genitalia has a strong association with diabetes. This infection appears as erythema with scaling and typical satellite papules and pustules. Paronychia is another sign.

It is important to remember that in men, Candida balanitis, balanoposthitis, and intertrigo can be presenting signs of diabetes.

Candidal infections improve with adequate metabolic control and treatment with topical midazoles or nystatin (Mycostatin).5,37

Infections with dermatophytes

Common superficial infections are caused by Trichophyton rubrum, T mentagrophytes, and Epidermophyton floccosum. In diabetic patients, onychomycosis or tinea pedis needs to be monitored for and treated, as it can be a port of entry for infection. This is especially true for patients with neurovascular complications and intertrigo.

Signs of T rubrum infection are noninflamed, white, powdery scaling or skin creases on the palms and soles, often with nail involvement. T mentagrophytes-associated intertrigo or interdigital infection presents as maceration and superficial scaling with an active red border. Treatments of choice are drying the local area and applying one of the newer topical imidazole antifungal agents.5,37

 

 

Bacterial infections

Pyodermic infections such as impetigo, folliculitis, carbuncles, furunculosis, ecthyma, and erysipelas can be more severe and widespread in diabetic patients. Therapy consists of adequate diabetic control and, if necessary, adequate systemic antibiotic therapy; deeper infections require intravenous antibiotics.

Erythrasma, caused by Corynebacterium minutissimum, occurs with increased frequency in obese diabetic patients, but it is often missed. Intertriginous areas are the main affected site. Sweat, friction, and maceration play a role in the development. Erythrasma presents as shiny, hyperpigmented patches with an active border. With the Wood’s lamp, a characteristic coral fluorescence is seen. Treatment consists of topical or systemic erythromycin, or both. Prevention of sweating, friction, and maceration can limit the chances of developing this infection.5,6,37

Rare infections

Poor metabolic control and ketoacidosis may set the stage for severe infections by otherwise nonpathogenic microorganisms, such as mucormycosis by Phycomycetes and anaerobic cellulitis by Clostridium species. Treatment consists of metabolic control, aggressive debride ment of devitalized tissue, and intravenous antimicrobial therapy.37

In older diabetic patients, malignant otitis externa, often caused by Pseudomonas aeruginosa, can be fatal. This invasive infection may spread from the external auditory canal to the base of the skull, the meninges, and the brain itself. Treatment consists of irrigation and drainage of the ear canal, antibiotics, and sometimes debridement. A cure rate of more than 90% can be achieved using parenteral or oral quinolones.3

CUTANEOUS REACTIONS TO INSULIN

Impurities in insulin preparations, the presence of cow or pig proteins, the insulin molecule itself, preservatives, or additives cause allergic reactions. The use of human recombinant insulin has decreased the incidence of insulin allergy, so that now it is reported in fewer than 1% of diabetic patients treated with insulin.6

Allergic reactions to insulin can be classified as immediate-local, generalized, delayed, or biphasic.

Immediate-local reactions reach maximum intensity in 15 to 30 minutes and usually subside within 1 hour. Clinically, one finds erythema, which may become urticarial. This reaction probably is mediated by immunoglobulin E (IgE).

Generalized reactions. Immediate reactions may progress to generalized erythema and urticaria. Anaphylaxis is unusual.

Delayed hypersensitivity reactions are the most common. They usually appear about 2 weeks after the start of insulin therapy as an itchy nodule at the site of injection, 4 to 24 hours after injection.

Biphasic, or dual, reactions are rare events and consist of an immediate and a delayed local reaction, often with a generalized illness resembling serum sickness. They are considered Arthus-immune complex reactions.6

Other complications of insulin injections

Other local cutaneous complications include keloids, hyperkeratotic papules, purpura, and localized pigmentation.

The treatment of choice for localized immediate allergic reactions is a change of insulin to a more purified product.17 Other tools to manage allergic reactions are antihistamines, the addition of glucocorticoids to insulin, discontinuation of therapy, desensitization therapy, or a change in the insulin delivery system.5,6

The most important immunologic problem is IgE-mediated anaphylaxis, which can be managed by temporary reduction in dose or by insulin desensitization. Serum sickness responds to corticosteroid therapy.38

Insulin therapy may also cause lipoatrophy and lipohypertrophy that can coexist in the same patient. Lipoatrophy presents as circumscribed, depressed areas of skin at the insulin injection site 6 to 24 months after the start of therapy. Children and obese women are affected most often. It may be caused by lipolytic components in the insulin preparation or by an inflammatory process mediated by the immune complex. Other theories involve cryotrauma from refrigerated insulin, mechanical trauma due to the angle of injection, surface alcohol contamination, or local hyperproduction of tumor necrosis factor alpha from macrophages induced by injected insulin. Since the introduction of purified recombinant human insulin, lipoatrophy has become rare.37,39 Duration of the presence of an insulin depot has been implicated as well. That is why Murao et al40 suggested substituting rapid-acting insulin.

Lipohypertrophy clinically resembles lipoma and presents as soft dermal nodules at the site of frequent injections. Lipohypertrophy is regarded as a local response to the lipogenic action of insulin and can be prevented by rotation of the injection site.5,17,37

SKIN EFFECTS OF INSULIN ANALOGUES

Cutaneous side effects are not often described in insulin analogues, but there have been case reports. A case of IgE-mediated anaphylaxis41 and one case of vitiligo42 were described with insulin lispro. One case of allergy was described with insulin glargine.43 Although insulin detemir is well tolerated in general, several cases of local injection site reactions have been reported.44,45 Treatment depends on the extent of the reaction and can include desensitization, changing the type of insulin, rotating the injection site, or a combination of these.41–45

 

 

SKIN EFFECTS OF ORAL HYPOGLYCEMIC AGENTS

First-generation sulfonylureas

Figure 4. (Left) Erythema exsudativum multiforme and (above) erythema nodosum in diabetic patients taking a first-generation sulfonylurea.
Most cutaneous reactions to oral hypoglycemic drugs have been reported with first-generation sulfonylureas (eg, chlorpropamide, tolbutamide [Orinase]). Between 1% and 5% of patients taking first-generation sulfonylureas develop cutaneous reactions within the first 2 months of treatment. Maculopapular eruptions are the most common reaction and often disappear with discontinuation of the medication. Other cutaneous reactions are generalized erythema, urticaria, lichenoid eruptions, erythema exsudativum multiforme (Figure 4), exfoliative dermatitis, erythema nodosum (Figure 4), and photosensitivity reactions. Even if a photo-patch test is negative in a patient with a photosensitivity reaction, the oral glucose-lowering drug should be switched.

In 10% to 30% of patients using chlorpropamide, an alcohol flush is induced, consisting of redness and warmth, headache, tachycardia, and occasionally dyspnea, starting about 15 minutes after alcohol consumption. Usually, the symptoms disappear after an hour. This reaction pattern seems to be inherited in an autosomal-dominant pattern.6,37

Second-generation sulfonylureas

Second-generation sulfonylureas such as glipizide (Glucotrol) and glimepiride (Amaryl) have also been associated with cutaneous reactions. The most frequent reactions associated with glipizide are photosensitivity, rash, urticaria, and pruritus. These are reported less often with glimepiride. Deerochanawong46 reported patients with skin rash after the use of glimepiride. A case of lichenoid drug eruption was described by Noakes.47

Other oral hypoglycemic drugs

Metformin (Glucophage), a biguanide-derivative antihyperglycemic drug, is the first-choice oral drug in type 2 diabetic patients. Dermal side effects reported include psoriatiform drug eruption,48 erythema exsudativum multiforme,49 and leukocytoclastic vasculitis.50,51Litt’s Drug Eruption Manual gives the risk of photosensitivity reaction to metformin as 1% to 10%52 but cites no reference for this statement. Erythema, exanthema, pruritus, and urticaria have also been reported as side effects of metformin.52

Acarbose (Precose) is minimally absorbed from the gut: only about 1% of a dose reaches the bloodstream,53 and thus it seldom causes adverse effects. Kono et al54 reported a case of acarbose-induced generalized erythema multiforme confirmed by a challenge test. The drug-induced lymphocyte stimulation test and patch test for acarbose were negative. Ahr et al55 reported that acarbose labeled with carbon 14 was poorly absorbed when given orally, but that up to 35% of this formulation of acarbose was absorbed after degradation by digestive enzymes, intestinal microorganisms, or both. Because the drug-induced lymphocyte stimulation test and the patch test were negative in the patient described by Kono et al,54 it is possible that the degradation products of acarbose induced the allergic reaction after absorption. Poszepczynska-Guigné et al56 described the first case of acute generalized exanthematous pustulosis induced after administration of acarbose.

Thiazolidinediones. Edema has been reported as an adverse cutaneous effect of rosiglitazone (Avandia) and pioglitazone (Actos).52

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  50. Klapholz L, Leitersdorf E, Weinrauch L. Leucocytoclastic vasculitis and pneumonitis induced by metformin. BMJ (Clin Res Ed) 1986; 293:483.
  51. Ben Salem C, Hmouda H, Slim R, Denguezli M, Belajouza C, Bouraoui K. Rare case of metformin-induced leucocytoclastic vasculitis. Ann Pharmacother 2006; 40:1685–1687.
  52. Litt JZ. Litt’s Drug Eruption Reference Manual. London: Taylor and Francis, 2001.
  53. Balfour JA, McTavish D. Acarbose: an update of its pharmacology and therapeutic use in diabetes mellitus. Drugs 1993; 46:1024–1054. Erratum in: Drugs 1994; 48:929.
  54. Kono T, Hayami M, Kobayashi H, Ishii M, Taniguchi S. Acarbose-induced generalized erythema multiforme. Lancet 1999; 354:396–397.
  55. Ahr HJ, Boberg M, Krause HP, et al. Pharmacokinetics of acarbose. Part 1: Absorption, concentration in plasma, metabolism, and excretion after single administration of 14C acarbose to rats, dogs and man. Arzneimittelforschung 1989; 39:1254–1260.
  56. Poszepczynska-Guigné E, Viguier M, Assier H, Pinquier L, Hochedez P, Dubertret L. Acute generalized exanthematous pustulosis induced by drugs with low-digestive absorption: acarbose and nystatin. Ann Dermatol Venereol 2003; 130:439–442.
References
  1. Landau J, Davis E. The small blood-vessels of the conjunctiva and nail bed in diabetes mellitus. Lancet 1960; 2:731
  2. Huntley A. Diabetes mellitus: review. Dermatology Online Journal 1995; vol 1(2). http://dermatology.cdlib.org/DOJvol1num2/diabetes/dmreview.html. Accessed July 30, 2008.
  3. Ahmed I, Goldstein B. Diabetes mellitus. Clin Dermatol 2006; 24:237–246.
  4. Petzelbauer P, Wolff K, Tappeiner G. Necrobiosis lipoidica: treatment with systemic corticoids. Br J Dermatol 1992; 126:542.
  5. Sibbald RG, Schachter RK. The skin and diabetes mellitus. Int J Dermatol 1984; 23:567–584.
  6. Ferringer T, Miller F. Cutaneous manifestations of diabetes mellitus. Dermatol Clin 2002; 20:483–492.
  7. Cohen O, Yaniv R, Karasik A, Trau H. Necrobiosis lipoidica and diabetic control revisited. Med Hypotheses 1996; 46:348–350.
  8. Nguyen K, Washenik K, Shupak J. Necrobiosis lipoidica diabeticorum treated with chloroquine. J Am Acad Dermatol 2002; 46 suppl 2:34–36.
  9. Stanway A, Rademaker M, Newman P. Healing of severe ulcerative necrobiosis lipoidica with cyclosporine. Australas J Dermatol 2004; 45:119–122.
  10. Dittmar M, Kahaly GJ. Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up. J Clin Endocrinol Metab 2003; 88:2983–2992.
  11. Forschner T, Buchholtz S, Stockfleth E. Current state of vitiligo therapy-evidence-based analysis of the literature. J Dtsch Dermatol Ges 2007; 5:467–475.
  12. Petrou-Amerikanou C, Markopoulos AK, Belazi M, Karamitsos D, Papanayotou P. Prevalence of oral lichen planus in diabetes mellitus according to the type of diabetes. Oral Dis 1998; 4:37–40.
  13. Mobini N, Toussaint S, Kamino H. Noninfectious, erythematous, papular, and squamous diseases. In:Elder DE, editor. Lever’s Histopathology of the Skin. 9th ed. Philadelphia: Lippincott Williams & Wilkins, 2005:179–214.
  14. Nikoleishvili LR, Kurashvili RB, Virsaladze DK. Characteristic changes of skin and its accessories in type 2 diabetes mellitus. Georgian Med News 2006; 131:43–46.
  15. Lithner F, Hietala S-O. Skeletal lesions of the feet in diabetics and their relationship to cutaneous erythema with or without necrosis of the feet. Acta Med Scand 1976; 200:155–161.
  16. Collier A, Matthews DM, Kellett HA, Clarke BF, Hunter JA. Change in skin thickness associated with cheiroarthropathy in insulin dependent diabetes mellitus. Br Med J (Clin Res Ed) 1986; 292:936.
  17. Perez MI, Kohn SR. Cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol 1994; 30:519–530.
  18. Libecco JF. Finger pebbles and diabetes: a case with broad involvement of the dorsal fingers and hands. Arch Dermatol 2001; 137:510–511.
  19. Brik R, Berant M, Vardi P. The scleroderma-like syndrome of insulin-dependent diabetes mellitus. Diabetes Metab Rev 1991; 7:121–128.
  20. Jelinek JE. Cutaneous manifestations of diabetes mellitus. Int J Dermatol 1994; 33:605–617.
  21. Huntley AC. The cutaneous manifestations of diabetes mellitus. J Am Acad Dermatol 1989; 7:427–455.
  22. Jennings AM, Milner PC, Ward JD. Hand abnormalities are associated with the complications of diabetes in type 2 diabetes. Diabet Med 1989; 6:43–47.
  23. Cole GW, Headley J, Skowsky R. Scleredema diabeticorum: a common and distinct cutaneous manifestation of diabetes mellitus. Diabetes Care 1983; 6:189–192.
  24. Kahana M, Grossman E, Feinstein A, Ronnen M, Cohen M, Millet MS. Skin tags: a cutaneous marker for diabetes mellitus. Acta Derm Venereol 1987; 67:175–177.
  25. Margolis J, Margolis LS. Skin tags—a frequent sign of diabetes mellitus [letter]. N Engl J Med 1976; 294:1184.
  26. Garcia Hidalgo L. Dermatological complications of obesity. Am J Clin Dermatol 2002; 3:497–506.
  27. Scheinfeld NS. Obesity and dermatology. Clin Dermatol 2004; 22:303–309.
  28. Crook MA. Skin tags and the atherogenic lipid profile. J Clin Pathol 2000; 53:873–874.
  29. Tompkins RR. Skin tags and diabetes. Arch Dermatol 1977; 113:1463.
  30. Sibbald RG, Landolt SJ, Toth D. Skin and diabetes. Endocrinol Metab Clin North Am 1996; 25:463–472.
  31. Hermanns-Le T, Scheen A, Pierard GE. Acanthosis nigricans associated with insulin resistance: pathophysiology and management. Am J Clin Dermatol 2004; 5:199–203.
  32. Katz RA. Treatment of acanthosis nigricans with oral isotretinoin. Arch Dermatol 1980; 116:110.
  33. Morton CA, Henderson IS, Jones MC, Lowe JG. Acquired perforating dermatosis in a British dialysis population. Br J Dermatol 1996; 135:671–677.
  34. Saray Y, Seçkin D, Bilezikçi B. Acquired perforating dermatosis: clinicopathological features in twenty-two cases. J Eur Acad Dermatol Venereol 2006; 20:679–688.
  35. Wilmer WA, Magro CM. Calciphylaxis:emerging concepts in prevention, diagnosis, and treatment. Dialysis 2002; 15:172–186.
  36. Muller SA. Dermatologic disorders associated with diabetes mellitus. Mayo Clin Proc 1966; 41:689.
  37. Meurer M, Stumvoll M, Szeimies RM. Hautveränderungen bei Diabetes mellitus. Hautartz 2004; 55:428–435.
  38. Grammer L. Insulin allergy. Clin Rev Allergy 1986; 4:189–200.
  39. Richardson T, Kerr D. Skin-related complications of insulin therapy: epidemiology and emerging management strategies. Am J Clin Dermatol 2003; 4:661–667.
  40. Murao S, Hirata K, Ishida T, Takahara J. Lipoatrophy induced by recombinant human insulin injection. Intern Med 1998; 37:1031–1033.
  41. Barranco R, Herrero T, Tornero P, et al. Systemic allergic reaction by a human insulin analog. Allergy 2003; 58:536–537.
  42. Burge MR, Carey JD. Vitiligo associated with subcutaneous insulin lispro infusion in type 1 diabetes. Diabetes Care 2004; 27:275–276.
  43. Durand-Gonzalez KN, Guillausseau N, Pecquet C, Gayno JP. Glargine insulin is not an alternative in insulin allergy. Diabetes Care 2003; 26:2216.
  44. Blumer IR. Severe injection site reaction to insulin detemir. Diabetes Care 2006; 29:946.
  45. Darmon P, Castera V, Koeppel MC, Petitjean C, Dutour A. Type III allergy to insulin detemir. Diabetes Care 2005; 28:2980.
  46. Deerochanawong C, Chandraprasert S. Glimepiride in type 2 diabetes mellitus Thai patients. J Med Assoc Thai 2001; 84:1221–1228.
  47. Noakes R. Lichenoid drug eruption as a result of the recently released sulfonylurea glimepiride. Australas J Dermatol 2003; 44:302–303.
  48. Koca R, Altinyazar HC, Yenidünya S, Tekin NS. Psoriasiform [sic] drug eruption associated with metformin hydrochloride: a case report. Dermatol Online J 2003; 9:11. http://dermatology.cdlib.org/93/case_reports/metformin/koca.html. Accessed July 30, 2008.
  49. Burger DE, Goyal S. Erythema multiforme from metformin. Ann Pharmacother 2004; 38:1537.
  50. Klapholz L, Leitersdorf E, Weinrauch L. Leucocytoclastic vasculitis and pneumonitis induced by metformin. BMJ (Clin Res Ed) 1986; 293:483.
  51. Ben Salem C, Hmouda H, Slim R, Denguezli M, Belajouza C, Bouraoui K. Rare case of metformin-induced leucocytoclastic vasculitis. Ann Pharmacother 2006; 40:1685–1687.
  52. Litt JZ. Litt’s Drug Eruption Reference Manual. London: Taylor and Francis, 2001.
  53. Balfour JA, McTavish D. Acarbose: an update of its pharmacology and therapeutic use in diabetes mellitus. Drugs 1993; 46:1024–1054. Erratum in: Drugs 1994; 48:929.
  54. Kono T, Hayami M, Kobayashi H, Ishii M, Taniguchi S. Acarbose-induced generalized erythema multiforme. Lancet 1999; 354:396–397.
  55. Ahr HJ, Boberg M, Krause HP, et al. Pharmacokinetics of acarbose. Part 1: Absorption, concentration in plasma, metabolism, and excretion after single administration of 14C acarbose to rats, dogs and man. Arzneimittelforschung 1989; 39:1254–1260.
  56. Poszepczynska-Guigné E, Viguier M, Assier H, Pinquier L, Hochedez P, Dubertret L. Acute generalized exanthematous pustulosis induced by drugs with low-digestive absorption: acarbose and nystatin. Ann Dermatol Venereol 2003; 130:439–442.
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KEY POINTS

  • Patients with type 2 diabetes more often develop skin infections, whereas those with type 1 more often have autoimmune-related lesions.
  • Insulin signaling supports normal skin proliferation, differentiation, and maintenance, and a lack of insulin may lead to impaired wound healing, which may affect insulin resorption.
  • Skin manifestations of diabetes may also serve as ports of entry for secondary infection.
  • A candidal infection (moniliasis) can be an early sign of undiagnosed diabetes.
  • Watch for dermal side effects of insulin injections and oral hypoglycemic drugs.
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A 90-year-old woman with an asymptomatic spot on her cheek

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A 90-year-old woman with an asymptomatic spot on her cheek
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Matthew F. Helm
Lin Lin, MD, PhD

(Photo courtesy of Dr. Michelle Bennett)
Figure 1. An asymmetrical, variegated, and raised lesion with irregular borders, on the patient’s right cheek.
A 90-year-old woman presents for evaluation of a pigmented lesion on the right cheek (Figure 1).

Q: Which is the best diagnosis?

  • Seborrheic keratosis
  • Pigmented basal cell carcinoma
  • Congenital nevus
  • Lentigo maligna melanoma
  • Actinic purpura

A: The answer is lentigo maligna melanoma. Biopsy revealed the spread of atypical melanocytes along the dermal-epidermal junction and in irregularly shaped and confluent nests. Focal invasion into the papillary dermis was noted when definitive excision was performed.

Lentigo maligna melanoma develops on sun-damaged skin.1 Although most common in older people, lentigo maligna melanoma is now sometimes encountered in younger people. In either case, it is identified using the ABCDE rule of asymmetry, irregular border, color variations, diameter larger than 6 mm, and evolution.2

Seborrheic keratosis often has a rough surface and looks “stuck on.” Basal cell carcinoma usually has a waxy texture, may have a “rolled” border, and usually has telangiectatic vessels at the margins. A congenital nevus is typically stable and long-standing. Many nevi have more uniform pigmentation and lack the different colors and hues typical of melanoma. Purpura usually resolves after a few weeks.

An adequate biopsy is essential for diagnosis and excludes the other entities mentioned in the differential diagnosis.

Surgical treatment with adequate margin control is the cornerstone of therapy.3,4 Topical imiquimod cream (Aldara) may be of value for precursor lentigo maligna lesions proven to be in situ,5 but this is not advocated for invasive disease. Since treatment of smaller lesions is much less difficult and disfiguring, clinicians should be suspicious of any persistent, evolving pigmentary abnormality on sun-damaged skin. Biopsy clarifies the diagnosis.

 

 

References

SUGGESTED READING

  1. Cohen PJ, Lambert WC, Hill GJ, Schwartz RA. Melanoma. In:Schwartz RA, editor. Skin Cancer: Recognition and Management. New York: Springer-Verlag; 1988:104–105.
  2. Brodell RT, Helms SE. The changing mole. Additional warning signs of malignant melanoma. Postgrad Med 1998; 104:145–148.
  3. Zitelli JA, Brown CD, Hanusa BH. Surgical margins for excision of primary cutaneous melanoma. J Am Acad Dermatol 1997; 37:422–429.
  4. Bub JL, Berg D, Slee A, Odland B. Management of lentigo maligna and lentigo maligna melanoma with staged excision: a 5-year follow-up. Arch Dermatol 2004; 140:552–558.
  5. Hopson B, richey D, Sajben FP. Treatment of lentigo maligna with imiquimod 5% cream. J Drugs Dermatol 2007; 6:1037–1040.
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Lin Lin, MD, PhD
Buffalo Medical Group, Williamsville, NY

Address: Lin Lin, MD, PhD, Buffalo Medical Group, 6255 Sheridan Drive, Suite 208A, Williamsville, NY 14221; e-mail [email protected]

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Lin Lin, MD, PhD
Buffalo Medical Group, Williamsville, NY

Address: Lin Lin, MD, PhD, Buffalo Medical Group, 6255 Sheridan Drive, Suite 208A, Williamsville, NY 14221; e-mail [email protected]

Author and Disclosure Information

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Department of Dermatology, State University of New York at Buffalo, Williamsville, NY

Lin Lin, MD, PhD
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Address: Lin Lin, MD, PhD, Buffalo Medical Group, 6255 Sheridan Drive, Suite 208A, Williamsville, NY 14221; e-mail [email protected]

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Article PDF
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(Photo courtesy of Dr. Michelle Bennett)
Figure 1. An asymmetrical, variegated, and raised lesion with irregular borders, on the patient’s right cheek.
A 90-year-old woman presents for evaluation of a pigmented lesion on the right cheek (Figure 1).

Q: Which is the best diagnosis?

  • Seborrheic keratosis
  • Pigmented basal cell carcinoma
  • Congenital nevus
  • Lentigo maligna melanoma
  • Actinic purpura

A: The answer is lentigo maligna melanoma. Biopsy revealed the spread of atypical melanocytes along the dermal-epidermal junction and in irregularly shaped and confluent nests. Focal invasion into the papillary dermis was noted when definitive excision was performed.

Lentigo maligna melanoma develops on sun-damaged skin.1 Although most common in older people, lentigo maligna melanoma is now sometimes encountered in younger people. In either case, it is identified using the ABCDE rule of asymmetry, irregular border, color variations, diameter larger than 6 mm, and evolution.2

Seborrheic keratosis often has a rough surface and looks “stuck on.” Basal cell carcinoma usually has a waxy texture, may have a “rolled” border, and usually has telangiectatic vessels at the margins. A congenital nevus is typically stable and long-standing. Many nevi have more uniform pigmentation and lack the different colors and hues typical of melanoma. Purpura usually resolves after a few weeks.

An adequate biopsy is essential for diagnosis and excludes the other entities mentioned in the differential diagnosis.

Surgical treatment with adequate margin control is the cornerstone of therapy.3,4 Topical imiquimod cream (Aldara) may be of value for precursor lentigo maligna lesions proven to be in situ,5 but this is not advocated for invasive disease. Since treatment of smaller lesions is much less difficult and disfiguring, clinicians should be suspicious of any persistent, evolving pigmentary abnormality on sun-damaged skin. Biopsy clarifies the diagnosis.

 

 

(Photo courtesy of Dr. Michelle Bennett)
Figure 1. An asymmetrical, variegated, and raised lesion with irregular borders, on the patient’s right cheek.
A 90-year-old woman presents for evaluation of a pigmented lesion on the right cheek (Figure 1).

Q: Which is the best diagnosis?

  • Seborrheic keratosis
  • Pigmented basal cell carcinoma
  • Congenital nevus
  • Lentigo maligna melanoma
  • Actinic purpura

A: The answer is lentigo maligna melanoma. Biopsy revealed the spread of atypical melanocytes along the dermal-epidermal junction and in irregularly shaped and confluent nests. Focal invasion into the papillary dermis was noted when definitive excision was performed.

Lentigo maligna melanoma develops on sun-damaged skin.1 Although most common in older people, lentigo maligna melanoma is now sometimes encountered in younger people. In either case, it is identified using the ABCDE rule of asymmetry, irregular border, color variations, diameter larger than 6 mm, and evolution.2

Seborrheic keratosis often has a rough surface and looks “stuck on.” Basal cell carcinoma usually has a waxy texture, may have a “rolled” border, and usually has telangiectatic vessels at the margins. A congenital nevus is typically stable and long-standing. Many nevi have more uniform pigmentation and lack the different colors and hues typical of melanoma. Purpura usually resolves after a few weeks.

An adequate biopsy is essential for diagnosis and excludes the other entities mentioned in the differential diagnosis.

Surgical treatment with adequate margin control is the cornerstone of therapy.3,4 Topical imiquimod cream (Aldara) may be of value for precursor lentigo maligna lesions proven to be in situ,5 but this is not advocated for invasive disease. Since treatment of smaller lesions is much less difficult and disfiguring, clinicians should be suspicious of any persistent, evolving pigmentary abnormality on sun-damaged skin. Biopsy clarifies the diagnosis.

 

 

References

SUGGESTED READING

  1. Cohen PJ, Lambert WC, Hill GJ, Schwartz RA. Melanoma. In:Schwartz RA, editor. Skin Cancer: Recognition and Management. New York: Springer-Verlag; 1988:104–105.
  2. Brodell RT, Helms SE. The changing mole. Additional warning signs of malignant melanoma. Postgrad Med 1998; 104:145–148.
  3. Zitelli JA, Brown CD, Hanusa BH. Surgical margins for excision of primary cutaneous melanoma. J Am Acad Dermatol 1997; 37:422–429.
  4. Bub JL, Berg D, Slee A, Odland B. Management of lentigo maligna and lentigo maligna melanoma with staged excision: a 5-year follow-up. Arch Dermatol 2004; 140:552–558.
  5. Hopson B, richey D, Sajben FP. Treatment of lentigo maligna with imiquimod 5% cream. J Drugs Dermatol 2007; 6:1037–1040.
References

SUGGESTED READING

  1. Cohen PJ, Lambert WC, Hill GJ, Schwartz RA. Melanoma. In:Schwartz RA, editor. Skin Cancer: Recognition and Management. New York: Springer-Verlag; 1988:104–105.
  2. Brodell RT, Helms SE. The changing mole. Additional warning signs of malignant melanoma. Postgrad Med 1998; 104:145–148.
  3. Zitelli JA, Brown CD, Hanusa BH. Surgical margins for excision of primary cutaneous melanoma. J Am Acad Dermatol 1997; 37:422–429.
  4. Bub JL, Berg D, Slee A, Odland B. Management of lentigo maligna and lentigo maligna melanoma with staged excision: a 5-year follow-up. Arch Dermatol 2004; 140:552–558.
  5. Hopson B, richey D, Sajben FP. Treatment of lentigo maligna with imiquimod 5% cream. J Drugs Dermatol 2007; 6:1037–1040.
Issue
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The hospital guy redux

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The hospital guy redux
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Brian F. Mandell, MD, PhD

In the September issue of the Journal, Dr. Thomas Lansdale discussed the pressures on internists trying to teach and practice medicine in 2008. He concluded that the system doesn’t work for him or his patients, and he now practices internal medicine in an alternative venue. I asked for comments and solutions from our readers. I certainly got them.

You responded to the parts of Dr. Lansdale’s commentary that struck a personal chord. Almost all responders shared his frustration. Many wrote that the American payer system fails to appropriately reward internists and primary care providers and called for restructuring the Medicare and third-party payer systems. Some of you took umbrage at his contention that hospitals are not safe, and that health care delivery systems do not always place quality care above economic imperatives as new programs and “centers of excellence” are implemented. And some of you reacted to the issues of physician satisfaction and difficulties in providing quality care in hospitals regulated by multiple agencies that generate unfunded mandates, while the hospitals already require high numbers of patients in order to survive financially.

I recently did a stint as rheumatology consultant at my hospital, and Dr. Lansdale’s commentary was fresh in my mind. I noticed with satisfaction that the physicians and nurses were using foam antiseptic on their hands. I noted the new checks on verbal orders and a successful emphasis on preventing deep vein thrombosis and bedsores. But I also noted more patient hand-offs between house staff and faculty, and difficulty in finding doctors who actually knew the patient (or doctors that patients recognized as being responsible for their care).

The electronic medical record is legible and available from all over the hospital, and I could tell who signed the notes. But many notes were actually cut-and-pasted from earlier notes, and thus I couldn’t always be sure who actually had said what and when. Technology is not an immediate panacea for the problem of limited physician time!

The house staff “lab” in the hospital with its microscope was closed due to regulatory concerns; thus, there was no easy way to look at a freshly spun urine sample for evidence of glomerulonephritis. This turned out to be a detriment to effective patient care: urine samples sent to the regular laboratory (with the usual transportation delay) rarely if ever reveal cellular casts. But we found creative, if inefficient, ways to deal with this and other problems.

At the end of the day, I realized that I still enjoy my time in the hospital. Patients’ problems can be presented to house staff and students at the bedside and their diagnoses and therapies discussed in real time. Junior physicians can observe how senior physicians talk to patients and families, including the many ways we have learned to say “I don’t know,” and learn to appreciate the value of a well-directed physical examination. There is still a synergy and intellectual satisfaction in being one of a group of senior consultants discussing the care of a shared patient who has complex medical problems.

With rational and caring involvement, individual physicians can alter the trajectory of patient management and remain the primary patient advocates within a health care system that can’t always easily deliver the quality that everyone desires. Caring, patient-focused physicians must remain in charge of health care delivery, lest we pay attention only to the financial and regulatory problems.

Tom, I am older and even more cynical than I was when we roamed the hospital together every third night and never went home on our post-call day until the last laboratory result had been checked and the last transfusion had been given. We inefficiently examined every patient’s urine ourselves (even from those being admitted for cardiac catheterization), and we had to convince patients of the (apparent) need for the urgent 3 AM blood draw to evaluate their 100.5° fever before we prepped the area and drew the blood. We drew blood for sedimentation rates and checked rapid plasma reagins at every admission and checked for urinary light chains in everyone with an elevated creatinine level and anemia, “just to be sure.” We blindly placed Swan-Ganz catheters to monitor many hypotensive patients in the intensive care units, and we aspirated pleural effusions on the basis of our percussive examination. We talked to patients and accepted enormous individual responsibility for their care, but we were also frequently numbed by the overwhelming intensity of the training and the practice.

I am all too aware of the many forces that are eroding physician-patient relationships and that can corrupt patient care in the name of efficiency, financial necessity, marketing advantage, or regulatory compliance. Many of these forces I hope to help change. But I remain a hospital guy because I can still make a difference. I still feel honored that patients entrust their care to me as we attempt to navigate our evolving and, yes, sometimes treacherous medical system. Evading the crocodiles and fighting insurance companies are now in my job description.

In this issue we run two letters in response to Dr. Lansdale’s commentary. In December we will publish more letters, though due to space limitations some will be abridged. We plan to run full text of many of the letters online at www.ccjm.org in December.

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In the September issue of the Journal, Dr. Thomas Lansdale discussed the pressures on internists trying to teach and practice medicine in 2008. He concluded that the system doesn’t work for him or his patients, and he now practices internal medicine in an alternative venue. I asked for comments and solutions from our readers. I certainly got them.

You responded to the parts of Dr. Lansdale’s commentary that struck a personal chord. Almost all responders shared his frustration. Many wrote that the American payer system fails to appropriately reward internists and primary care providers and called for restructuring the Medicare and third-party payer systems. Some of you took umbrage at his contention that hospitals are not safe, and that health care delivery systems do not always place quality care above economic imperatives as new programs and “centers of excellence” are implemented. And some of you reacted to the issues of physician satisfaction and difficulties in providing quality care in hospitals regulated by multiple agencies that generate unfunded mandates, while the hospitals already require high numbers of patients in order to survive financially.

I recently did a stint as rheumatology consultant at my hospital, and Dr. Lansdale’s commentary was fresh in my mind. I noticed with satisfaction that the physicians and nurses were using foam antiseptic on their hands. I noted the new checks on verbal orders and a successful emphasis on preventing deep vein thrombosis and bedsores. But I also noted more patient hand-offs between house staff and faculty, and difficulty in finding doctors who actually knew the patient (or doctors that patients recognized as being responsible for their care).

The electronic medical record is legible and available from all over the hospital, and I could tell who signed the notes. But many notes were actually cut-and-pasted from earlier notes, and thus I couldn’t always be sure who actually had said what and when. Technology is not an immediate panacea for the problem of limited physician time!

The house staff “lab” in the hospital with its microscope was closed due to regulatory concerns; thus, there was no easy way to look at a freshly spun urine sample for evidence of glomerulonephritis. This turned out to be a detriment to effective patient care: urine samples sent to the regular laboratory (with the usual transportation delay) rarely if ever reveal cellular casts. But we found creative, if inefficient, ways to deal with this and other problems.

At the end of the day, I realized that I still enjoy my time in the hospital. Patients’ problems can be presented to house staff and students at the bedside and their diagnoses and therapies discussed in real time. Junior physicians can observe how senior physicians talk to patients and families, including the many ways we have learned to say “I don’t know,” and learn to appreciate the value of a well-directed physical examination. There is still a synergy and intellectual satisfaction in being one of a group of senior consultants discussing the care of a shared patient who has complex medical problems.

With rational and caring involvement, individual physicians can alter the trajectory of patient management and remain the primary patient advocates within a health care system that can’t always easily deliver the quality that everyone desires. Caring, patient-focused physicians must remain in charge of health care delivery, lest we pay attention only to the financial and regulatory problems.

Tom, I am older and even more cynical than I was when we roamed the hospital together every third night and never went home on our post-call day until the last laboratory result had been checked and the last transfusion had been given. We inefficiently examined every patient’s urine ourselves (even from those being admitted for cardiac catheterization), and we had to convince patients of the (apparent) need for the urgent 3 AM blood draw to evaluate their 100.5° fever before we prepped the area and drew the blood. We drew blood for sedimentation rates and checked rapid plasma reagins at every admission and checked for urinary light chains in everyone with an elevated creatinine level and anemia, “just to be sure.” We blindly placed Swan-Ganz catheters to monitor many hypotensive patients in the intensive care units, and we aspirated pleural effusions on the basis of our percussive examination. We talked to patients and accepted enormous individual responsibility for their care, but we were also frequently numbed by the overwhelming intensity of the training and the practice.

I am all too aware of the many forces that are eroding physician-patient relationships and that can corrupt patient care in the name of efficiency, financial necessity, marketing advantage, or regulatory compliance. Many of these forces I hope to help change. But I remain a hospital guy because I can still make a difference. I still feel honored that patients entrust their care to me as we attempt to navigate our evolving and, yes, sometimes treacherous medical system. Evading the crocodiles and fighting insurance companies are now in my job description.

In this issue we run two letters in response to Dr. Lansdale’s commentary. In December we will publish more letters, though due to space limitations some will be abridged. We plan to run full text of many of the letters online at www.ccjm.org in December.

In the September issue of the Journal, Dr. Thomas Lansdale discussed the pressures on internists trying to teach and practice medicine in 2008. He concluded that the system doesn’t work for him or his patients, and he now practices internal medicine in an alternative venue. I asked for comments and solutions from our readers. I certainly got them.

You responded to the parts of Dr. Lansdale’s commentary that struck a personal chord. Almost all responders shared his frustration. Many wrote that the American payer system fails to appropriately reward internists and primary care providers and called for restructuring the Medicare and third-party payer systems. Some of you took umbrage at his contention that hospitals are not safe, and that health care delivery systems do not always place quality care above economic imperatives as new programs and “centers of excellence” are implemented. And some of you reacted to the issues of physician satisfaction and difficulties in providing quality care in hospitals regulated by multiple agencies that generate unfunded mandates, while the hospitals already require high numbers of patients in order to survive financially.

I recently did a stint as rheumatology consultant at my hospital, and Dr. Lansdale’s commentary was fresh in my mind. I noticed with satisfaction that the physicians and nurses were using foam antiseptic on their hands. I noted the new checks on verbal orders and a successful emphasis on preventing deep vein thrombosis and bedsores. But I also noted more patient hand-offs between house staff and faculty, and difficulty in finding doctors who actually knew the patient (or doctors that patients recognized as being responsible for their care).

The electronic medical record is legible and available from all over the hospital, and I could tell who signed the notes. But many notes were actually cut-and-pasted from earlier notes, and thus I couldn’t always be sure who actually had said what and when. Technology is not an immediate panacea for the problem of limited physician time!

The house staff “lab” in the hospital with its microscope was closed due to regulatory concerns; thus, there was no easy way to look at a freshly spun urine sample for evidence of glomerulonephritis. This turned out to be a detriment to effective patient care: urine samples sent to the regular laboratory (with the usual transportation delay) rarely if ever reveal cellular casts. But we found creative, if inefficient, ways to deal with this and other problems.

At the end of the day, I realized that I still enjoy my time in the hospital. Patients’ problems can be presented to house staff and students at the bedside and their diagnoses and therapies discussed in real time. Junior physicians can observe how senior physicians talk to patients and families, including the many ways we have learned to say “I don’t know,” and learn to appreciate the value of a well-directed physical examination. There is still a synergy and intellectual satisfaction in being one of a group of senior consultants discussing the care of a shared patient who has complex medical problems.

With rational and caring involvement, individual physicians can alter the trajectory of patient management and remain the primary patient advocates within a health care system that can’t always easily deliver the quality that everyone desires. Caring, patient-focused physicians must remain in charge of health care delivery, lest we pay attention only to the financial and regulatory problems.

Tom, I am older and even more cynical than I was when we roamed the hospital together every third night and never went home on our post-call day until the last laboratory result had been checked and the last transfusion had been given. We inefficiently examined every patient’s urine ourselves (even from those being admitted for cardiac catheterization), and we had to convince patients of the (apparent) need for the urgent 3 AM blood draw to evaluate their 100.5° fever before we prepped the area and drew the blood. We drew blood for sedimentation rates and checked rapid plasma reagins at every admission and checked for urinary light chains in everyone with an elevated creatinine level and anemia, “just to be sure.” We blindly placed Swan-Ganz catheters to monitor many hypotensive patients in the intensive care units, and we aspirated pleural effusions on the basis of our percussive examination. We talked to patients and accepted enormous individual responsibility for their care, but we were also frequently numbed by the overwhelming intensity of the training and the practice.

I am all too aware of the many forces that are eroding physician-patient relationships and that can corrupt patient care in the name of efficiency, financial necessity, marketing advantage, or regulatory compliance. Many of these forces I hope to help change. But I remain a hospital guy because I can still make a difference. I still feel honored that patients entrust their care to me as we attempt to navigate our evolving and, yes, sometimes treacherous medical system. Evading the crocodiles and fighting insurance companies are now in my job description.

In this issue we run two letters in response to Dr. Lansdale’s commentary. In December we will publish more letters, though due to space limitations some will be abridged. We plan to run full text of many of the letters online at www.ccjm.org in December.

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Using biochemical markers of bone turnover in clinical practice

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Using biochemical markers of bone turnover in clinical practice
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Frederick R. Singer, MD
David R. Eyre, PhD

Figure 1.
A variety of biochemical assays that reflect the activity of osteoblasts (the bone-forming cells) and osteoclasts (the bone-resorbing cells) have been developed for clinical use (Figure 1). They have helped increase our understanding of the bone remodeling cycle, the pathogenesis of skeletal disorders, and the response of these disorders to therapy.1–4

See related editorial

Although no guidelines to date recommend their widespread use in clinical practice, we believe they will eventually be accepted. For example, markers of bone resorption are excellent indices of disease activity in patients with osteoporosis due to menopause, immobilization, or autoimmune processes, as well as Paget disease of bone or bone metastases. Normalization of the test results can be used to help establish the efficacy of treatment.

Similarly, markers of bone formation are excellent indices of disease activity in Paget disease, osteomalacia and rickets, osteoblastic bone metastases, and to a lesser extent in renal osteodystrophy. Again, successful treatment is associated with normalization of the tests.

This review summarizes some aspects of bone physiology and the pathogenesis of various metabolic bone disorders as a guide for clinicians considering using biochemical markers of osteoblast and osteoclast activity in patient management.

MARKERS OF BONE FORMATION

Osteoblasts are mononuclear cells that attach to bone surfaces and form new bone, most commonly at sites that recently underwent resorption. They produce type I collagen and other matrix components of osteoid, and they also mineralize the osteoid with hydroxyapatite.

Growing children have many more osteoblasts than adults.5 In elderly women, osteoblasts may increase in number in response to the increase in bone resorption brought on by estrogen deficiency. In elderly men, osteoblast activity may decrease,6 possibly because of decreasing levels of serum insulin-like growth factor 1 and testosterone.7

Markers of bone formation are measured in serum. Some are enzymes or other proteins secreted by osteoblasts, others are byproducts of type I collagen deposition.

Total alkaline phosphatase

Alkaline phosphatase, introduced into clinical use in 1929, was the first biochemical marker of bone turnover and is still the one most widely used in clinical practice. This enzyme is found in the plasma membrane of osteoblasts and in cells of the liver, kidney, intestine, spleen, and placenta. Its function is still not precisely known, but it is thought to play a role in osteoid formation and mineralization.

Bone alkaline phosphatase

In normal adults, about half the alkaline phosphatase in the serum comes from bone.1 Because alkaline phosphatase from different types of cells differs in its carbohydrate content, workers have been able to develop relatively specific immunoassays for alkaline phosphatase from bone, although there still is cross-reactivity of up to 20% between the bone and liver enzymes.2

Osteocalcin

Osteocalcin is a large peptide that is synthesized by osteoblasts, odontoblasts, and some chondrocytes. It binds to hydroxyapatite, and much of it is deposited in the bone matrix. Because osteocalcin fragments are released from the bone matrix during resorption, assays for circulating osteocalcin and its fragments reflect both bone formation and resorption.8 The exact function of osteocalcin in bone is still unclear, but recent studies raise the surprising possibility that it is a hormone that influences energy metabolism by modulating the production and action of insulin.9

Procollagen type I propeptides

Procollagen type I propeptides are cleaved from the ends of the procollagen molecule and can be detected in the circulation.1 Those from the amino-terminal end are called PINPs; those from the carboxy-terminal end are called PICPs. Although these propeptides are also synthesized in the skin, tendons, ligaments, cornea, blood vessels, fibrocartilage, and many other tissues, their main source is bone. The level of each of the propeptides in blood is thought to reflect the amount of newly synthesized collagen.

MARKERS OF BONE RESORPTION

Osteoclasts are multinucleated cells that resorb bone. They initiate bone remodeling and help shape growing bone and so are more numerous in children. They also liberate skeletal calcium to maintain a normal serum calcium concentration.5 Postmenopausal women who are estrogen-deficient tend to produce more osteoclasts, which accounts for the bone loss that can occur after menopause.

Markers of bone resorption are measured in serum or urine. The most direct indicators are fragments of bone collagen produced by osteoclast activity.1

Hydroxyproline

Hydroxyproline is an amino acid common to and characteristic of all forms of collagen, and urinary hydroxyproline excretion is the oldest test of bone resorption. However, this test lacks specificity for bone resorption because excreted hydroxyproline also comes from other tissues, particularly from skin collagen (which can turn over rapidly in certain disorders), from newly synthesized collagen that is not incorporated into tissue, and from dietary collagen and gelatin. Because it is less specific than newer tests, it is no longer widely used.

 

 

Collagen cross-links

Urinary pyridinoline and deoxypyridinoline are more specific markers of bone resorption.1

Pyridinolines are cross-linking amino acids that strengthen collagen fibrils in the extra-cellular matrix. They are found in the main fibril-forming collagens (types I, II, and III) of many tissues. Pyridinoline is the major chemical form, but deoxypyridinoline is also unusually abundant in bone collagen and hence is a relatively selective bone marker.

NTx. Since pyridinolines are not metabolized and are largely excreted as small peptides when produced by osteoclastic bone resorption, immunoassays have been developed that selectively measure cross-link-containing peptide fragments in urine and serum. The first was an assay that recognizes an N-telopeptide of collagen type I (NTx) in urine10 and serum.11 The recognized feature in this sequence is fully generated during the process of osteoclastic proteolysis and so requires no further metabolism by the liver or kidney for its production. Results from second-morning urine collections correlate well with those from 24-hour collections, which simplifies patient evaluation.

CTx. Several other assays target structural variants of a peptide sequence that originates from the carboxy-terminal cross-linking region of collagen type I (CTx).12,13

Other markers of bone resorption

Two enzymes found in osteoclasts have received attention as markers of osteoclast activity.

Serum tartrate-resistant acid phosphatase (TRAP) 5b has not been studied extensively in patients but appears to correlate with other markers of bone resorption.14

Serum cathepsin K is of interest because it is the primary proteolytic enzyme used by osteoclasts to degrade bone type I collagen during resorption. Several studies suggest it may be valuable as a marker of bone resorption,15 but more studies are required to evaluate its performance relative to established bone resorption markers.

Receptor activator of nuclear factor kappa (RANK), RANK ligand, and its decoy receptor osteoprotegerin are the pivotal regulators of osteoclast recruitment and activity.16 They may eventually be used as markers of bone metabolism, though the broad role of RANK ligand signaling in the immune system may limit its specificity.

FACTORS THAT INFLUENCE ASSAY RESULTS

To avoid being misled, clinicians who use biochemical markers of bone turnover should be familiar with factors that influence assay results.3

Diurnal and day-to-day variability

The most important biologic factors probably are diurnal and day-to-day variability in bone-forming and bone-resorbing activities. Levels of bone turnover markers are highest in the early morning and lowest in the afternoon and evening.

Levels of urinary markers can vary 20% to 30% from the highest to lowest value of the day. Serum markers change to a smaller degree except for serum CTx, which can vary by more than 60% during the day.17

In general, the day-to-day variability of urinary markers of bone resorption is similar in range to their diurnal variability. The serum markers of bone formation appear to vary less from day to day.

Eating, calcium intake

Blood for measurement of serum CTx should be taken in the morning after overnight fasting to avoid the large decrease that occurs after eating. An increase in calcium intake also can lower the levels of bone resorption markers, particularly in people whose calcium intake was previously low.18 Presumably, this effect is mediated by inhibition of parathyroid hormone secretion.

Sample handling

Improper collection and handling of specimens can seriously affect assay precision. The optimal time to collect samples is in the morning. Careful sample collection and storage are particularly important in measuring serum osteocalcin and TRAP. It is also important to use the same laboratory for serial measurements, since assay results can vary considerably among laboratories, even if they use identical methods.

BONE TURNOVER THROUGHOUT LIFE

In children, bone turnover can be more than 10 times greater than in adults because of three physiologic processes interacting in the skeleton: bone modeling, remodeling, and growth. Levels of bone formation and resorption markers therefore are much higher in children than in adults.19 Unfortunately, no studies have compared all the available markers in the same pediatric reference population.

In puberty, bone growth accelerates, with an increase in bone turnover markers that reflects the effect of hormones that induce the growth spurt.1

Postmenopausal women who do not use hormone replacement therapy have higher levels of bone resorption and formation markers than premenopausal women.20 Levels in postmenopausal women on hormone replacement are no different than in premenopausal women.20,21 In postmenopausal women not on estrogen, urinary levels of NTx have been reported to discriminate between normal bone mineral density (lowest NTx levels), osteopenia, and osteoporosis (highest levels).22 Normal levels of NTx are found in a small percentage of women. This may be explained by the variable levels of serum estradiol in post-menopausal women.23

Elderly men, in contrast, have variable findings.24–28 However, accelerated bone turnover has been noted in men with full-blown hypogonadism caused by androgen suppression therapy.29

 

 

CLINICAL APPLICATIONS OF BONE TURNOVER MARKERS

In postmenopausal osteoporosis

Reproduced from Garnero P, et al. Markers of bone resorption predict hip fracture in elderly women: The EPIDOS Prospective Study. J Bone Miner Res1996; 11:1531–1538. With permission from the American Society for Bone and Mineral Research.
Figure 2. The combination of the assessment of bone mineral density (BMD) and the bone resorption rate to predict hip fracture risk in the elderly. Low BMD was defined according to the World Health Organization guidelines, ie, by a value lower than 2.5 standard deviations (SD) below the young adult mean (T score less than −2.5). High bone resorption was defined by carboxy-terminal cross-linking fragments of collagen type I (CTx) or free deoxypyridinoline (D-Pyr) values higher than the upper limit (mean + 2 SD) of the premenopausal range. Women with both low hip BMD and high bone resorption were at a higher risk of hip fracture than women with either low hip BMD or high bone resorption.
To assess fracture risk. Osteoporosis is diagnosed on the basis of bone mineral density. Although the lower the bone density the greater the risk of fractures, markers of bone resorption can independently predict hip fractures, and a better marker of risk is the combination of low density in the hip and high levels of markers of bone resorption (CTx and deoxypyridinoline) (Figure 2).30

Markers of bone formation are somewhat less likely to be elevated than markers of bone resorption, and if they are elevated, they decrease as expected in response to therapy that inhibits bone resorption, though more gradually and to a lesser extent than the resorption markers.31–35

To monitor bisphosphonate therapy. Antiresorptive drugs such as bisphosphonates reduce the risk of fracture, as they increase bone density and decrease the rate of bone resorption, as shown in many clinical trials.31–35 Because the rate of bone resorption reaches a nadir within 3 to 6 months of starting bisphosphonate therapy and because the increase in bone density after 1 year is quite modest (about 3%–4%), most of the decrease in vertebral fracture incidence, which becomes apparent during the first year of treatment, probably can be attributed more to normalization of bone resorption (and a less perforated structure) than to the increase in bone density.36 This would suggest that it is more appropriate to document that bone resorption has been inhibited than to measure bone density every year when following patients taking antiresorptive agents.

Furthermore, effective antiresorptive therapy reduces the levels of resorption markers by 50% to 70%,32–35 whereas after 1 year bone density has generally not increased more than the error of the bone density measurement. This observation has led to the suggestion that bone density measurements generally should not be done more often than every 2 years when following the effects of antiresorptive therapy. Even with a 20% to 30% day-to-day variation in levels of bone resorption markers, it is easier to document the efficacy of therapy with resorption biomarkers than with bone density.

To document compliance. Another reason to consider measuring a resorption marker (after 3 months of therapy) is to document compliance, a considerable problem in the treatment of an asymptomatic disorder.

To help decide when to restart bisphosphonate therapy. After long-term treatment with a bisphosphonate, the drug may be retained in the skeleton for years. This seems particularly true of alendronate (Fosamax).37 After 5 years of continuous alendronate treatment, bone resorption continues to be suppressed near the maximal level, in some patients for years after they stop taking the drug.38

Once the bone resorption marker begins to approach the pretreatment level, it would signal a possible need to restart the therapy. If a pretreatment level was not measured, an estimate of significant bone resorption would be signaled when the resorption marker is more than 20% above the mean premenopausal level. For urinary NTx this would be more than 42 nmol bone collagen equivalents/mmol creatinine.

Chen P, et al. Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis. J Bone Miner Res 2005; 20:962-970. Permission from the American Society for Bone and Mineral Research.
Figure 3. The relationships between absolute changes in serum concentrations of carboxy-terminal peptide of collagen type I (PICP) concentrations at 1 month (400 patients), serum concentrations of N-terminal peptide of collagen type I (PINP) at 3 months (602 patients), and lumbar spine bone mineral density (BMD) changes at 18 months in postmenopausal women with osteoporosis treated with teriparatide (Forteo). The relationships between changes in biochemical markers and changes in lumbar spine BMD were evaluated by Spearman rank correlation analysis.
To monitor teriparatide therapy. It has been reported that the long-term efficacy of the anabolic drug teriparatide (Forteo) is predicted by measuring bone markers 1 to 3 months after the start of therapy.39,40 The rise of serum procollagen propeptides (both types) correlated well with an increase in lumbar bone density at 18 months (Figure 3).39 A rise in serum PICP of at least 46 ng/mL at 1 month and a rise in serum PINP of at least 17.2 ng/mL at 3 months almost always predicted a significant increase in bone mineral density at 18 months.

In glucocorticoid-induced osteoporosis

Glucocorticoid therapy causes bone loss and an increased incidence of fractures when given in high doses or for prolonged periods by the oral, parenteral, or inhaled routes.41

The pathogenesis of the bone loss has been explored by measurements of bone turnover markers. During glucocorticoid therapy, levels of bone formation markers are generally low and those of bone resorption markers are either normal or low.42–44 Presumably, the reduction in bone resorption is not enough to overcome the reduction in bone formation, and bone loss ensues. In children, the effects on bone formation are particularly profound, as linear growth may be retarded.44

Giving a bisphosphonate during glucocorticoid therapy is quite effective in increasing bone density and preventing fractures.45–47 Patients who receive alendronate have lower levels of bone formation and resorption markers than do untreated subjects.45 Presumably, bone resorption is inhibited more than bone formation, accounting for the skeletal benefits.

In a recent study in patients with glucocorticoid-induced osteoporosis, bone mineral density of the lumbar spine increased more than twice as much with teriparatide than with alendronate over an 18-month period.48 As would be expected from the results of teriparatide therapy in postmenopausal osteoporosis, indices of both bone formation and resorption rose to a peak at 6 months, with formation greater than resorption.

In immobilization-induced osteoporosis

Studies of normal volunteers placed on bed rest indicate that urinary CTx and NTx excretion increase significantly after 24 hours, no doubt reflecting a rapid increase in osteoclast activity.49 In a 16-week study of bed rest in volunteers, markers of bone formation were reduced and markers of bone resorption increased, demonstrating the mechanisms for the profound and rapid loss of bone in immobilized patients.50

In a long-term cross-sectional study of paraplegic men with spinal cord injuries, bone turnover patterns changed over time.51 During the first year after injury, urinary deoxypyridinoline excretion was markedly elevated, whereas blood total alkaline phosphatase and osteocalcin levels were normal to slightly elevated. Over a 30-year period after injury, the bone resorption marker returned to normal levels in most patients and the bone formation markers were normal. Fracture incidence rose but leveled off after 20 years.

Bisphosphonate therapy in spinal cord injury patients reduces urinary NTx and prevents bone loss.52,53 These agents have also proven effective in reversing hypercalcemia in immobilized patients.54

 

 

In inflammatory bowel disease

Patients with inflammatory bowel disease, especially Crohn disease, have low bone mass and are at risk of fractures.55 These complications could be due to glucocorticoid therapy, hypogonadism, vitamin D defeciency, weight loss, and high circulating levels of bone-active cytokines released by inflammatory cells residing in the diseased intestine.

From Dresner-Pollak R,et al. Increased urinary N-telopeptide cross-linked type 1 collagen predicts bone loss in patients with inflammatory bowel disease. Am J Gastroenterology 2000; 95:699–704, with permission from Blackwell Publishing.
Figure 4. The relationship between baseline urinary N-telopeptide cross-linked type 1 collagen (NTx) and the annual percent change of spine bone mineral density in (BMD) patients with inflammatory bowel disease over 2 years.
Elevated levels of urinary NTx have been reported to predict bone loss in the lumbar spine after 2 years of follow-up (Figure 4).56 The cytokines interleukin 1, interleukin 6, and tumor necrosis factor may be responsible for the increased bone resorption.56

Bone formation markers have not been found to be outside the normal range, although both interleukin 1 and tumor necrosis factor alpha are known to inhibit bone formation.

Bisphosphonate treatment produces an increase in bone density concomitant with decreases in markers of bone resorption and formation.57,58 Of considerable interest is the observation that infliximab (anti-tumor necrosis factor alpha; Remicade) generally produces a rise in bone formation markers, with a smaller and inconsistent effect on bone resorption.59,60

In rheumatoid arthritis

The incidence of osteoporosis and fractures is also increased In patients with rheumatoid arthritis.61 As in patients with inflammatory bowel disease, a variety of factors can contribute to bone loss, including glucocorticoid therapy, hypogonadism, vitamin D deficiency, immobility, and elevated levels of bone-active cytokines.

Generally, studies have reported increased bone resorption based on type I collagen markers,62,63 whereas patients with osteoarthritis have levels of these bone resorption markers no different from those of control subjects.62 Although serum total TRAP protein is elevated in rheumatoid arthritis patients, this is probably due to the 5a isoform, the origin of which may be macrophages and dendritric cells.64

The influence of abnormalities in bone formation on bone loss is less clear. Levels of bone formation markers have been reported to be normal,65 elevated,66 or reduced.67

Treatment of rheumatoid arthritis with high-dose glucocorticoid pulse therapy is effective in controlling the symptoms and some manifestations of the immune system in patients with the disorder. The latter effect would be expected to have a beneficial effect on bone metabolism. This appears to be the case, as there are only transient decreases in bone formation markers and no significant reduction in bone density.68 Similarly, there is only a transient decrease in serum osteocalcin after an intra-articular injection of a glucocorticoid, and no effect on urinary pyridino-line.69

As would be expected, bisphosphonate therapy prevents bone loss in rheumatoid arthritis patients treated with glucocorticoids.70,71 Both oral and intravenous therapy decrease the levels of bone turnover markers.70–72 Infliximab therapy was shown to reduce the levels of bone resorption markers but not of PINP (a bone formation marker).73

In primary hyperparathyroidism

Hypersecretion of parathyroid hormone increases osteoclastic activity, with a secondary increase in osteoblastic activity. Bone loss may ensue and an increase in fracture incidence may be a consequence, particularly in post-menopausal women, who have the highest incidence of the disorder.74

Before screening chemistry panels became widely used during routine medical evaluations, it was not unusual to find elevated serum total alkaline phosphatase levels in patients discovered to have primary hyperparathyroidism. Today, this finding is not so common, as the disorder is diagnosed at a much earlier stage. Nevertheless, more specific and sensitive markers of bone turnover have made it possible to demonstrate the metabolic abnormalities that reflect the skeletal pathology in patients with primary hyperparathyroidism and its response to various therapies.75,76

On average, patients with untreated primary hyperparathyroidism have high levels of markers of bone resorption and formation, except in the mildest cases.73,74 Bone turnover returns to normal within 6 months to a year after successful parathyroidectomy.77,78 This response correlates with improvement in bone density, primarily in the lumbar spine.77,78

In patients who do not undergo surgery, alternative means of preventing bone loss include estrogen replacement in estrogendeficient postmenopausal women,76 bisphosphonates,79,80 and cinacalcet (Sensipar).81 Estrogen,76 raloxifene (Evista),82 and alendronate79,80 all reduce levels of bone resorption and formation markers, and estrogen76 and alendronate79,80 increase bone density. Although cinacalcet usually restores the serum calcium to the normal range and prevents bone loss, it only reduces serum parathyroid hormone levels by about 20%, and both bone resorption and formation markers increase above baseline.81 This could be related to fluctuations in serum parathyroid hormone that occur during each day of therapy.

In osteomalacia and rickets

Osteomalacia and rickets of any cause are characterized by increased osteoblastic activity. If the underlying cause is vitamin D deficiency, genetic or acquired defects in calcitriol synthesis, or vitamin D resistance, then hyper-parathyroidism with increased bone resorption is a secondary feature.

Serum total alkaline phosphatase activity has been a useful marker of disease activity for many years, although the newer markers, except for serum osteocalcin,83 are potentially more sensitive. The insensitivity of osteocalcin as an index of osteoblastic activity is unexplained but could be related to the state of differentiation of the osteoblasts. Bone resorption markers are elevated in vitamin D deficiency84 but are not widely used in clinical practice, as serum parathyroid hormone is an excellent indirect means of assessing the presence of increased bone resorption and the response to therapy.

In renal osteodystrophy

Bone disease associated with renal failure is termed renal osteodystrophy and is quite heterogeneous.85 Microscopic examination of a bone biopsy specimen is still considered the gold standard for diagnosis, and measurement in serum of intact parathyroid hormone is an important guide to diagnosis and response to therapy.

Nevertheless, recent studies suggest that serum markers of bone formation and resorption may be of additional help in assessing bone turnover.86 At present it is not certain whether any of the newer markers are superior to serum total alkaline phosphatase activity. Future studies that correlate bone histology with bone turnover markers should clarify the value of the various markers.

 

 

In cancer

Bone metastases are a common complication in cancer patients. They are classified as osteolytic, osteoblastic, or mixed on the basis of radiographic features. Biochemical markers of bone turnover have proven useful in assessing the magnitude of the metastases, the response to therapy, and even the prognosis for survival.87

Osteolytic metastases, which are common in breast cancer, are associated with increases in bone resorption markers, and after treatment with intravenous bisphosphonates the levels can decrease nearly 70%.88,89

Patients with higher levels of urinary NTx had a higher risk of skeletal complications and disease progression than patients with low levels across multiple tumor groups, including multiple myeloma.87

In osteoblastic metastases. Prostate cancer patients, who typically have predominantly osteoblastic lesions, have elevations of serum total alkaline phosphatase activity and other markers of bone formation.90 In addition, they have elevated bone resorption markers. Urinary NTx decreased markedly but serum bone-specific alkaline phosphatase decreased only slightly after treatment with intravenous zoledronic acid (Zometa),91 whereas androgen ablation therapy has inconsistent effects on bone turnover.92,93 High levels of these markers again predict poor prognosis.93,94

In hormone-suppression therapy. Two of the most successful cancer therapies, aromatase inhibitors for breast cancer95 and androgen ablation for prostate cancer,96 accelerate bone loss through marked suppression of gonadal steroids. Bone resorption and formation markers increase and bone loss ensues, with resorption exceeding formation. Estrogen suppression appears mainly responsible in both sexes, since raloxifene prevents bone loss in prostate cancer patients.97

Bisphosphonates are highly effective in preventing bone loss in either sex.98–100 A single infusion of zoledronic acid in androgen-ablated prostate cancer patients can prevent bone loss for at least 1 year.100

In Paget disease of bone

Paget disease of bone evolves over many years, from an early osteolytic phase to dominance of secondary osteoblastic activity. In patients with extensive polyostotic disease, bone resorption and formation marker levels may be higher than in almost any other skeletal disorder. An exception is serum osteocalcin,101 which once again usually does not accurately reflect the rate of bone formation.

Bisphosphonates, given orally or intravenously, produce an early decrease in bone resorption followed by a fall in bone formation.102 In clinical practice it appears adequate to use the least expensive test, serum total alkaline phosphatase activity, to assess disease activity and the response to therapy.103

Acknowledgments: Grant support to FRS from the Edythe and Eli Broad Foundation and Lois Rosen. Grant support to DRE from the National Institutes of Health (NIAMS: AR37318, AR36794).

References
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  3. Seibel MJ. Clinical use of markers of bone turnover in metastatic bone disease. Nat Clin Pract Oncol. 2005; 2:504–517.
  4. Seibel MJ. Biochemical markers of bone turnover: part II: clinical applications in the management of osteoporosis. Clin Biochem Rev. 2006; 27:123–138.
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Frederick R. Singer, MD
Endocrine and Bone Disease Program, John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, CA, and David Geffen School of Medicine at University of California, Los Angeles

David R. Eyre, PhD
Ernest M. Burgess Chair of Orthopaedic Investigation, Department of Orthopaedics and Sports Medicine, University of Washington School of Medicine, Seattle

Address: Frederick Singer, MD, Endocrine and Bone Disease Program, John Wayne Cancer Institute, 2200 Santa Monica Boulevard, Santa Monica, CA 90404; e-mail [email protected]

Dr. Singer has disclosed that he has been an investigator, consultant, and speaker for Merck, Novartis, and Proctor and Gamble and a consultant for Amgen.

Dr. Eyre has disclosed that he receives royalties for patents held by the University of Washington for bone resorption markers.

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Endocrine and Bone Disease Program, John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, CA, and David Geffen School of Medicine at University of California, Los Angeles

David R. Eyre, PhD
Ernest M. Burgess Chair of Orthopaedic Investigation, Department of Orthopaedics and Sports Medicine, University of Washington School of Medicine, Seattle

Address: Frederick Singer, MD, Endocrine and Bone Disease Program, John Wayne Cancer Institute, 2200 Santa Monica Boulevard, Santa Monica, CA 90404; e-mail [email protected]

Dr. Singer has disclosed that he has been an investigator, consultant, and speaker for Merck, Novartis, and Proctor and Gamble and a consultant for Amgen.

Dr. Eyre has disclosed that he receives royalties for patents held by the University of Washington for bone resorption markers.

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Frederick R. Singer, MD
Endocrine and Bone Disease Program, John Wayne Cancer Institute at Saint John’s Health Center, Santa Monica, CA, and David Geffen School of Medicine at University of California, Los Angeles

David R. Eyre, PhD
Ernest M. Burgess Chair of Orthopaedic Investigation, Department of Orthopaedics and Sports Medicine, University of Washington School of Medicine, Seattle

Address: Frederick Singer, MD, Endocrine and Bone Disease Program, John Wayne Cancer Institute, 2200 Santa Monica Boulevard, Santa Monica, CA 90404; e-mail [email protected]

Dr. Singer has disclosed that he has been an investigator, consultant, and speaker for Merck, Novartis, and Proctor and Gamble and a consultant for Amgen.

Dr. Eyre has disclosed that he receives royalties for patents held by the University of Washington for bone resorption markers.

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Related Articles
Biochemical markers of bone turnover: Useful but underused

Figure 1.
A variety of biochemical assays that reflect the activity of osteoblasts (the bone-forming cells) and osteoclasts (the bone-resorbing cells) have been developed for clinical use (Figure 1). They have helped increase our understanding of the bone remodeling cycle, the pathogenesis of skeletal disorders, and the response of these disorders to therapy.1–4

See related editorial

Although no guidelines to date recommend their widespread use in clinical practice, we believe they will eventually be accepted. For example, markers of bone resorption are excellent indices of disease activity in patients with osteoporosis due to menopause, immobilization, or autoimmune processes, as well as Paget disease of bone or bone metastases. Normalization of the test results can be used to help establish the efficacy of treatment.

Similarly, markers of bone formation are excellent indices of disease activity in Paget disease, osteomalacia and rickets, osteoblastic bone metastases, and to a lesser extent in renal osteodystrophy. Again, successful treatment is associated with normalization of the tests.

This review summarizes some aspects of bone physiology and the pathogenesis of various metabolic bone disorders as a guide for clinicians considering using biochemical markers of osteoblast and osteoclast activity in patient management.

MARKERS OF BONE FORMATION

Osteoblasts are mononuclear cells that attach to bone surfaces and form new bone, most commonly at sites that recently underwent resorption. They produce type I collagen and other matrix components of osteoid, and they also mineralize the osteoid with hydroxyapatite.

Growing children have many more osteoblasts than adults.5 In elderly women, osteoblasts may increase in number in response to the increase in bone resorption brought on by estrogen deficiency. In elderly men, osteoblast activity may decrease,6 possibly because of decreasing levels of serum insulin-like growth factor 1 and testosterone.7

Markers of bone formation are measured in serum. Some are enzymes or other proteins secreted by osteoblasts, others are byproducts of type I collagen deposition.

Total alkaline phosphatase

Alkaline phosphatase, introduced into clinical use in 1929, was the first biochemical marker of bone turnover and is still the one most widely used in clinical practice. This enzyme is found in the plasma membrane of osteoblasts and in cells of the liver, kidney, intestine, spleen, and placenta. Its function is still not precisely known, but it is thought to play a role in osteoid formation and mineralization.

Bone alkaline phosphatase

In normal adults, about half the alkaline phosphatase in the serum comes from bone.1 Because alkaline phosphatase from different types of cells differs in its carbohydrate content, workers have been able to develop relatively specific immunoassays for alkaline phosphatase from bone, although there still is cross-reactivity of up to 20% between the bone and liver enzymes.2

Osteocalcin

Osteocalcin is a large peptide that is synthesized by osteoblasts, odontoblasts, and some chondrocytes. It binds to hydroxyapatite, and much of it is deposited in the bone matrix. Because osteocalcin fragments are released from the bone matrix during resorption, assays for circulating osteocalcin and its fragments reflect both bone formation and resorption.8 The exact function of osteocalcin in bone is still unclear, but recent studies raise the surprising possibility that it is a hormone that influences energy metabolism by modulating the production and action of insulin.9

Procollagen type I propeptides

Procollagen type I propeptides are cleaved from the ends of the procollagen molecule and can be detected in the circulation.1 Those from the amino-terminal end are called PINPs; those from the carboxy-terminal end are called PICPs. Although these propeptides are also synthesized in the skin, tendons, ligaments, cornea, blood vessels, fibrocartilage, and many other tissues, their main source is bone. The level of each of the propeptides in blood is thought to reflect the amount of newly synthesized collagen.

MARKERS OF BONE RESORPTION

Osteoclasts are multinucleated cells that resorb bone. They initiate bone remodeling and help shape growing bone and so are more numerous in children. They also liberate skeletal calcium to maintain a normal serum calcium concentration.5 Postmenopausal women who are estrogen-deficient tend to produce more osteoclasts, which accounts for the bone loss that can occur after menopause.

Markers of bone resorption are measured in serum or urine. The most direct indicators are fragments of bone collagen produced by osteoclast activity.1

Hydroxyproline

Hydroxyproline is an amino acid common to and characteristic of all forms of collagen, and urinary hydroxyproline excretion is the oldest test of bone resorption. However, this test lacks specificity for bone resorption because excreted hydroxyproline also comes from other tissues, particularly from skin collagen (which can turn over rapidly in certain disorders), from newly synthesized collagen that is not incorporated into tissue, and from dietary collagen and gelatin. Because it is less specific than newer tests, it is no longer widely used.

 

 

Collagen cross-links

Urinary pyridinoline and deoxypyridinoline are more specific markers of bone resorption.1

Pyridinolines are cross-linking amino acids that strengthen collagen fibrils in the extra-cellular matrix. They are found in the main fibril-forming collagens (types I, II, and III) of many tissues. Pyridinoline is the major chemical form, but deoxypyridinoline is also unusually abundant in bone collagen and hence is a relatively selective bone marker.

NTx. Since pyridinolines are not metabolized and are largely excreted as small peptides when produced by osteoclastic bone resorption, immunoassays have been developed that selectively measure cross-link-containing peptide fragments in urine and serum. The first was an assay that recognizes an N-telopeptide of collagen type I (NTx) in urine10 and serum.11 The recognized feature in this sequence is fully generated during the process of osteoclastic proteolysis and so requires no further metabolism by the liver or kidney for its production. Results from second-morning urine collections correlate well with those from 24-hour collections, which simplifies patient evaluation.

CTx. Several other assays target structural variants of a peptide sequence that originates from the carboxy-terminal cross-linking region of collagen type I (CTx).12,13

Other markers of bone resorption

Two enzymes found in osteoclasts have received attention as markers of osteoclast activity.

Serum tartrate-resistant acid phosphatase (TRAP) 5b has not been studied extensively in patients but appears to correlate with other markers of bone resorption.14

Serum cathepsin K is of interest because it is the primary proteolytic enzyme used by osteoclasts to degrade bone type I collagen during resorption. Several studies suggest it may be valuable as a marker of bone resorption,15 but more studies are required to evaluate its performance relative to established bone resorption markers.

Receptor activator of nuclear factor kappa (RANK), RANK ligand, and its decoy receptor osteoprotegerin are the pivotal regulators of osteoclast recruitment and activity.16 They may eventually be used as markers of bone metabolism, though the broad role of RANK ligand signaling in the immune system may limit its specificity.

FACTORS THAT INFLUENCE ASSAY RESULTS

To avoid being misled, clinicians who use biochemical markers of bone turnover should be familiar with factors that influence assay results.3

Diurnal and day-to-day variability

The most important biologic factors probably are diurnal and day-to-day variability in bone-forming and bone-resorbing activities. Levels of bone turnover markers are highest in the early morning and lowest in the afternoon and evening.

Levels of urinary markers can vary 20% to 30% from the highest to lowest value of the day. Serum markers change to a smaller degree except for serum CTx, which can vary by more than 60% during the day.17

In general, the day-to-day variability of urinary markers of bone resorption is similar in range to their diurnal variability. The serum markers of bone formation appear to vary less from day to day.

Eating, calcium intake

Blood for measurement of serum CTx should be taken in the morning after overnight fasting to avoid the large decrease that occurs after eating. An increase in calcium intake also can lower the levels of bone resorption markers, particularly in people whose calcium intake was previously low.18 Presumably, this effect is mediated by inhibition of parathyroid hormone secretion.

Sample handling

Improper collection and handling of specimens can seriously affect assay precision. The optimal time to collect samples is in the morning. Careful sample collection and storage are particularly important in measuring serum osteocalcin and TRAP. It is also important to use the same laboratory for serial measurements, since assay results can vary considerably among laboratories, even if they use identical methods.

BONE TURNOVER THROUGHOUT LIFE

In children, bone turnover can be more than 10 times greater than in adults because of three physiologic processes interacting in the skeleton: bone modeling, remodeling, and growth. Levels of bone formation and resorption markers therefore are much higher in children than in adults.19 Unfortunately, no studies have compared all the available markers in the same pediatric reference population.

In puberty, bone growth accelerates, with an increase in bone turnover markers that reflects the effect of hormones that induce the growth spurt.1

Postmenopausal women who do not use hormone replacement therapy have higher levels of bone resorption and formation markers than premenopausal women.20 Levels in postmenopausal women on hormone replacement are no different than in premenopausal women.20,21 In postmenopausal women not on estrogen, urinary levels of NTx have been reported to discriminate between normal bone mineral density (lowest NTx levels), osteopenia, and osteoporosis (highest levels).22 Normal levels of NTx are found in a small percentage of women. This may be explained by the variable levels of serum estradiol in post-menopausal women.23

Elderly men, in contrast, have variable findings.24–28 However, accelerated bone turnover has been noted in men with full-blown hypogonadism caused by androgen suppression therapy.29

 

 

CLINICAL APPLICATIONS OF BONE TURNOVER MARKERS

In postmenopausal osteoporosis

Reproduced from Garnero P, et al. Markers of bone resorption predict hip fracture in elderly women: The EPIDOS Prospective Study. J Bone Miner Res1996; 11:1531–1538. With permission from the American Society for Bone and Mineral Research.
Figure 2. The combination of the assessment of bone mineral density (BMD) and the bone resorption rate to predict hip fracture risk in the elderly. Low BMD was defined according to the World Health Organization guidelines, ie, by a value lower than 2.5 standard deviations (SD) below the young adult mean (T score less than −2.5). High bone resorption was defined by carboxy-terminal cross-linking fragments of collagen type I (CTx) or free deoxypyridinoline (D-Pyr) values higher than the upper limit (mean + 2 SD) of the premenopausal range. Women with both low hip BMD and high bone resorption were at a higher risk of hip fracture than women with either low hip BMD or high bone resorption.
To assess fracture risk. Osteoporosis is diagnosed on the basis of bone mineral density. Although the lower the bone density the greater the risk of fractures, markers of bone resorption can independently predict hip fractures, and a better marker of risk is the combination of low density in the hip and high levels of markers of bone resorption (CTx and deoxypyridinoline) (Figure 2).30

Markers of bone formation are somewhat less likely to be elevated than markers of bone resorption, and if they are elevated, they decrease as expected in response to therapy that inhibits bone resorption, though more gradually and to a lesser extent than the resorption markers.31–35

To monitor bisphosphonate therapy. Antiresorptive drugs such as bisphosphonates reduce the risk of fracture, as they increase bone density and decrease the rate of bone resorption, as shown in many clinical trials.31–35 Because the rate of bone resorption reaches a nadir within 3 to 6 months of starting bisphosphonate therapy and because the increase in bone density after 1 year is quite modest (about 3%–4%), most of the decrease in vertebral fracture incidence, which becomes apparent during the first year of treatment, probably can be attributed more to normalization of bone resorption (and a less perforated structure) than to the increase in bone density.36 This would suggest that it is more appropriate to document that bone resorption has been inhibited than to measure bone density every year when following patients taking antiresorptive agents.

Furthermore, effective antiresorptive therapy reduces the levels of resorption markers by 50% to 70%,32–35 whereas after 1 year bone density has generally not increased more than the error of the bone density measurement. This observation has led to the suggestion that bone density measurements generally should not be done more often than every 2 years when following the effects of antiresorptive therapy. Even with a 20% to 30% day-to-day variation in levels of bone resorption markers, it is easier to document the efficacy of therapy with resorption biomarkers than with bone density.

To document compliance. Another reason to consider measuring a resorption marker (after 3 months of therapy) is to document compliance, a considerable problem in the treatment of an asymptomatic disorder.

To help decide when to restart bisphosphonate therapy. After long-term treatment with a bisphosphonate, the drug may be retained in the skeleton for years. This seems particularly true of alendronate (Fosamax).37 After 5 years of continuous alendronate treatment, bone resorption continues to be suppressed near the maximal level, in some patients for years after they stop taking the drug.38

Once the bone resorption marker begins to approach the pretreatment level, it would signal a possible need to restart the therapy. If a pretreatment level was not measured, an estimate of significant bone resorption would be signaled when the resorption marker is more than 20% above the mean premenopausal level. For urinary NTx this would be more than 42 nmol bone collagen equivalents/mmol creatinine.

Chen P, et al. Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis. J Bone Miner Res 2005; 20:962-970. Permission from the American Society for Bone and Mineral Research.
Figure 3. The relationships between absolute changes in serum concentrations of carboxy-terminal peptide of collagen type I (PICP) concentrations at 1 month (400 patients), serum concentrations of N-terminal peptide of collagen type I (PINP) at 3 months (602 patients), and lumbar spine bone mineral density (BMD) changes at 18 months in postmenopausal women with osteoporosis treated with teriparatide (Forteo). The relationships between changes in biochemical markers and changes in lumbar spine BMD were evaluated by Spearman rank correlation analysis.
To monitor teriparatide therapy. It has been reported that the long-term efficacy of the anabolic drug teriparatide (Forteo) is predicted by measuring bone markers 1 to 3 months after the start of therapy.39,40 The rise of serum procollagen propeptides (both types) correlated well with an increase in lumbar bone density at 18 months (Figure 3).39 A rise in serum PICP of at least 46 ng/mL at 1 month and a rise in serum PINP of at least 17.2 ng/mL at 3 months almost always predicted a significant increase in bone mineral density at 18 months.

In glucocorticoid-induced osteoporosis

Glucocorticoid therapy causes bone loss and an increased incidence of fractures when given in high doses or for prolonged periods by the oral, parenteral, or inhaled routes.41

The pathogenesis of the bone loss has been explored by measurements of bone turnover markers. During glucocorticoid therapy, levels of bone formation markers are generally low and those of bone resorption markers are either normal or low.42–44 Presumably, the reduction in bone resorption is not enough to overcome the reduction in bone formation, and bone loss ensues. In children, the effects on bone formation are particularly profound, as linear growth may be retarded.44

Giving a bisphosphonate during glucocorticoid therapy is quite effective in increasing bone density and preventing fractures.45–47 Patients who receive alendronate have lower levels of bone formation and resorption markers than do untreated subjects.45 Presumably, bone resorption is inhibited more than bone formation, accounting for the skeletal benefits.

In a recent study in patients with glucocorticoid-induced osteoporosis, bone mineral density of the lumbar spine increased more than twice as much with teriparatide than with alendronate over an 18-month period.48 As would be expected from the results of teriparatide therapy in postmenopausal osteoporosis, indices of both bone formation and resorption rose to a peak at 6 months, with formation greater than resorption.

In immobilization-induced osteoporosis

Studies of normal volunteers placed on bed rest indicate that urinary CTx and NTx excretion increase significantly after 24 hours, no doubt reflecting a rapid increase in osteoclast activity.49 In a 16-week study of bed rest in volunteers, markers of bone formation were reduced and markers of bone resorption increased, demonstrating the mechanisms for the profound and rapid loss of bone in immobilized patients.50

In a long-term cross-sectional study of paraplegic men with spinal cord injuries, bone turnover patterns changed over time.51 During the first year after injury, urinary deoxypyridinoline excretion was markedly elevated, whereas blood total alkaline phosphatase and osteocalcin levels were normal to slightly elevated. Over a 30-year period after injury, the bone resorption marker returned to normal levels in most patients and the bone formation markers were normal. Fracture incidence rose but leveled off after 20 years.

Bisphosphonate therapy in spinal cord injury patients reduces urinary NTx and prevents bone loss.52,53 These agents have also proven effective in reversing hypercalcemia in immobilized patients.54

 

 

In inflammatory bowel disease

Patients with inflammatory bowel disease, especially Crohn disease, have low bone mass and are at risk of fractures.55 These complications could be due to glucocorticoid therapy, hypogonadism, vitamin D defeciency, weight loss, and high circulating levels of bone-active cytokines released by inflammatory cells residing in the diseased intestine.

From Dresner-Pollak R,et al. Increased urinary N-telopeptide cross-linked type 1 collagen predicts bone loss in patients with inflammatory bowel disease. Am J Gastroenterology 2000; 95:699–704, with permission from Blackwell Publishing.
Figure 4. The relationship between baseline urinary N-telopeptide cross-linked type 1 collagen (NTx) and the annual percent change of spine bone mineral density in (BMD) patients with inflammatory bowel disease over 2 years.
Elevated levels of urinary NTx have been reported to predict bone loss in the lumbar spine after 2 years of follow-up (Figure 4).56 The cytokines interleukin 1, interleukin 6, and tumor necrosis factor may be responsible for the increased bone resorption.56

Bone formation markers have not been found to be outside the normal range, although both interleukin 1 and tumor necrosis factor alpha are known to inhibit bone formation.

Bisphosphonate treatment produces an increase in bone density concomitant with decreases in markers of bone resorption and formation.57,58 Of considerable interest is the observation that infliximab (anti-tumor necrosis factor alpha; Remicade) generally produces a rise in bone formation markers, with a smaller and inconsistent effect on bone resorption.59,60

In rheumatoid arthritis

The incidence of osteoporosis and fractures is also increased In patients with rheumatoid arthritis.61 As in patients with inflammatory bowel disease, a variety of factors can contribute to bone loss, including glucocorticoid therapy, hypogonadism, vitamin D deficiency, immobility, and elevated levels of bone-active cytokines.

Generally, studies have reported increased bone resorption based on type I collagen markers,62,63 whereas patients with osteoarthritis have levels of these bone resorption markers no different from those of control subjects.62 Although serum total TRAP protein is elevated in rheumatoid arthritis patients, this is probably due to the 5a isoform, the origin of which may be macrophages and dendritric cells.64

The influence of abnormalities in bone formation on bone loss is less clear. Levels of bone formation markers have been reported to be normal,65 elevated,66 or reduced.67

Treatment of rheumatoid arthritis with high-dose glucocorticoid pulse therapy is effective in controlling the symptoms and some manifestations of the immune system in patients with the disorder. The latter effect would be expected to have a beneficial effect on bone metabolism. This appears to be the case, as there are only transient decreases in bone formation markers and no significant reduction in bone density.68 Similarly, there is only a transient decrease in serum osteocalcin after an intra-articular injection of a glucocorticoid, and no effect on urinary pyridino-line.69

As would be expected, bisphosphonate therapy prevents bone loss in rheumatoid arthritis patients treated with glucocorticoids.70,71 Both oral and intravenous therapy decrease the levels of bone turnover markers.70–72 Infliximab therapy was shown to reduce the levels of bone resorption markers but not of PINP (a bone formation marker).73

In primary hyperparathyroidism

Hypersecretion of parathyroid hormone increases osteoclastic activity, with a secondary increase in osteoblastic activity. Bone loss may ensue and an increase in fracture incidence may be a consequence, particularly in post-menopausal women, who have the highest incidence of the disorder.74

Before screening chemistry panels became widely used during routine medical evaluations, it was not unusual to find elevated serum total alkaline phosphatase levels in patients discovered to have primary hyperparathyroidism. Today, this finding is not so common, as the disorder is diagnosed at a much earlier stage. Nevertheless, more specific and sensitive markers of bone turnover have made it possible to demonstrate the metabolic abnormalities that reflect the skeletal pathology in patients with primary hyperparathyroidism and its response to various therapies.75,76

On average, patients with untreated primary hyperparathyroidism have high levels of markers of bone resorption and formation, except in the mildest cases.73,74 Bone turnover returns to normal within 6 months to a year after successful parathyroidectomy.77,78 This response correlates with improvement in bone density, primarily in the lumbar spine.77,78

In patients who do not undergo surgery, alternative means of preventing bone loss include estrogen replacement in estrogendeficient postmenopausal women,76 bisphosphonates,79,80 and cinacalcet (Sensipar).81 Estrogen,76 raloxifene (Evista),82 and alendronate79,80 all reduce levels of bone resorption and formation markers, and estrogen76 and alendronate79,80 increase bone density. Although cinacalcet usually restores the serum calcium to the normal range and prevents bone loss, it only reduces serum parathyroid hormone levels by about 20%, and both bone resorption and formation markers increase above baseline.81 This could be related to fluctuations in serum parathyroid hormone that occur during each day of therapy.

In osteomalacia and rickets

Osteomalacia and rickets of any cause are characterized by increased osteoblastic activity. If the underlying cause is vitamin D deficiency, genetic or acquired defects in calcitriol synthesis, or vitamin D resistance, then hyper-parathyroidism with increased bone resorption is a secondary feature.

Serum total alkaline phosphatase activity has been a useful marker of disease activity for many years, although the newer markers, except for serum osteocalcin,83 are potentially more sensitive. The insensitivity of osteocalcin as an index of osteoblastic activity is unexplained but could be related to the state of differentiation of the osteoblasts. Bone resorption markers are elevated in vitamin D deficiency84 but are not widely used in clinical practice, as serum parathyroid hormone is an excellent indirect means of assessing the presence of increased bone resorption and the response to therapy.

In renal osteodystrophy

Bone disease associated with renal failure is termed renal osteodystrophy and is quite heterogeneous.85 Microscopic examination of a bone biopsy specimen is still considered the gold standard for diagnosis, and measurement in serum of intact parathyroid hormone is an important guide to diagnosis and response to therapy.

Nevertheless, recent studies suggest that serum markers of bone formation and resorption may be of additional help in assessing bone turnover.86 At present it is not certain whether any of the newer markers are superior to serum total alkaline phosphatase activity. Future studies that correlate bone histology with bone turnover markers should clarify the value of the various markers.

 

 

In cancer

Bone metastases are a common complication in cancer patients. They are classified as osteolytic, osteoblastic, or mixed on the basis of radiographic features. Biochemical markers of bone turnover have proven useful in assessing the magnitude of the metastases, the response to therapy, and even the prognosis for survival.87

Osteolytic metastases, which are common in breast cancer, are associated with increases in bone resorption markers, and after treatment with intravenous bisphosphonates the levels can decrease nearly 70%.88,89

Patients with higher levels of urinary NTx had a higher risk of skeletal complications and disease progression than patients with low levels across multiple tumor groups, including multiple myeloma.87

In osteoblastic metastases. Prostate cancer patients, who typically have predominantly osteoblastic lesions, have elevations of serum total alkaline phosphatase activity and other markers of bone formation.90 In addition, they have elevated bone resorption markers. Urinary NTx decreased markedly but serum bone-specific alkaline phosphatase decreased only slightly after treatment with intravenous zoledronic acid (Zometa),91 whereas androgen ablation therapy has inconsistent effects on bone turnover.92,93 High levels of these markers again predict poor prognosis.93,94

In hormone-suppression therapy. Two of the most successful cancer therapies, aromatase inhibitors for breast cancer95 and androgen ablation for prostate cancer,96 accelerate bone loss through marked suppression of gonadal steroids. Bone resorption and formation markers increase and bone loss ensues, with resorption exceeding formation. Estrogen suppression appears mainly responsible in both sexes, since raloxifene prevents bone loss in prostate cancer patients.97

Bisphosphonates are highly effective in preventing bone loss in either sex.98–100 A single infusion of zoledronic acid in androgen-ablated prostate cancer patients can prevent bone loss for at least 1 year.100

In Paget disease of bone

Paget disease of bone evolves over many years, from an early osteolytic phase to dominance of secondary osteoblastic activity. In patients with extensive polyostotic disease, bone resorption and formation marker levels may be higher than in almost any other skeletal disorder. An exception is serum osteocalcin,101 which once again usually does not accurately reflect the rate of bone formation.

Bisphosphonates, given orally or intravenously, produce an early decrease in bone resorption followed by a fall in bone formation.102 In clinical practice it appears adequate to use the least expensive test, serum total alkaline phosphatase activity, to assess disease activity and the response to therapy.103

Acknowledgments: Grant support to FRS from the Edythe and Eli Broad Foundation and Lois Rosen. Grant support to DRE from the National Institutes of Health (NIAMS: AR37318, AR36794).

Figure 1.
A variety of biochemical assays that reflect the activity of osteoblasts (the bone-forming cells) and osteoclasts (the bone-resorbing cells) have been developed for clinical use (Figure 1). They have helped increase our understanding of the bone remodeling cycle, the pathogenesis of skeletal disorders, and the response of these disorders to therapy.1–4

See related editorial

Although no guidelines to date recommend their widespread use in clinical practice, we believe they will eventually be accepted. For example, markers of bone resorption are excellent indices of disease activity in patients with osteoporosis due to menopause, immobilization, or autoimmune processes, as well as Paget disease of bone or bone metastases. Normalization of the test results can be used to help establish the efficacy of treatment.

Similarly, markers of bone formation are excellent indices of disease activity in Paget disease, osteomalacia and rickets, osteoblastic bone metastases, and to a lesser extent in renal osteodystrophy. Again, successful treatment is associated with normalization of the tests.

This review summarizes some aspects of bone physiology and the pathogenesis of various metabolic bone disorders as a guide for clinicians considering using biochemical markers of osteoblast and osteoclast activity in patient management.

MARKERS OF BONE FORMATION

Osteoblasts are mononuclear cells that attach to bone surfaces and form new bone, most commonly at sites that recently underwent resorption. They produce type I collagen and other matrix components of osteoid, and they also mineralize the osteoid with hydroxyapatite.

Growing children have many more osteoblasts than adults.5 In elderly women, osteoblasts may increase in number in response to the increase in bone resorption brought on by estrogen deficiency. In elderly men, osteoblast activity may decrease,6 possibly because of decreasing levels of serum insulin-like growth factor 1 and testosterone.7

Markers of bone formation are measured in serum. Some are enzymes or other proteins secreted by osteoblasts, others are byproducts of type I collagen deposition.

Total alkaline phosphatase

Alkaline phosphatase, introduced into clinical use in 1929, was the first biochemical marker of bone turnover and is still the one most widely used in clinical practice. This enzyme is found in the plasma membrane of osteoblasts and in cells of the liver, kidney, intestine, spleen, and placenta. Its function is still not precisely known, but it is thought to play a role in osteoid formation and mineralization.

Bone alkaline phosphatase

In normal adults, about half the alkaline phosphatase in the serum comes from bone.1 Because alkaline phosphatase from different types of cells differs in its carbohydrate content, workers have been able to develop relatively specific immunoassays for alkaline phosphatase from bone, although there still is cross-reactivity of up to 20% between the bone and liver enzymes.2

Osteocalcin

Osteocalcin is a large peptide that is synthesized by osteoblasts, odontoblasts, and some chondrocytes. It binds to hydroxyapatite, and much of it is deposited in the bone matrix. Because osteocalcin fragments are released from the bone matrix during resorption, assays for circulating osteocalcin and its fragments reflect both bone formation and resorption.8 The exact function of osteocalcin in bone is still unclear, but recent studies raise the surprising possibility that it is a hormone that influences energy metabolism by modulating the production and action of insulin.9

Procollagen type I propeptides

Procollagen type I propeptides are cleaved from the ends of the procollagen molecule and can be detected in the circulation.1 Those from the amino-terminal end are called PINPs; those from the carboxy-terminal end are called PICPs. Although these propeptides are also synthesized in the skin, tendons, ligaments, cornea, blood vessels, fibrocartilage, and many other tissues, their main source is bone. The level of each of the propeptides in blood is thought to reflect the amount of newly synthesized collagen.

MARKERS OF BONE RESORPTION

Osteoclasts are multinucleated cells that resorb bone. They initiate bone remodeling and help shape growing bone and so are more numerous in children. They also liberate skeletal calcium to maintain a normal serum calcium concentration.5 Postmenopausal women who are estrogen-deficient tend to produce more osteoclasts, which accounts for the bone loss that can occur after menopause.

Markers of bone resorption are measured in serum or urine. The most direct indicators are fragments of bone collagen produced by osteoclast activity.1

Hydroxyproline

Hydroxyproline is an amino acid common to and characteristic of all forms of collagen, and urinary hydroxyproline excretion is the oldest test of bone resorption. However, this test lacks specificity for bone resorption because excreted hydroxyproline also comes from other tissues, particularly from skin collagen (which can turn over rapidly in certain disorders), from newly synthesized collagen that is not incorporated into tissue, and from dietary collagen and gelatin. Because it is less specific than newer tests, it is no longer widely used.

 

 

Collagen cross-links

Urinary pyridinoline and deoxypyridinoline are more specific markers of bone resorption.1

Pyridinolines are cross-linking amino acids that strengthen collagen fibrils in the extra-cellular matrix. They are found in the main fibril-forming collagens (types I, II, and III) of many tissues. Pyridinoline is the major chemical form, but deoxypyridinoline is also unusually abundant in bone collagen and hence is a relatively selective bone marker.

NTx. Since pyridinolines are not metabolized and are largely excreted as small peptides when produced by osteoclastic bone resorption, immunoassays have been developed that selectively measure cross-link-containing peptide fragments in urine and serum. The first was an assay that recognizes an N-telopeptide of collagen type I (NTx) in urine10 and serum.11 The recognized feature in this sequence is fully generated during the process of osteoclastic proteolysis and so requires no further metabolism by the liver or kidney for its production. Results from second-morning urine collections correlate well with those from 24-hour collections, which simplifies patient evaluation.

CTx. Several other assays target structural variants of a peptide sequence that originates from the carboxy-terminal cross-linking region of collagen type I (CTx).12,13

Other markers of bone resorption

Two enzymes found in osteoclasts have received attention as markers of osteoclast activity.

Serum tartrate-resistant acid phosphatase (TRAP) 5b has not been studied extensively in patients but appears to correlate with other markers of bone resorption.14

Serum cathepsin K is of interest because it is the primary proteolytic enzyme used by osteoclasts to degrade bone type I collagen during resorption. Several studies suggest it may be valuable as a marker of bone resorption,15 but more studies are required to evaluate its performance relative to established bone resorption markers.

Receptor activator of nuclear factor kappa (RANK), RANK ligand, and its decoy receptor osteoprotegerin are the pivotal regulators of osteoclast recruitment and activity.16 They may eventually be used as markers of bone metabolism, though the broad role of RANK ligand signaling in the immune system may limit its specificity.

FACTORS THAT INFLUENCE ASSAY RESULTS

To avoid being misled, clinicians who use biochemical markers of bone turnover should be familiar with factors that influence assay results.3

Diurnal and day-to-day variability

The most important biologic factors probably are diurnal and day-to-day variability in bone-forming and bone-resorbing activities. Levels of bone turnover markers are highest in the early morning and lowest in the afternoon and evening.

Levels of urinary markers can vary 20% to 30% from the highest to lowest value of the day. Serum markers change to a smaller degree except for serum CTx, which can vary by more than 60% during the day.17

In general, the day-to-day variability of urinary markers of bone resorption is similar in range to their diurnal variability. The serum markers of bone formation appear to vary less from day to day.

Eating, calcium intake

Blood for measurement of serum CTx should be taken in the morning after overnight fasting to avoid the large decrease that occurs after eating. An increase in calcium intake also can lower the levels of bone resorption markers, particularly in people whose calcium intake was previously low.18 Presumably, this effect is mediated by inhibition of parathyroid hormone secretion.

Sample handling

Improper collection and handling of specimens can seriously affect assay precision. The optimal time to collect samples is in the morning. Careful sample collection and storage are particularly important in measuring serum osteocalcin and TRAP. It is also important to use the same laboratory for serial measurements, since assay results can vary considerably among laboratories, even if they use identical methods.

BONE TURNOVER THROUGHOUT LIFE

In children, bone turnover can be more than 10 times greater than in adults because of three physiologic processes interacting in the skeleton: bone modeling, remodeling, and growth. Levels of bone formation and resorption markers therefore are much higher in children than in adults.19 Unfortunately, no studies have compared all the available markers in the same pediatric reference population.

In puberty, bone growth accelerates, with an increase in bone turnover markers that reflects the effect of hormones that induce the growth spurt.1

Postmenopausal women who do not use hormone replacement therapy have higher levels of bone resorption and formation markers than premenopausal women.20 Levels in postmenopausal women on hormone replacement are no different than in premenopausal women.20,21 In postmenopausal women not on estrogen, urinary levels of NTx have been reported to discriminate between normal bone mineral density (lowest NTx levels), osteopenia, and osteoporosis (highest levels).22 Normal levels of NTx are found in a small percentage of women. This may be explained by the variable levels of serum estradiol in post-menopausal women.23

Elderly men, in contrast, have variable findings.24–28 However, accelerated bone turnover has been noted in men with full-blown hypogonadism caused by androgen suppression therapy.29

 

 

CLINICAL APPLICATIONS OF BONE TURNOVER MARKERS

In postmenopausal osteoporosis

Reproduced from Garnero P, et al. Markers of bone resorption predict hip fracture in elderly women: The EPIDOS Prospective Study. J Bone Miner Res1996; 11:1531–1538. With permission from the American Society for Bone and Mineral Research.
Figure 2. The combination of the assessment of bone mineral density (BMD) and the bone resorption rate to predict hip fracture risk in the elderly. Low BMD was defined according to the World Health Organization guidelines, ie, by a value lower than 2.5 standard deviations (SD) below the young adult mean (T score less than −2.5). High bone resorption was defined by carboxy-terminal cross-linking fragments of collagen type I (CTx) or free deoxypyridinoline (D-Pyr) values higher than the upper limit (mean + 2 SD) of the premenopausal range. Women with both low hip BMD and high bone resorption were at a higher risk of hip fracture than women with either low hip BMD or high bone resorption.
To assess fracture risk. Osteoporosis is diagnosed on the basis of bone mineral density. Although the lower the bone density the greater the risk of fractures, markers of bone resorption can independently predict hip fractures, and a better marker of risk is the combination of low density in the hip and high levels of markers of bone resorption (CTx and deoxypyridinoline) (Figure 2).30

Markers of bone formation are somewhat less likely to be elevated than markers of bone resorption, and if they are elevated, they decrease as expected in response to therapy that inhibits bone resorption, though more gradually and to a lesser extent than the resorption markers.31–35

To monitor bisphosphonate therapy. Antiresorptive drugs such as bisphosphonates reduce the risk of fracture, as they increase bone density and decrease the rate of bone resorption, as shown in many clinical trials.31–35 Because the rate of bone resorption reaches a nadir within 3 to 6 months of starting bisphosphonate therapy and because the increase in bone density after 1 year is quite modest (about 3%–4%), most of the decrease in vertebral fracture incidence, which becomes apparent during the first year of treatment, probably can be attributed more to normalization of bone resorption (and a less perforated structure) than to the increase in bone density.36 This would suggest that it is more appropriate to document that bone resorption has been inhibited than to measure bone density every year when following patients taking antiresorptive agents.

Furthermore, effective antiresorptive therapy reduces the levels of resorption markers by 50% to 70%,32–35 whereas after 1 year bone density has generally not increased more than the error of the bone density measurement. This observation has led to the suggestion that bone density measurements generally should not be done more often than every 2 years when following the effects of antiresorptive therapy. Even with a 20% to 30% day-to-day variation in levels of bone resorption markers, it is easier to document the efficacy of therapy with resorption biomarkers than with bone density.

To document compliance. Another reason to consider measuring a resorption marker (after 3 months of therapy) is to document compliance, a considerable problem in the treatment of an asymptomatic disorder.

To help decide when to restart bisphosphonate therapy. After long-term treatment with a bisphosphonate, the drug may be retained in the skeleton for years. This seems particularly true of alendronate (Fosamax).37 After 5 years of continuous alendronate treatment, bone resorption continues to be suppressed near the maximal level, in some patients for years after they stop taking the drug.38

Once the bone resorption marker begins to approach the pretreatment level, it would signal a possible need to restart the therapy. If a pretreatment level was not measured, an estimate of significant bone resorption would be signaled when the resorption marker is more than 20% above the mean premenopausal level. For urinary NTx this would be more than 42 nmol bone collagen equivalents/mmol creatinine.

Chen P, et al. Early changes in biochemical markers of bone formation predict BMD response to teriparatide in postmenopausal women with osteoporosis. J Bone Miner Res 2005; 20:962-970. Permission from the American Society for Bone and Mineral Research.
Figure 3. The relationships between absolute changes in serum concentrations of carboxy-terminal peptide of collagen type I (PICP) concentrations at 1 month (400 patients), serum concentrations of N-terminal peptide of collagen type I (PINP) at 3 months (602 patients), and lumbar spine bone mineral density (BMD) changes at 18 months in postmenopausal women with osteoporosis treated with teriparatide (Forteo). The relationships between changes in biochemical markers and changes in lumbar spine BMD were evaluated by Spearman rank correlation analysis.
To monitor teriparatide therapy. It has been reported that the long-term efficacy of the anabolic drug teriparatide (Forteo) is predicted by measuring bone markers 1 to 3 months after the start of therapy.39,40 The rise of serum procollagen propeptides (both types) correlated well with an increase in lumbar bone density at 18 months (Figure 3).39 A rise in serum PICP of at least 46 ng/mL at 1 month and a rise in serum PINP of at least 17.2 ng/mL at 3 months almost always predicted a significant increase in bone mineral density at 18 months.

In glucocorticoid-induced osteoporosis

Glucocorticoid therapy causes bone loss and an increased incidence of fractures when given in high doses or for prolonged periods by the oral, parenteral, or inhaled routes.41

The pathogenesis of the bone loss has been explored by measurements of bone turnover markers. During glucocorticoid therapy, levels of bone formation markers are generally low and those of bone resorption markers are either normal or low.42–44 Presumably, the reduction in bone resorption is not enough to overcome the reduction in bone formation, and bone loss ensues. In children, the effects on bone formation are particularly profound, as linear growth may be retarded.44

Giving a bisphosphonate during glucocorticoid therapy is quite effective in increasing bone density and preventing fractures.45–47 Patients who receive alendronate have lower levels of bone formation and resorption markers than do untreated subjects.45 Presumably, bone resorption is inhibited more than bone formation, accounting for the skeletal benefits.

In a recent study in patients with glucocorticoid-induced osteoporosis, bone mineral density of the lumbar spine increased more than twice as much with teriparatide than with alendronate over an 18-month period.48 As would be expected from the results of teriparatide therapy in postmenopausal osteoporosis, indices of both bone formation and resorption rose to a peak at 6 months, with formation greater than resorption.

In immobilization-induced osteoporosis

Studies of normal volunteers placed on bed rest indicate that urinary CTx and NTx excretion increase significantly after 24 hours, no doubt reflecting a rapid increase in osteoclast activity.49 In a 16-week study of bed rest in volunteers, markers of bone formation were reduced and markers of bone resorption increased, demonstrating the mechanisms for the profound and rapid loss of bone in immobilized patients.50

In a long-term cross-sectional study of paraplegic men with spinal cord injuries, bone turnover patterns changed over time.51 During the first year after injury, urinary deoxypyridinoline excretion was markedly elevated, whereas blood total alkaline phosphatase and osteocalcin levels were normal to slightly elevated. Over a 30-year period after injury, the bone resorption marker returned to normal levels in most patients and the bone formation markers were normal. Fracture incidence rose but leveled off after 20 years.

Bisphosphonate therapy in spinal cord injury patients reduces urinary NTx and prevents bone loss.52,53 These agents have also proven effective in reversing hypercalcemia in immobilized patients.54

 

 

In inflammatory bowel disease

Patients with inflammatory bowel disease, especially Crohn disease, have low bone mass and are at risk of fractures.55 These complications could be due to glucocorticoid therapy, hypogonadism, vitamin D defeciency, weight loss, and high circulating levels of bone-active cytokines released by inflammatory cells residing in the diseased intestine.

From Dresner-Pollak R,et al. Increased urinary N-telopeptide cross-linked type 1 collagen predicts bone loss in patients with inflammatory bowel disease. Am J Gastroenterology 2000; 95:699–704, with permission from Blackwell Publishing.
Figure 4. The relationship between baseline urinary N-telopeptide cross-linked type 1 collagen (NTx) and the annual percent change of spine bone mineral density in (BMD) patients with inflammatory bowel disease over 2 years.
Elevated levels of urinary NTx have been reported to predict bone loss in the lumbar spine after 2 years of follow-up (Figure 4).56 The cytokines interleukin 1, interleukin 6, and tumor necrosis factor may be responsible for the increased bone resorption.56

Bone formation markers have not been found to be outside the normal range, although both interleukin 1 and tumor necrosis factor alpha are known to inhibit bone formation.

Bisphosphonate treatment produces an increase in bone density concomitant with decreases in markers of bone resorption and formation.57,58 Of considerable interest is the observation that infliximab (anti-tumor necrosis factor alpha; Remicade) generally produces a rise in bone formation markers, with a smaller and inconsistent effect on bone resorption.59,60

In rheumatoid arthritis

The incidence of osteoporosis and fractures is also increased In patients with rheumatoid arthritis.61 As in patients with inflammatory bowel disease, a variety of factors can contribute to bone loss, including glucocorticoid therapy, hypogonadism, vitamin D deficiency, immobility, and elevated levels of bone-active cytokines.

Generally, studies have reported increased bone resorption based on type I collagen markers,62,63 whereas patients with osteoarthritis have levels of these bone resorption markers no different from those of control subjects.62 Although serum total TRAP protein is elevated in rheumatoid arthritis patients, this is probably due to the 5a isoform, the origin of which may be macrophages and dendritric cells.64

The influence of abnormalities in bone formation on bone loss is less clear. Levels of bone formation markers have been reported to be normal,65 elevated,66 or reduced.67

Treatment of rheumatoid arthritis with high-dose glucocorticoid pulse therapy is effective in controlling the symptoms and some manifestations of the immune system in patients with the disorder. The latter effect would be expected to have a beneficial effect on bone metabolism. This appears to be the case, as there are only transient decreases in bone formation markers and no significant reduction in bone density.68 Similarly, there is only a transient decrease in serum osteocalcin after an intra-articular injection of a glucocorticoid, and no effect on urinary pyridino-line.69

As would be expected, bisphosphonate therapy prevents bone loss in rheumatoid arthritis patients treated with glucocorticoids.70,71 Both oral and intravenous therapy decrease the levels of bone turnover markers.70–72 Infliximab therapy was shown to reduce the levels of bone resorption markers but not of PINP (a bone formation marker).73

In primary hyperparathyroidism

Hypersecretion of parathyroid hormone increases osteoclastic activity, with a secondary increase in osteoblastic activity. Bone loss may ensue and an increase in fracture incidence may be a consequence, particularly in post-menopausal women, who have the highest incidence of the disorder.74

Before screening chemistry panels became widely used during routine medical evaluations, it was not unusual to find elevated serum total alkaline phosphatase levels in patients discovered to have primary hyperparathyroidism. Today, this finding is not so common, as the disorder is diagnosed at a much earlier stage. Nevertheless, more specific and sensitive markers of bone turnover have made it possible to demonstrate the metabolic abnormalities that reflect the skeletal pathology in patients with primary hyperparathyroidism and its response to various therapies.75,76

On average, patients with untreated primary hyperparathyroidism have high levels of markers of bone resorption and formation, except in the mildest cases.73,74 Bone turnover returns to normal within 6 months to a year after successful parathyroidectomy.77,78 This response correlates with improvement in bone density, primarily in the lumbar spine.77,78

In patients who do not undergo surgery, alternative means of preventing bone loss include estrogen replacement in estrogendeficient postmenopausal women,76 bisphosphonates,79,80 and cinacalcet (Sensipar).81 Estrogen,76 raloxifene (Evista),82 and alendronate79,80 all reduce levels of bone resorption and formation markers, and estrogen76 and alendronate79,80 increase bone density. Although cinacalcet usually restores the serum calcium to the normal range and prevents bone loss, it only reduces serum parathyroid hormone levels by about 20%, and both bone resorption and formation markers increase above baseline.81 This could be related to fluctuations in serum parathyroid hormone that occur during each day of therapy.

In osteomalacia and rickets

Osteomalacia and rickets of any cause are characterized by increased osteoblastic activity. If the underlying cause is vitamin D deficiency, genetic or acquired defects in calcitriol synthesis, or vitamin D resistance, then hyper-parathyroidism with increased bone resorption is a secondary feature.

Serum total alkaline phosphatase activity has been a useful marker of disease activity for many years, although the newer markers, except for serum osteocalcin,83 are potentially more sensitive. The insensitivity of osteocalcin as an index of osteoblastic activity is unexplained but could be related to the state of differentiation of the osteoblasts. Bone resorption markers are elevated in vitamin D deficiency84 but are not widely used in clinical practice, as serum parathyroid hormone is an excellent indirect means of assessing the presence of increased bone resorption and the response to therapy.

In renal osteodystrophy

Bone disease associated with renal failure is termed renal osteodystrophy and is quite heterogeneous.85 Microscopic examination of a bone biopsy specimen is still considered the gold standard for diagnosis, and measurement in serum of intact parathyroid hormone is an important guide to diagnosis and response to therapy.

Nevertheless, recent studies suggest that serum markers of bone formation and resorption may be of additional help in assessing bone turnover.86 At present it is not certain whether any of the newer markers are superior to serum total alkaline phosphatase activity. Future studies that correlate bone histology with bone turnover markers should clarify the value of the various markers.

 

 

In cancer

Bone metastases are a common complication in cancer patients. They are classified as osteolytic, osteoblastic, or mixed on the basis of radiographic features. Biochemical markers of bone turnover have proven useful in assessing the magnitude of the metastases, the response to therapy, and even the prognosis for survival.87

Osteolytic metastases, which are common in breast cancer, are associated with increases in bone resorption markers, and after treatment with intravenous bisphosphonates the levels can decrease nearly 70%.88,89

Patients with higher levels of urinary NTx had a higher risk of skeletal complications and disease progression than patients with low levels across multiple tumor groups, including multiple myeloma.87

In osteoblastic metastases. Prostate cancer patients, who typically have predominantly osteoblastic lesions, have elevations of serum total alkaline phosphatase activity and other markers of bone formation.90 In addition, they have elevated bone resorption markers. Urinary NTx decreased markedly but serum bone-specific alkaline phosphatase decreased only slightly after treatment with intravenous zoledronic acid (Zometa),91 whereas androgen ablation therapy has inconsistent effects on bone turnover.92,93 High levels of these markers again predict poor prognosis.93,94

In hormone-suppression therapy. Two of the most successful cancer therapies, aromatase inhibitors for breast cancer95 and androgen ablation for prostate cancer,96 accelerate bone loss through marked suppression of gonadal steroids. Bone resorption and formation markers increase and bone loss ensues, with resorption exceeding formation. Estrogen suppression appears mainly responsible in both sexes, since raloxifene prevents bone loss in prostate cancer patients.97

Bisphosphonates are highly effective in preventing bone loss in either sex.98–100 A single infusion of zoledronic acid in androgen-ablated prostate cancer patients can prevent bone loss for at least 1 year.100

In Paget disease of bone

Paget disease of bone evolves over many years, from an early osteolytic phase to dominance of secondary osteoblastic activity. In patients with extensive polyostotic disease, bone resorption and formation marker levels may be higher than in almost any other skeletal disorder. An exception is serum osteocalcin,101 which once again usually does not accurately reflect the rate of bone formation.

Bisphosphonates, given orally or intravenously, produce an early decrease in bone resorption followed by a fall in bone formation.102 In clinical practice it appears adequate to use the least expensive test, serum total alkaline phosphatase activity, to assess disease activity and the response to therapy.103

Acknowledgments: Grant support to FRS from the Edythe and Eli Broad Foundation and Lois Rosen. Grant support to DRE from the National Institutes of Health (NIAMS: AR37318, AR36794).

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  94. Cook RJ, Coleman R, Brown J, et al. Markers of bone metabolism and survival in men with hormone-refractory metastatic prostate cancer. Clin Cancer Res. 2006; 12:3361–3367.
  95. Eastell R, Hannon RA, Cuzick J, Dowsett M, Clack G, Adams JE. Effect of an aromatase inhibitor on BMD and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230). J Bone Miner Res. 2006; 21:1215–1223.
  96. Smith MR. Treatment-related osteoporosis in men with prostate cancer. Clin Cancer Res 2006; 12:6315s–6319s.
  97. Smith MR, Fallon MA, Lee H, Finkelstein JS. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab. 2004; 89:3841–3846.
  98. Confavreux CB, Fontana A, Guastalla JP, Munoz F, Brun J, Delmas PD. Estrogen-dependent increase in bone turnover and bone loss in postmenopausal women with breast cancer treated with anastrozole. Prevention with bisphosphonates. Bone. 2007; 41:346–352.
  99. Greenspan SL, Nelson JB, Trump DL, Resnick NM. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial. Ann Intern Med. 2007; 146:416–424.
  100. Michaelson MD, Kaufman DS, Lee H, et al. Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol. 2007; 25:1038–1042.
  101. Kaddam IM, Iqbal SJ, Holland S, Wong M, Manning D. Comparison of serum osteocalcin with total and bone specific alkaline phosphatase and urinary hydroxyproline:creatinine ratio in patients with Paget’s disease of bone. Ann Clin Biochem. 1994; 31:327–330.
  102. Reid IR, Miller P, Lyles K, et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med. 2005; 353:898–908.
  103. Reid IR, Davidson JS, Wattie D, et al. Comparative responses of bone turnover markers to bisphosphonate therapy in Paget’s disease of bone. Bone. 2004; 35:224–230.
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  66. Manrique F, Gamardo J, de Elguezabal K, et al. Abnormalities of bone mineral density and bone metabolism in Venezuelan patients with rheumatoid arthritis. J Clin Rheumatol. 2003; 9:219–227.
  67. Garnero P, Jouvenne P, Buchs N, Delmas PD, Miossec P. Uncoupling of bone metabolism in rheumatoid arthritis patients with or without joint destruction: assessment with serum type I collagen breakdown products. Bone. 1999; 24:381–385.
  68. Frediani B, Falsetti P, Bisogno S, et al. Effects of high dose methyl-prednisolone pulse therapy on bone mass and biochemical markers of bone metabolism in patients with active rheumatoid arthritis: a 12-month randomized prospective controlled study. J Rheumatol. 2004; 31:1083–1087.
  69. Emkey RD, Lindsay R, Lyssy J, Weisberg JS, Dempster DW, Shen V. The systemic effect of intraarticular administration of corticosteroid on markers of bone formation and bone resorption in patients with rheumatoid arthritis. Arthritis Rheum. 1996; 39:277–282.
  70. Lange U, Illgner U, Teichmann J, Schleenbecker H. Skeletal benefit after one year of risedronate therapy in patients with rheumatoid arthritis and glucocorticoid-induced osteoporosis: a prospective study. Int J Clin Pharmacol Res. 2004; 24:33–38.
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  72. Cremers SC, Lodder MC, Den Hartigh J, et al. Short term whole body retention in relation to rate of bone resorption and cartilage degradation after intravenous bisphosphonate (pamidronate) in rheumatoid arthritis. J Rheumatol. 2004; 31:1732–1737.
  73. Chopin F, Garnero P, Le Henanff A, et al. Long term effects of infliximab on bone and cartilage turnover markers in patients with rheumatoid arthritis. Ann Rheum Dis. 2007; 67:353–357.
  74. Khosla S, Melton LJ, Wermers RA, Crowson CS, O’Fallon W, Riggs B. Primary hyperparathyroidism and the risk of fracture: a population-based study. J Bone Miner Res. 1999; 14:1700–1707.
  75. Guo CY, Thomas WE, al-Dehaimi AW, Assiri AM, Eastell R. Longitudinal changes in bone mineral density and bone turnover in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab. 1996; 81:3487–3491.
  76. Orr-Walker BJ, Evans MC, Clearwater JM, Horne A, Grey AB, Reid IR. Effects of hormone replacement therapy on bone mineral density in postmenopausal women with primary hyperparathyroidism: four-year follow-up and comparison with healthy postmenopausal women. Arch Intern Med. 2000; 160:2161–2166.
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  78. Tamura Y, Araki A, Chiba Y, Mori S, Hosoi T, Horiuchi T. Remarkable increase in lumbar spine bone mineral density and amelioration in biochemical markers of bone turnover after parathyroidectomy in elderly patients with primary hyperparathyroidism: a 5-year follow-up study. J Bone Miner Metab. 2007; 25:226–231.
  79. Chow CC, Chan WB, Li JK, et al. Oral alendronate increases bone mineral density in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab. 2003; 88:581–587.
  80. Khan AA, Bilezikian JP, Kung AW, et al. Alendronate in primary hyperparathyroidism: a double-blind, randomized, placebo-controlled trial. J Clin Endocrinol Metab. 2004; 89:3319–3325.
  81. Peacock M, Bilezikian JP, Klassen PS, Guo MD, Turner SA, Shoback D. Cinacalcet hydrochloride maintains long-term normocalcemia in patients with primary hyperparathyroidism. J Clin Endocrinol Metab. 2005; 90:135–141.
  82. Rubin MR, Lee KH, McMahon DJ, Silverberg SJ. Raloxifene lowers serum calcium and markers of bone turnover in postmenopausal women with primary hyperparathyroidism. J Clin Endocrinol Metab. 2003; 88:1174–1178.
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  95. Eastell R, Hannon RA, Cuzick J, Dowsett M, Clack G, Adams JE. Effect of an aromatase inhibitor on BMD and bone turnover markers: 2-year results of the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial (18233230). J Bone Miner Res. 2006; 21:1215–1223.
  96. Smith MR. Treatment-related osteoporosis in men with prostate cancer. Clin Cancer Res 2006; 12:6315s–6319s.
  97. Smith MR, Fallon MA, Lee H, Finkelstein JS. Raloxifene to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer: a randomized controlled trial. J Clin Endocrinol Metab. 2004; 89:3841–3846.
  98. Confavreux CB, Fontana A, Guastalla JP, Munoz F, Brun J, Delmas PD. Estrogen-dependent increase in bone turnover and bone loss in postmenopausal women with breast cancer treated with anastrozole. Prevention with bisphosphonates. Bone. 2007; 41:346–352.
  99. Greenspan SL, Nelson JB, Trump DL, Resnick NM. Effect of once-weekly oral alendronate on bone loss in men receiving androgen deprivation therapy for prostate cancer: a randomized trial. Ann Intern Med. 2007; 146:416–424.
  100. Michaelson MD, Kaufman DS, Lee H, et al. Randomized controlled trial of annual zoledronic acid to prevent gonadotropin-releasing hormone agonist-induced bone loss in men with prostate cancer. J Clin Oncol. 2007; 25:1038–1042.
  101. Kaddam IM, Iqbal SJ, Holland S, Wong M, Manning D. Comparison of serum osteocalcin with total and bone specific alkaline phosphatase and urinary hydroxyproline:creatinine ratio in patients with Paget’s disease of bone. Ann Clin Biochem. 1994; 31:327–330.
  102. Reid IR, Miller P, Lyles K, et al. Comparison of a single infusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med. 2005; 353:898–908.
  103. Reid IR, Davidson JS, Wattie D, et al. Comparative responses of bone turnover markers to bisphosphonate therapy in Paget’s disease of bone. Bone. 2004; 35:224–230.
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Using biochemical markers of bone turnover in clinical practice
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KEY POINTS

  • Biomarkers of bone formation and resorption reflect the overall osteoblastic and osteoclastic activity in the skeleton and in some situations may serve as surrogates for histologic examination of bone.
  • Biomarkers of bone turnover can be used to document the effects of therapeutic agents in some patients with osteoporosis and possibly reduce the need for frequent bone density testing.
  • In cancer patients with bone metastases, biomarkers of bone resorption provide evidence of the efficacy of antiresorptive therapy. The baseline levels also have prognostic value: patients with the highest levels have the worst prognosis.
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Biochemical markers of bone turnover: Useful but underused

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Biochemical markers of bone turnover: Useful but underused
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Angelo A. Licata, MD, PhD

Biochemical markers of bone turnover are commonly used as tests in the management of bone disorders, as explained very elegantly by Drs. Singer and Eyre in this issue of the Journal.1

See the article

These tests assess the activity of osteoblastic cells or osteoclastic cells in a variety of bone diseases. Such tests do not establish the diagnosis of a disease, but rather they reflect the activity of the skeleton. Because the activity of osteoblasts and the activity of osteoclasts are chemically coupled, markers of blastic and clastic activity move in the same direction. In states of high bone metabolism or turnover, marker levels are high, predicting bone loss and fracture risk. Therapies that slow down bone metabolism make these levels decrease; anabolic drugs that stimulate bone growth do the opposite.

The utility of these markers in general practice is not well appreciated. In part this is because the results can vary if the tests are not appropriately done, causing frustration for some clinicians, who erroneously conclude that these markers lack utility.

WILL INSURANCE PAY FOR TESTING?

In addition, these tests are a source of confrontation with third-party payers who refuse to pay for them, even though they are approved by Medicare and have appropriate Current Procedural Terminology codes assigned to them. The reasons cited for denying payment are that the tests are not diagnostic, that they do not predict risk, and that they are not useful in patient management.

Wrong on all counts! First of all, these markers were never meant to diagnose a specific bone disease. They reflect high bone activity or turnover and potential bone loss, and high levels indicate that further assessment is needed. (In much the same way, an elevated prostate-specific antigen level may or may not mean the patient has prostate cancer, but it does mean further assessment is needed.)

Second, these tests do address fracture risk, either when used alone or when combined with bone densitometry measurements. A high level of a turnover marker indicates a risk of fracture similar to that of a T score lower than −2.5, with an odds ratio in the range of 2.4 to 2.8. 2 Moreover, if a patient has a low T score and a high marker level, his or her risk is even higher, with an odds ratio of 4.1.

Third, the argument about the tests’ lack of ability to help in patient management is completely untrue, as shown by information reviewed by Drs. Singer and Eyre, 1 and by other data recently published. 3 These tests can indicate whether bone physiology is responding to antiresorptive and anabolic drug therapy: marker activity should decline with antiresorptive drugs and increase with anabolic agents.

And this occurs months to years before bone densitometry even reflects a change! The failure of test values to respond appropriately should prompt physicians to find out why. Is the patient not taking the medicine appropriately? Or more worrisome, is he or she not taking it at all?

AN ADDED BENEFIT: BETTER ADHERENCE

The latter point brings up a common problem seen in practice—lack of adherence to drug therapy. Studies have repeatedly shown that only 50% to 60% of osteoporotic patients actually continue taking their oral medicine for a year or so. 4, 5 The reasons are unclear but may include cost, side effects, inconvenience in administration, and lack of any sign that the drug is doing anything. Bone densitometry may not always show changes that encourage patients to continue using expensive medicines.

Bone markers may be a solution to this dilemma. Changes in a bone marker help clinicians know that the patient is properly using therapy. 6 Moreover, these changes tell the patient that treatment is working. In my experience, relaying this type of information to the patient encourages adherence. Studies have indicated that markers do indeed help patients stay adherent to therapy and avoid fractures. 7, 8 Hence, these markers can indicate the risk of fracture and are useful in managing patients and promoting compliance.

It is unclear when third-party carriers will begin reading the appropriate literature to confirm these points, but practitioners need to recognize that there is a valid reason for using these tests.

References
  1. Singer FR, Eyre DR. Using biochemical markers of bone turnover in clinical practice. Cleve Clin J Med. 2008; 75:739–750.
  2. Johnell O, Odén A, De Laet C, Garnero P, Delmas PD, Kanis JA. Biochemical indices of bone turnover and the assessment of fracture probability. Osteoporos Int. 2002; 13:523–526.
  3. Delmas PD, Eastell R, Garnero P, Seibel MJ, Stepan JCommittee of Scientific Advisors of the International Osteoporosis Foundation. The use of biochemical markers of bone turnover in osteoporosis. Osteoporos Int 2000; 11(suppl 6):S2–S17.
  4. Ivaska KK, Lenora J, Gerdhem P, Akesson K, Väänänen HK, Obrant KJ. Serial assessment of serum bone metabolism markers identifies women with the highest rate of bone loss and osteoporosis risk. J Clin Endocrinol Metab. 2008; 93:2622–2632.
  5. Briesacher BA, Andrade SE, Fouayzi H, Chan KA. Comparison of drug adherence rates among patients with seven different medical conditions. Pharmacotherapy. 2008; 28:437–443.
  6. Eastell R, Krege JH, Chen P, Glass EV, Reginster JY. Development of an algorithm for using PINP to monitor treatment of patients with teriparatide. Curr Med Res Opin. 2006; 22:61–66.
  7. Briesacher BA, Andrade SE, Yood RA, Kahler KH. Consequences of poor compliance with bisphosphonates. Bone. 2007; 41:882–887.
  8. Delmas PD, Vrijens B, Eastell R, et al. Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab. 2007; 92:1296–1304.
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Biochemical markers of bone turnover are commonly used as tests in the management of bone disorders, as explained very elegantly by Drs. Singer and Eyre in this issue of the Journal.1

See the article

These tests assess the activity of osteoblastic cells or osteoclastic cells in a variety of bone diseases. Such tests do not establish the diagnosis of a disease, but rather they reflect the activity of the skeleton. Because the activity of osteoblasts and the activity of osteoclasts are chemically coupled, markers of blastic and clastic activity move in the same direction. In states of high bone metabolism or turnover, marker levels are high, predicting bone loss and fracture risk. Therapies that slow down bone metabolism make these levels decrease; anabolic drugs that stimulate bone growth do the opposite.

The utility of these markers in general practice is not well appreciated. In part this is because the results can vary if the tests are not appropriately done, causing frustration for some clinicians, who erroneously conclude that these markers lack utility.

WILL INSURANCE PAY FOR TESTING?

In addition, these tests are a source of confrontation with third-party payers who refuse to pay for them, even though they are approved by Medicare and have appropriate Current Procedural Terminology codes assigned to them. The reasons cited for denying payment are that the tests are not diagnostic, that they do not predict risk, and that they are not useful in patient management.

Wrong on all counts! First of all, these markers were never meant to diagnose a specific bone disease. They reflect high bone activity or turnover and potential bone loss, and high levels indicate that further assessment is needed. (In much the same way, an elevated prostate-specific antigen level may or may not mean the patient has prostate cancer, but it does mean further assessment is needed.)

Second, these tests do address fracture risk, either when used alone or when combined with bone densitometry measurements. A high level of a turnover marker indicates a risk of fracture similar to that of a T score lower than −2.5, with an odds ratio in the range of 2.4 to 2.8. 2 Moreover, if a patient has a low T score and a high marker level, his or her risk is even higher, with an odds ratio of 4.1.

Third, the argument about the tests’ lack of ability to help in patient management is completely untrue, as shown by information reviewed by Drs. Singer and Eyre, 1 and by other data recently published. 3 These tests can indicate whether bone physiology is responding to antiresorptive and anabolic drug therapy: marker activity should decline with antiresorptive drugs and increase with anabolic agents.

And this occurs months to years before bone densitometry even reflects a change! The failure of test values to respond appropriately should prompt physicians to find out why. Is the patient not taking the medicine appropriately? Or more worrisome, is he or she not taking it at all?

AN ADDED BENEFIT: BETTER ADHERENCE

The latter point brings up a common problem seen in practice—lack of adherence to drug therapy. Studies have repeatedly shown that only 50% to 60% of osteoporotic patients actually continue taking their oral medicine for a year or so. 4, 5 The reasons are unclear but may include cost, side effects, inconvenience in administration, and lack of any sign that the drug is doing anything. Bone densitometry may not always show changes that encourage patients to continue using expensive medicines.

Bone markers may be a solution to this dilemma. Changes in a bone marker help clinicians know that the patient is properly using therapy. 6 Moreover, these changes tell the patient that treatment is working. In my experience, relaying this type of information to the patient encourages adherence. Studies have indicated that markers do indeed help patients stay adherent to therapy and avoid fractures. 7, 8 Hence, these markers can indicate the risk of fracture and are useful in managing patients and promoting compliance.

It is unclear when third-party carriers will begin reading the appropriate literature to confirm these points, but practitioners need to recognize that there is a valid reason for using these tests.

Biochemical markers of bone turnover are commonly used as tests in the management of bone disorders, as explained very elegantly by Drs. Singer and Eyre in this issue of the Journal.1

See the article

These tests assess the activity of osteoblastic cells or osteoclastic cells in a variety of bone diseases. Such tests do not establish the diagnosis of a disease, but rather they reflect the activity of the skeleton. Because the activity of osteoblasts and the activity of osteoclasts are chemically coupled, markers of blastic and clastic activity move in the same direction. In states of high bone metabolism or turnover, marker levels are high, predicting bone loss and fracture risk. Therapies that slow down bone metabolism make these levels decrease; anabolic drugs that stimulate bone growth do the opposite.

The utility of these markers in general practice is not well appreciated. In part this is because the results can vary if the tests are not appropriately done, causing frustration for some clinicians, who erroneously conclude that these markers lack utility.

WILL INSURANCE PAY FOR TESTING?

In addition, these tests are a source of confrontation with third-party payers who refuse to pay for them, even though they are approved by Medicare and have appropriate Current Procedural Terminology codes assigned to them. The reasons cited for denying payment are that the tests are not diagnostic, that they do not predict risk, and that they are not useful in patient management.

Wrong on all counts! First of all, these markers were never meant to diagnose a specific bone disease. They reflect high bone activity or turnover and potential bone loss, and high levels indicate that further assessment is needed. (In much the same way, an elevated prostate-specific antigen level may or may not mean the patient has prostate cancer, but it does mean further assessment is needed.)

Second, these tests do address fracture risk, either when used alone or when combined with bone densitometry measurements. A high level of a turnover marker indicates a risk of fracture similar to that of a T score lower than −2.5, with an odds ratio in the range of 2.4 to 2.8. 2 Moreover, if a patient has a low T score and a high marker level, his or her risk is even higher, with an odds ratio of 4.1.

Third, the argument about the tests’ lack of ability to help in patient management is completely untrue, as shown by information reviewed by Drs. Singer and Eyre, 1 and by other data recently published. 3 These tests can indicate whether bone physiology is responding to antiresorptive and anabolic drug therapy: marker activity should decline with antiresorptive drugs and increase with anabolic agents.

And this occurs months to years before bone densitometry even reflects a change! The failure of test values to respond appropriately should prompt physicians to find out why. Is the patient not taking the medicine appropriately? Or more worrisome, is he or she not taking it at all?

AN ADDED BENEFIT: BETTER ADHERENCE

The latter point brings up a common problem seen in practice—lack of adherence to drug therapy. Studies have repeatedly shown that only 50% to 60% of osteoporotic patients actually continue taking their oral medicine for a year or so. 4, 5 The reasons are unclear but may include cost, side effects, inconvenience in administration, and lack of any sign that the drug is doing anything. Bone densitometry may not always show changes that encourage patients to continue using expensive medicines.

Bone markers may be a solution to this dilemma. Changes in a bone marker help clinicians know that the patient is properly using therapy. 6 Moreover, these changes tell the patient that treatment is working. In my experience, relaying this type of information to the patient encourages adherence. Studies have indicated that markers do indeed help patients stay adherent to therapy and avoid fractures. 7, 8 Hence, these markers can indicate the risk of fracture and are useful in managing patients and promoting compliance.

It is unclear when third-party carriers will begin reading the appropriate literature to confirm these points, but practitioners need to recognize that there is a valid reason for using these tests.

References
  1. Singer FR, Eyre DR. Using biochemical markers of bone turnover in clinical practice. Cleve Clin J Med. 2008; 75:739–750.
  2. Johnell O, Odén A, De Laet C, Garnero P, Delmas PD, Kanis JA. Biochemical indices of bone turnover and the assessment of fracture probability. Osteoporos Int. 2002; 13:523–526.
  3. Delmas PD, Eastell R, Garnero P, Seibel MJ, Stepan JCommittee of Scientific Advisors of the International Osteoporosis Foundation. The use of biochemical markers of bone turnover in osteoporosis. Osteoporos Int 2000; 11(suppl 6):S2–S17.
  4. Ivaska KK, Lenora J, Gerdhem P, Akesson K, Väänänen HK, Obrant KJ. Serial assessment of serum bone metabolism markers identifies women with the highest rate of bone loss and osteoporosis risk. J Clin Endocrinol Metab. 2008; 93:2622–2632.
  5. Briesacher BA, Andrade SE, Fouayzi H, Chan KA. Comparison of drug adherence rates among patients with seven different medical conditions. Pharmacotherapy. 2008; 28:437–443.
  6. Eastell R, Krege JH, Chen P, Glass EV, Reginster JY. Development of an algorithm for using PINP to monitor treatment of patients with teriparatide. Curr Med Res Opin. 2006; 22:61–66.
  7. Briesacher BA, Andrade SE, Yood RA, Kahler KH. Consequences of poor compliance with bisphosphonates. Bone. 2007; 41:882–887.
  8. Delmas PD, Vrijens B, Eastell R, et al. Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab. 2007; 92:1296–1304.
References
  1. Singer FR, Eyre DR. Using biochemical markers of bone turnover in clinical practice. Cleve Clin J Med. 2008; 75:739–750.
  2. Johnell O, Odén A, De Laet C, Garnero P, Delmas PD, Kanis JA. Biochemical indices of bone turnover and the assessment of fracture probability. Osteoporos Int. 2002; 13:523–526.
  3. Delmas PD, Eastell R, Garnero P, Seibel MJ, Stepan JCommittee of Scientific Advisors of the International Osteoporosis Foundation. The use of biochemical markers of bone turnover in osteoporosis. Osteoporos Int 2000; 11(suppl 6):S2–S17.
  4. Ivaska KK, Lenora J, Gerdhem P, Akesson K, Väänänen HK, Obrant KJ. Serial assessment of serum bone metabolism markers identifies women with the highest rate of bone loss and osteoporosis risk. J Clin Endocrinol Metab. 2008; 93:2622–2632.
  5. Briesacher BA, Andrade SE, Fouayzi H, Chan KA. Comparison of drug adherence rates among patients with seven different medical conditions. Pharmacotherapy. 2008; 28:437–443.
  6. Eastell R, Krege JH, Chen P, Glass EV, Reginster JY. Development of an algorithm for using PINP to monitor treatment of patients with teriparatide. Curr Med Res Opin. 2006; 22:61–66.
  7. Briesacher BA, Andrade SE, Yood RA, Kahler KH. Consequences of poor compliance with bisphosphonates. Bone. 2007; 41:882–887.
  8. Delmas PD, Vrijens B, Eastell R, et al. Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab. 2007; 92:1296–1304.
Issue
Cleveland Clinic Journal of Medicine - 75(10)
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Cleveland Clinic Journal of Medicine - 75(10)
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Biochemical markers of bone turnover: Useful but underused
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