There has been little improvement in the impact of asthma on patient morbidity and limitations on activity over the past decade, indicating the need for better utilization of existing therapies and improved patient self-management. This CME supplement discusses the role of small-airway inflammation in asthma and its possible relevance in the selection of anti-inflammatory therapy. While anti-inflammatory therapy is the mainstay of treatment for persistent asthma, long-acting ß-agonists (LABAs) are often used inappropriately, which has caused the FDA to take several actions due to safety concerns. While some of these actions have been questioned as inconsistent with current evidence-based guidelines, patient self-management should be reinforced at each patient visit and supported by a written asthma action plan.
Sponsor
This supplement was sponsored by the Primary Care Education Consortium and supp…
This supplement was sponsored by the Primary Care Education Consortium and supp…
Sponsor
This supplement was sponsored by the Primary Care Education Consortium and supp…
There has been little improvement in the impact of asthma on patient morbidity and limitations on activity over the past decade, indicating the need for better utilization of existing therapies and improved patient self-management. This CME supplement discusses the role of small-airway inflammation in asthma and its possible relevance in the selection of anti-inflammatory therapy. While anti-inflammatory therapy is the mainstay of treatment for persistent asthma, long-acting ß-agonists (LABAs) are often used inappropriately, which has caused the FDA to take several actions due to safety concerns. While some of these actions have been questioned as inconsistent with current evidence-based guidelines, patient self-management should be reinforced at each patient visit and supported by a written asthma action plan.
There has been little improvement in the impact of asthma on patient morbidity and limitations on activity over the past decade, indicating the need for better utilization of existing therapies and improved patient self-management. This CME supplement discusses the role of small-airway inflammation in asthma and its possible relevance in the selection of anti-inflammatory therapy. While anti-inflammatory therapy is the mainstay of treatment for persistent asthma, long-acting ß-agonists (LABAs) are often used inappropriately, which has caused the FDA to take several actions due to safety concerns. While some of these actions have been questioned as inconsistent with current evidence-based guidelines, patient self-management should be reinforced at each patient visit and supported by a written asthma action plan.
Many patients with type 2 diabetes eventually need insulin, as their ability to produce their own insulin from pancreatic beta cells declines progressively.1 The questions remain as to when insulin therapy should be started, and which regimen is the most appropriate.
Guidelines from professional societies differ on these points,2,3 as do individual clinicians. Moreover, antidiabetic treatment is an evolving topic. Many new drugs—oral agents as well as injectable analogues of glucagon-like peptide-1 (GLP1) and insulin formulations—have become available in the last 15 years.
In this paper, I advocate an individualized approach and review the indications for insulin treatment, the available preparations, the pros and cons of each regimen, and how the properties of each type of insulin influence attempts to intensify the regimen.
Coexisting physiologic and medical conditions such as pregnancy and chronic renal failure and drugs such as glucocorticoids may alter insulin requirements. I will not cover these special situations, as they deserve separate, detailed discussions.
WHEN SHOULD INSULIN BE STARTED? TWO VIEWS
Early on, patients can be adequately managed with lifestyle modifications and oral hypoglycemic agents or injections of a GLP1 analogue, either alone or in combination with oral medication. Later, some patients reach a point at which insulin therapy becomes the main treatment, similar to patients with type 1 diabetes.
The American Diabetes Association (ADA), in a consensus statement,2 has called for using insulin early in the disease if lifestyle management and monotherapy with metformin (Glucophage) fail to control glucose or if lifestyle management is not adequate and metformin is contraindicated. The ADA’s goal hemoglobin A1c level is less than 7% for most patients.
The American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE), in another consensus statement, use an algorithm stratified by hemoglobin A1c level, in which insulin is mostly reserved for when combination therapy fails.3 Their goal hemoglobin A1c level is 6.5% or less for most patients.
Comment. Both consensus statements make exceptions for patients presenting with very high blood glucose and hemoglobin A1c levels and those who have contraindications to drugs other than insulin. These patients should start insulin immediately, along with lifestyle management.2,3
Both consensus statements give priority to safety. The AACE/ACE statement gives more weight to the risk of hypoglycemia with insulin treatment, whereas the ADA gives more weight to the risk of edema and congestive heart failure with thiazolidinedione drugs (although both insulin and thiazolidinediones cause weight gain) and to adequate validation of treatments in clinical trials.
Ongoing clinical trials may add insight to this issue. For example, the Outcome Reduction With Initial Glargine Intervention (ORIGIN) study is investigating the effects of the long-acting insulin glargine (Lantus) in early diabetes with regard to glycemic control, safety, and cardiovascular outcomes.4 This study is expected to end this year (2011). The safety of alternative treatment options is also under investigation and scrutiny. In the interim, individualized treatment should be considered, as we will see below.
MY VIEW: AN INDIVIDUALIZED APPROACH
The decision to start insulin therapy should be made individually, based on several factors:
Whether the patient is willing to try it
The degree of hyperglycemia
How relevant the potential side effects of insulin are to the patient compared with those of other hypoglycemic agents
Whether oral hypoglycemic agents with or without GLP1 analogues are expected to provide the desired benefit
The patient’s work schedule and lifestyle factors
Cost
The availability of nurses, diabetes educators, and others to implement and follow the insulin treatment.
Will patients accept insulin?
Factors that affect whether patients comply with a treatment include the number of pills or injections they must take per day, how often they must check their blood glucose, adverse effects, lifestyle limitations caused by the treatment (especially insulin), and cost. Most patients feel better when their glucose levels are under good control, which is a major motivation for initiating and adhering to insulin. The anticipated reduction of diabetic complications further enhances compliance.
Education promotes compliance. Patients need to know that type 2 diabetes tends to progress and that in time their treatment will have to be intensified, with higher doses of their current drugs and new drugs added or substituted, possibly including insulin. This information is best given early, ie, when the diagnosis is made, even if hyperglycemia is mild at that time.
With newer insulin preparations and delivery devices available, more patients are finding insulin treatment acceptable.
The glycemic goal should be individualized
The key issue is glycemic control. If glycemic control is worsening or if the hemoglobin A1c level remains above the goal, then the treatment strategy should be readdressed.
In general, one should try to achieve the best possible glycemic control with the few est adverse effects. Adequate dietary management with a regular meal schedule and predictable carbohydrate intake for each meal helps to avoid or at least minimize the two most important adverse effects of insulin, ie, weight gain and hypoglycemia.
For most patients, I believe a goal hemoglobin A1c level of less than 7% is reasonable.2 For others, a less stringent goal might be more appropriate, such as 7.5%. Several factors affect this decision, including whether the patient is willing to follow a complex insulin regimen (such as a basal-bolus regimen), his or her work schedule, other lifestyle factors, the duration of diabetes, the type or types of insulin used, coexisting medical conditions, the frequency of hypoglycemia, unawareness of hypoglycemia, age, prognosis, life expectancy, and cost.5
If hyperglycemia is severe (Table 1),2 the goal might not be clear when insulin therapy is started. It should become obvious with ongoing follow-up.
Previously untreated patients presenting with severe hyperglycemia are a heterogeneous group. Many of them have had diabetes for a relatively short time and were recently diagnosed. These patients are likely to safely achieve near-normal glycemic control. Some of them might be adequately treated with oral hypoglycemic agents; if insulin is used, transitioning from insulin to oral hypoglycemic agents may be feasible.2
Some untreated patients may have had diabetes for several years and have advanced disease and therefore might be more difficult to treat. Only 21 (57%) of 37 previously untreated patients intensively treated with insulin reached the goal fasting glucose level of less than 126 mg/dL in one study.6 The only way to evaluate the feasibility of achieving near-normal glycemia safely is by following the patient’s progress over time.
The patient’s glycemic goal should be reevaluated periodically and may need to be adjusted over time, based on changes in any of the factors discussed above.
Risk of hypoglycemia
The goal should be looser in difficult-to-treat patients, ie, those with frequent hypoglycemia and decreased awareness of hypoglycemia.
Patients with advanced diabetes whose glucose levels continue to fluctuate widely after lifestyle management and the insulin regimen have been addressed should also have a looser goal. These fluctuations of glucose levels are surrogate markers for the degree of insulin deficiency. Attempting to achieve near-normal glycemic levels in this situation would be associated with a higher risk of hypoglycemia.
A higher risk of hypoglycemia and its complications (eg, falling and accidents, especially among operators of heavy machinery, construction workers, and drivers) is another reason for adopting a relaxed goal of glycemic control.
Table 2 summarizes risk factors for hypoglycemia.5,7–9 Relationships between insulin dosage, hemoglobin A1c level, and the risk of hypoglycemia have not been consistent among studies.8 Several important risk factors for hypoglycemia are not reported in prospective clinical studies because of exclusion criteria in those studies.
ADDING BASAL INSULIN TO ORAL HYPOGLYCEMIC THERAPY
When glycemic control worsens or is not adequate despite the use of oral hypoglycemic agents, often the next step is to add basal insulin therapy, ie, once-daily doses of a long-acting insulin.
NPH, detemir, or glargine?
Most often, glargine or detemir (Levemir) insulin is used. Detemir can also be given twice daily if needed. If cost is a concern, neutral protamine Hagedorn (NPH, Humulin N, Novolin N) insulin once daily at bedtime or twice daily is a reasonable alternative.
Costs of basal insulins are $22 to $50 per 1,000-unit vial for NPH, $70 to $90 per 1,000-unit vial for detemir and glargine, and $170 to $200 for a box of five detemir or glargine pens (containing 1,500 units total). Complicating this issue, vials should not be used for more than 1 month, and thus, the cost of vials vs pens depends on dosage.
Detemir vs NPH. In a trial in patients with inadequately controlled type 2 diabetes who had never taken insulin before and who were taking one or more oral hypoglycemic drugs, the addition of detemir insulin once daily or NPH at bedtime resulted in similar improvements in hemoglobin A1c (a decrease of about 1.5%).10
Detemir had several advantages over NPH. First, the incidence of nocturnal hypoglycemia was 50% lower with detemir at bedtime than with NPH at bedtime, and 87% lower with detemir in the morning than with bedtime NPH.10 In another trial,11 the risk of hypoglycemia at any time of day was 47% lower with insulin detemir than with NPH, and the risk of nocturnal hypoglycemia was 55% lower.
The risk of nocturnal hypoglycemia is lower if detemir is taken in the morning than at bedtime, although the total frequency of hypoglycemic episodes is the same.10 Therefore, another decision after starting basal insulin, based on the patient’s glucose trends and frequency of hypoglycemic events, would be whether insulin should be taken in the morning or at bedtime.
The second advantage of detemir is that it causes less weight gain: 0.7 kg at 20 weeks with detemir at bedtime vs 1.6 kg with NPH at bedtime.10
Further, detemir insulin was associated with less within-subject variability in the fasting glucose level than with NPH when these insulins were used in a basal-bolus regimen.12
Hermansen et al11 found that if the dosage of basal insulin was aggressively increased, 70% of patients achieved a hemoglobin A1c target of less than 7% with either NPH or detemir insulin, with fewer hypoglycemic episodes in patients treated with detemir.
Therefore, adding basal insulin to oral therapy is adequate for many patients who are new to insulin. Many patients would need more, such as the addition of insulin before meals.
Glargine vs NPH. Compared with adding NPH, adding glargine to a regimen of oral hypoglycemic agents controls blood glucose levels better and with less fluctuation in glucose levels, a lower risk of hypoglycemia, and less weight gain.13–15 These results were the same when using glargine with either metformin13 or glimeperide (Amaryl).14
Glargine is usually given once daily at bedtime. One study suggested that giving it in the morning is more effective.14
Detemir vs glargine. Studies that compared detemir and glargine revealed more similarities than differences in their clinical benefits.16,17 Both preparations effectively lower glucose levels and improve quality of life.18
Titrating the insulin regimen is a key in achieving adequate glycemic control. This includes teaching patients how to adjust their insulin, for example by increasing the dosage of glargine or detemir by 2 units every 4 to 7 days until adequate glycemic control is achieved, unless hypoglycemia becomes a barrier.
BASAL VS PRANDIAL INSULIN
Once-daily insulin injection is relatively convenient, but it comes with a limitation: it does not adequately control postprandial hyperglycemia. A solution is insulin before meals, ie, prandial insulin.
Kazda et al19 compared three regimens in patients not taking oral hypoglycemic agents: rapid-acting insulin lispro (Humalog) before each meal, a mix of 50% lispro and 50% protamine lispro (Humalog Mix 50/50) (the protamine delays its release) before each meal, and glargine at bedtime. The absolute change in hemoglobin A1c was −0.3% in the glargine group, −1.1% in the lispro group, and −1.2% in the lispro mix group. The glargine group had better control of fasting glucose.
Similar advantages of better glycemic control and fewer nocturnal hypoglycemic episodes were seen in trials of a mixture of 25% lispro and 75% protamine lispro before meals compared with glargine insulin in patients on simultaneous treatment with oral hypoglycemic agents.20,21 Buse et al21 reported that more patients achieved a hemoglobin A1c level below 7% with this lispro mix (47%) than with glargine (40%). The absolute difference in mean hemoglobin A1c between the two groups was minimal, although it reached statistical significance. As expected, weight gain was less in the glargine group.21
Kann et al22 reported that glycemic control was also better with a mixture of 30% aspart and 70% protamine aspart (NovoLog Mix 70/30) twice a day along with metformin than with glargine insulin once a day along with oral glimepiride, a sulfonylurea. Further, in this study, weight gain was noted in the glargine-glimepiride group only.22 Therefore, the advantage of less weight gain has not been always reproducible in glargine studies.
Comment. These studies point to the contribution of postprandial glucose to hemoglobin A1c.23–25 In patients with satisfactory glycemic control, the postprandial glucose level seems to be the major contributor to hemoglobin A1c. When glycemic control worsens, the contribution of fasting glucose to hemoglobin A1c increases.23
Premixed insulins (lispro mix and aspart mix) provide basal coverage and control postprandial hyperglycemia. Therefore, prandial premixed insulin therapy is expected to be superior to basal insulin therapy. Premixed insulin could be considered as a simplified basal-bolus regimen (see below).
The superiority of prandial (rapid-acting) insulin alone over basal insulin therapy, as seen in the study by Kazda et al,19 has not been reproducible in other studies. For example, in one study, once-daily glargine resulted in a similar improvement in hemoglobin A1c, a lower rate of hypoglycemic episodes, and greater patient satisfaction with treatment compared with lispro insulin before meals.26 This issue remains debatable because all the trials have been open-label and thus are subject to limitations.
The main lesson is that either glargine or lispro monotherapy is a reasonable option and results in better glycemic control in patients for whom two oral hypoglycemic agents have failed. Further, both fasting and postprandial hyperglycemia are important to address. In patients with severe hyperglycemia, a combination of prandial and basal insulin may be indicated. One would expect neither basal nor prandial (bolus) insulin to be adequate in this situation.
In conclusion, adding basal insulin to oral hypoglycemic agents is a reasonable option in the advancement of diabetes therapy and has become a common way to introduce insulin. It is simple and less labor-intensive for patients and medical groups than a basal-bolus regimen. Patients usually find it acceptable. The future availability of an easy-to-deliver, safe, and effective prandial insulin may change the current treatment paradigm; several newer prandial insulins are under investigation.
In advanced diabetes, both prandial and fasting glucose levels are crucial to address. Some patients may need to be started on both basal and prandial insulin simultaneously, depending on their degree of hyperglycemia, the duration of diabetes, coexisting medical conditions, and the goal of glycemic control.
BASAL-BOLUS INSULIN REGIMENS
In the advanced stages of type 2 diabetes, as insulin deficiency worsens, patients need to start giving themselves injections of a rapid-acting insulin—regular, lispro, aspart, or glulisine (Apidra) before meals, in addition to once- or twice-daily basal insulin injections. Such a “basal-bolus” regimen could also be used for newly diagnosed patients presenting with severe hyperglycemia. In addition, some patients on basal insulin plus oral hypoglycemic drugs may develop contraindications to their oral drugs. Adding bolus insulin becomes the main option for these patients too.
For others, a basal-bolus regimen might be chosen purely because of cost. For example, a regimen of NPH and regular insulin (multiple daily injections or premixed) would be significantly less expensive than multiple oral hypoglycemic agents.
Currently, only a few classes of oral hypoglycemic drugs are available in generic formulations. For example, generic glimeperide and metformin cost as little as $4 to $12 per month, while the costs of brand-name oral hypoglycemic agents are in the range of $170 to $200 per month. In contrast, premixed NPH plus regular insulin such as Novolin 70/30 and Humulin 70/30 cost between $22 and $70 per vial.
A basal-bolus regimen should provide 50% of the total daily insulin in the form of basal insulin. A regimen of 50% basal and 50% bolus seemed to provide better glycemic control than a regimen of 35% basal and 65% bolus in several studies.27,28
In patients already taking a single daily dose of basal insulin along with oral hypoglycemic agents, the dosage of basal insulin is usually raised gradually until adequate glycemic control is achieved. A main question is when to add prandial insulin. There is no clear cutoff for a basal insulin dosage at which prandial insulin should be added.
In the Treat-to-Target Trial,29 almost 60% of patients achieved a hemoglobin A1c level of 7% or less with the addition of either glargine or NPH insulin (basal insulin only) to oral hypoglycemic agents during 24 weeks of follow-up. As expected, glargine caused less nocturnal hypoglycemia. Fewer than half the patients who achieved a hemoglobin A1c level less than 7% had no documented nocturnal hypoglycemia (33% of glargine-treated patients and 27% of NPH-treated patients).
Type 2 diabetes is progressive1; over time, patients treated with once-daily basal insulin often require multiple daily injections.
Adding prandial to basal insulin clearly results in better glycemic control and less glucose variability.19,20,22,30–33 Two major factors in deciding to start prandial insulin are the degree of hyperglycemia and the patient’s acceptance of multiple daily injections. The higher the blood glucose levels, the sooner prandial insulin should be added, especially if hyperglycemia is influencing the prognosis of a coexisting condition or a diabetic complication (eg, an infected foot ulcer).
Adding prandial insulin should be also considered if the dosage of basal insulin has progressively been increased and the hemoglobin A1c level is not improving, especially if a patient has both inadequate glycemic control and frequent hypoglycemia, or if the morning glucose level is within the desired range (indicating there is no room for a further increase in the basal insulin dose) in association with inadequate control of hemoglobin A1c.
What is the best basal insulin for a basal-bolus regimen?
Glargine and detemir were shown to be equally effective as the basal component of a basal-bolus regimen.34,35 Findings were similar to those of studies comparing NPH, detemir, and glargine added, by themselves, to oral hypoglycemic agents. When possible, either glargine or detemir is favored because of less hypoglycemia and less weight gain than with NPH. Weight gain is the least with detemir.
Adding prandial insulin to a basal regimen
In general, whether to add prandial insulin can be decided on the basis of the patient’s record of blood glucose monitoring. Insulin could be added before breakfast if the pre-lunch glucose level is elevated, or before lunch if the dinnertime blood glucose level is elevated, or before dinner if the bedtime blood glucose level is elevated—or a combination of these. Prandial insulin can be started at a low dose (4–6 units) and increased gradually.
Figure 1.For patients taking NPH at bedtime, adding another dose of NPH in the morning is a reasonable option for managing pre-dinner hyperglycemia (Figure 1).2
In the case of poor glycemic control on a high dosage of basal insulin, a reasonable first step would be to change the regimen to a basal-bolus regimen (about 50% basal and 50% bolus) with no change or a small decrease in the total daily dosage of insulin to avoid hypoglycemia. For example, in a patient on 80 units of glargine or detemir insulin who has inadequate control, the regimen could be changed to 35 units of either glargine or detemir and 10 to 12 units of lispro, aspart, or glulisine before each meal as the bolus component.
Further adjustments of the insulin dosage can be made according to the results of glucose monitoring before each meal and at bedtime. In all case scenarios, the insulin regimen should be re-evaluated routinely during the advancement of therapy from single daily injection of basal insulin to multiple daily injections. Redistribution of total insulin dosage to 50% basal and 50% bolus (divided into three doses before meals) should be considered for patients who continue to have fluctuations of glucose levels, inadequate control, or frequent hypoglycemia. This ratio seems to provide better control for most patients.27,28
Starting with a basal-bolus regimen
For patients new to insulin who are starting a basal-bolus regimen, a dosage based on total body weight could be considered. The requirements vary significantly based on dietary management, level of physical activity, stress (especially illnesses), use of oral hypoglycemic agents, and degree of hyperglycemia.
A lower dosage of insulin (0.2 units per kg) should be considered for people with mild stress, with milder hyperglycemia, or on treatment with oral hypoglycemic agents. Elderly patients and patients with renal or liver failure are at higher risk of hypoglycemia and should also receive a lower dosage of insulin, at least to start with.
Others could be started on a dosage of 0.3 to 0.5 units/kg. Fifty percent of the calculated dosage could be given as basal insulin and 50% given as bolus (divided into three doses, before meals). Subsequently, the dosage would need to be titrated on the basis of the record of glucose monitoring.
Choosing a prandial insulin
Rapid-acting insulin analogues (lispro, aspart, and glulisine) control postprandial glucose levels better than regular insulin and cause less hypoglycemia. Their pharmacokinetics enable them to be taken within a few minutes of the start of a meal, or even after the meal if the patient forgets to take an injection before the meal.
For example, in one study,36 taking aspart immediately before the meal provided better glycemic control than taking regular insulin 30 minutes before meals. In a basal-bolus regimen, the use of aspart along with detemir resulted in glycemic control similar to that provided by twice-daily NPH and regular insulin, with less hypoglycemia.37
The dosage of prandial insulin can be adjusted according to the amount of carbohydrates in each meal (the insulin-to-carbohydrate ratio), as in patients with type 1 diabetes. This approach was associated with less weight gain.38
IS THERE STILL A ROLE FOR PREMIXED INSULIN PREPARATIONS?
Basal-bolus insulin regimens have gained popularity because the prandial doses can easily be adjusted according to carbohydrate intake, glucose level (on a sliding scale), variations in meal time, missed meals (eg, when having a procedure), and exercise. For example, the dose of prandial insulin can be reduced if the patient expects to exercise within 2 or 3 hours after the meal.
Some patients may not accept giving themselves four or five injections per day with a basal-bolus regimen. They may accept a simpler regimen, ie, giving themselves three injections of a premixed insulin per day, one before each meal.
Compared with a basal-bolus regimen, the possibility of achieving adequate glycemic control using lispro mix (50% lispro, 50% lispro protamine suspension) before meals seemed to depend on the goal of glycemic control. Its use in one study showed similar ability to achieve hemoglobin A1c less than 7.5% compared with a basal-bolus regimen of glargine and lispro. For a goal hemoglobin A1c level of less than 7%, the use of glargine and lispro was superior. The rate of hypoglycemia was similar with both strategies.39 These findings imply that the goal hemoglobin A1c should be more relaxed (< 7.5%) when using lispro mix (50% lispro) three times daily before meals.
Biphasic insulin aspart (a mix of aspart and protamine aspart) given three times daily provided similar improvement in glycemic control with no difference in the frequency of hypoglycemia compared with a basal-bolus regimen of NPH and aspart.40 Further, the use of biphasic insulin aspart seemed to provide better glycemic control with less weight gain compared with premixed human insulin (70% NPH, 30% regular insulin).41
Therefore, simpler premixed insulin regimens remain reasonable options for selected patients who do not accept a more complex insulin regimen (basal-bolus) or cannot adhere to it for any reason, especially if premixed insulin is given before meals three times daily. In fact, recent studies have focused on comparing premixed insulin three times daily with basal-bolus regimens (detemir or glargine as basal insulin along with pre-meal insulin analogue).
Glycemic control is harder to achieve with premixed insulin twice daily, mainly because of a higher frequency of hypoglycemia.42 In Europe, the use of premixed insulin three times daily is a popular option, whereas in the United States, a twice-daily schedule has been more common.
COST VS CONTROL
Newer insulin analogues make insulin treatment safer and more accepted by patients. The availability of several options for insulin regimens allows individualization of the treatment according to the patient’s acceptance, the safety profile, and the cost.
Patient selection and insulin titration are key issues in ensuring the achievement of adequate control with the fewest side effects. Lifestyle management (diet and physical activity) enhances the efficacy of insulin therapy and reduces the chances of side effects, namely fluctuation of glucose levels, hypoglycemic episodes, and weight gain.
Human insulins (NPH and regular) remain the least expensive, especially when using premixed NPH-regular insulin 70/30. Their use should be considered when the cost of medication is a major concern for the patient. A more relaxed goal of glycemic control may be considered in order to avoid hypoglycemia when using those insulin preparations, such as a hemoglobin A1c level less than 7.5% or even in the range of 7.5% to 8.5%, depending on the expected seasonal variation of hemoglobin A1c (which is higher in winter43), individual factors, and whether the premixed insulin is used twice or three times daily.
RE-EVALUATE THE REGIMEN ROUTINELY
The insulin regimen should be re-evaluated routinely. It might need to be changed in response to the dynamic multifactorial process of progression of diabetes, change in stress level, presence or resolution of intercurrent illnesses, risk of hypoglycemia, concerns about weight gain, and cost.
Finally, adjustment of the regimen should be considered in response to improvement of glycemic control related to improvement of dietary management, exercising, weight loss, and medical therapies.
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Monnier L, Colette C, Monnier L, Colette C. Contributions of fasting and postprandial glucose to hemoglobin A1c. Endocr Pract2006; 12(suppl 1):42–46.
Woerle HJ, Pimenta WP, Meyer C, et al. Diagnostic and therapeutic implications of relationships between fasting, 2-hour postchallenge plasma glucose and hemoglobin A1c values. Arch Intern Med2004; 164:1627–1632.
Bretzel RG, Nuber U, Landgraf W, Owens DR, Bradley C, Linn T. Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial. Lancet2008; 371:1073–1084.
Tamaki M, Shimizu T, Kanazawa A, Fujitani Y, Watada H, Kawamori R, Hirose T. Effects of changes in basal/total daily insulin ratio in type 2 diabetes patients on intensive insulin therapy including insulin glargine (JUN-LAN Study 6). Diabetes Res Clin Pract2008; 81:e1–e3.
Yokoyama H, Tada J, Kamikawa F, Kanno S, Yokota Y, Kuramitsu M. Efficacy of conversion from bedtime NPH insulin to morning insulin glargine in type 2 diabetic patients on basal-prandial insulin therapy. Diabetes Res Clin Pract2006; 73:35–40.
Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators. The Treat-To-Target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care2003; 26:3080–3086.
Davies M, Sinnassamy P, Storms F, Gomis R; ATLANTUS Study Group. Insulin glargine-based therapy improves glycemic control in patients with type 2 diabetes sub-optimally controlled on premixed insulin therapies. Diabetes Res Clin Pract2008; 79:368–375.
Jacober SJ, Scism-Bacon JL, Zagar AJ. A comparison of intensive mixture therapy with basal insulin therapy in insulin-naïve patients with type 2 diabetes receiving oral antidiabetes agents. Diabetes Obes Metab2006; 8:448–455.
Hirsch IB, Yuan H, Campaigne BN, Tan MH. Impact of prandial plus basal vs basal insulin on glycemic variability in type 2 diabetic patients. Endocr Pract2009; 15:343–348.
Robbins DC, Beisswenger PJ, Ceriello A, et al. Mealtime 50/50 basal + prandial insulin analogue mixture with a basal insulin analogue, both plus metformin, in the achievement of target HbA1c and pre- and postprandial blood glucose levels in patients with type 2 diabetes: a multinational, 24-week, randomized, open-label, parallel-group comparison. Clin Ther2007; 29:2349–2364.
Hollander P, Cooper J, Bregnhøj J, Pedersen CB. A 52-week, multinational, open-label, parallel-group, noninferiority, treat-to-target trial comparing insulin detemir with insulin glargine in a basal-bolus regimen with mealtime insulin aspart in patients with type 2 diabetes. Clin Ther2008; 30:1976–1987.
Raskin P, Gylvin T, Weng W, Chaykin L. Comparison of insulin detemir and insulin glargine using a basal-bolus regimen in a randomized, controlled clinical study in patients with type 2 diabetes. Diabetes Metab Res Rev2009; 25:542–548.
Perriello G, Pampanelli S, Porcellati F, et al. Insulin aspart improves meal time glycaemic control in patients with type 2 diabetes: a randomized, stratified, double-blind and cross-over trial. Diabet Med2005; 22:606–611.
Umpierrez GE, Hor T, Smiley D, et al. Comparison of inpatient insulin regimens with detemir plus aspart versus neutral protamine hagedorn plus regular in medical patients with type 2 diabetes. J Clin Endocrinol Metab2009; 94:564–569.
Bergenstal RM, Johnson M, Powers MA, et al. Adjust to target in type 2 diabetes: comparison of a simple algorithm with carbohydrate counting for adjustment of mealtime insulin glulisine. Diabetes Care2008; 31:1305–1310.
Rosenstock J, Ahmann AJ, Colon G, Scism-Bacon J, Jiang H, Martin S. Advancing insulin therapy in type 2 diabetes previously treated with glargine plus oral agents: prandial premixed (insulin lispro protamine suspension/lispro) versus basal/bolus (glargine/lispro) therapy. Diabetes Care2008; 31:20–25.
Ligthelm RJ, Mouritzen U, Lynggaard H, et al. Biphasic insulin aspart given thrice daily is as efficacious as a basal-bolus insulin regimen with four daily injections: a randomised open-label parallel group four months comparison in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes2006; 114:511–519.
Velojic-Golubovic M, Mikic D, Pesic M, Dimic D, Radenkovic S, Antic S. Biphasic insulin aspart 30: better glycemic control than with premixed human insulin 30 in obese patients with type 2 diabetes. J Endocrinol Invest2009; 32:23–27.
Holman RR, Farmer AJ, Davies MJ, et al; 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl Med2009; 361:1736–1747.
Tseng CL, Brimacombe M, Xie M, et al. Seasonal patterns in monthly hemoglobin A1c values. Am J Epidemiol2005; 161:565–574.
Dr. Hamaty has disclosed that he has been a reviewer for Eli Lilly and is a principal investigator in the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial, funded by Sanofi-Aventis.
Dr. Hamaty has disclosed that he has been a reviewer for Eli Lilly and is a principal investigator in the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial, funded by Sanofi-Aventis.
Author and Disclosure Information
Marwan Hamaty, MD, MBA Department of Endocrinology, Diabetes, and Metabolism, Diabetes Center, Endocrine and Metabolism Institute, Cleveland Clinic
Dr. Hamaty has disclosed that he has been a reviewer for Eli Lilly and is a principal investigator in the Outcome Reduction With Initial Glargine Intervention (ORIGIN) trial, funded by Sanofi-Aventis.
Many patients with type 2 diabetes eventually need insulin, as their ability to produce their own insulin from pancreatic beta cells declines progressively.1 The questions remain as to when insulin therapy should be started, and which regimen is the most appropriate.
Guidelines from professional societies differ on these points,2,3 as do individual clinicians. Moreover, antidiabetic treatment is an evolving topic. Many new drugs—oral agents as well as injectable analogues of glucagon-like peptide-1 (GLP1) and insulin formulations—have become available in the last 15 years.
In this paper, I advocate an individualized approach and review the indications for insulin treatment, the available preparations, the pros and cons of each regimen, and how the properties of each type of insulin influence attempts to intensify the regimen.
Coexisting physiologic and medical conditions such as pregnancy and chronic renal failure and drugs such as glucocorticoids may alter insulin requirements. I will not cover these special situations, as they deserve separate, detailed discussions.
WHEN SHOULD INSULIN BE STARTED? TWO VIEWS
Early on, patients can be adequately managed with lifestyle modifications and oral hypoglycemic agents or injections of a GLP1 analogue, either alone or in combination with oral medication. Later, some patients reach a point at which insulin therapy becomes the main treatment, similar to patients with type 1 diabetes.
The American Diabetes Association (ADA), in a consensus statement,2 has called for using insulin early in the disease if lifestyle management and monotherapy with metformin (Glucophage) fail to control glucose or if lifestyle management is not adequate and metformin is contraindicated. The ADA’s goal hemoglobin A1c level is less than 7% for most patients.
The American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE), in another consensus statement, use an algorithm stratified by hemoglobin A1c level, in which insulin is mostly reserved for when combination therapy fails.3 Their goal hemoglobin A1c level is 6.5% or less for most patients.
Comment. Both consensus statements make exceptions for patients presenting with very high blood glucose and hemoglobin A1c levels and those who have contraindications to drugs other than insulin. These patients should start insulin immediately, along with lifestyle management.2,3
Both consensus statements give priority to safety. The AACE/ACE statement gives more weight to the risk of hypoglycemia with insulin treatment, whereas the ADA gives more weight to the risk of edema and congestive heart failure with thiazolidinedione drugs (although both insulin and thiazolidinediones cause weight gain) and to adequate validation of treatments in clinical trials.
Ongoing clinical trials may add insight to this issue. For example, the Outcome Reduction With Initial Glargine Intervention (ORIGIN) study is investigating the effects of the long-acting insulin glargine (Lantus) in early diabetes with regard to glycemic control, safety, and cardiovascular outcomes.4 This study is expected to end this year (2011). The safety of alternative treatment options is also under investigation and scrutiny. In the interim, individualized treatment should be considered, as we will see below.
MY VIEW: AN INDIVIDUALIZED APPROACH
The decision to start insulin therapy should be made individually, based on several factors:
Whether the patient is willing to try it
The degree of hyperglycemia
How relevant the potential side effects of insulin are to the patient compared with those of other hypoglycemic agents
Whether oral hypoglycemic agents with or without GLP1 analogues are expected to provide the desired benefit
The patient’s work schedule and lifestyle factors
Cost
The availability of nurses, diabetes educators, and others to implement and follow the insulin treatment.
Will patients accept insulin?
Factors that affect whether patients comply with a treatment include the number of pills or injections they must take per day, how often they must check their blood glucose, adverse effects, lifestyle limitations caused by the treatment (especially insulin), and cost. Most patients feel better when their glucose levels are under good control, which is a major motivation for initiating and adhering to insulin. The anticipated reduction of diabetic complications further enhances compliance.
Education promotes compliance. Patients need to know that type 2 diabetes tends to progress and that in time their treatment will have to be intensified, with higher doses of their current drugs and new drugs added or substituted, possibly including insulin. This information is best given early, ie, when the diagnosis is made, even if hyperglycemia is mild at that time.
With newer insulin preparations and delivery devices available, more patients are finding insulin treatment acceptable.
The glycemic goal should be individualized
The key issue is glycemic control. If glycemic control is worsening or if the hemoglobin A1c level remains above the goal, then the treatment strategy should be readdressed.
In general, one should try to achieve the best possible glycemic control with the few est adverse effects. Adequate dietary management with a regular meal schedule and predictable carbohydrate intake for each meal helps to avoid or at least minimize the two most important adverse effects of insulin, ie, weight gain and hypoglycemia.
For most patients, I believe a goal hemoglobin A1c level of less than 7% is reasonable.2 For others, a less stringent goal might be more appropriate, such as 7.5%. Several factors affect this decision, including whether the patient is willing to follow a complex insulin regimen (such as a basal-bolus regimen), his or her work schedule, other lifestyle factors, the duration of diabetes, the type or types of insulin used, coexisting medical conditions, the frequency of hypoglycemia, unawareness of hypoglycemia, age, prognosis, life expectancy, and cost.5
If hyperglycemia is severe (Table 1),2 the goal might not be clear when insulin therapy is started. It should become obvious with ongoing follow-up.
Previously untreated patients presenting with severe hyperglycemia are a heterogeneous group. Many of them have had diabetes for a relatively short time and were recently diagnosed. These patients are likely to safely achieve near-normal glycemic control. Some of them might be adequately treated with oral hypoglycemic agents; if insulin is used, transitioning from insulin to oral hypoglycemic agents may be feasible.2
Some untreated patients may have had diabetes for several years and have advanced disease and therefore might be more difficult to treat. Only 21 (57%) of 37 previously untreated patients intensively treated with insulin reached the goal fasting glucose level of less than 126 mg/dL in one study.6 The only way to evaluate the feasibility of achieving near-normal glycemia safely is by following the patient’s progress over time.
The patient’s glycemic goal should be reevaluated periodically and may need to be adjusted over time, based on changes in any of the factors discussed above.
Risk of hypoglycemia
The goal should be looser in difficult-to-treat patients, ie, those with frequent hypoglycemia and decreased awareness of hypoglycemia.
Patients with advanced diabetes whose glucose levels continue to fluctuate widely after lifestyle management and the insulin regimen have been addressed should also have a looser goal. These fluctuations of glucose levels are surrogate markers for the degree of insulin deficiency. Attempting to achieve near-normal glycemic levels in this situation would be associated with a higher risk of hypoglycemia.
A higher risk of hypoglycemia and its complications (eg, falling and accidents, especially among operators of heavy machinery, construction workers, and drivers) is another reason for adopting a relaxed goal of glycemic control.
Table 2 summarizes risk factors for hypoglycemia.5,7–9 Relationships between insulin dosage, hemoglobin A1c level, and the risk of hypoglycemia have not been consistent among studies.8 Several important risk factors for hypoglycemia are not reported in prospective clinical studies because of exclusion criteria in those studies.
ADDING BASAL INSULIN TO ORAL HYPOGLYCEMIC THERAPY
When glycemic control worsens or is not adequate despite the use of oral hypoglycemic agents, often the next step is to add basal insulin therapy, ie, once-daily doses of a long-acting insulin.
NPH, detemir, or glargine?
Most often, glargine or detemir (Levemir) insulin is used. Detemir can also be given twice daily if needed. If cost is a concern, neutral protamine Hagedorn (NPH, Humulin N, Novolin N) insulin once daily at bedtime or twice daily is a reasonable alternative.
Costs of basal insulins are $22 to $50 per 1,000-unit vial for NPH, $70 to $90 per 1,000-unit vial for detemir and glargine, and $170 to $200 for a box of five detemir or glargine pens (containing 1,500 units total). Complicating this issue, vials should not be used for more than 1 month, and thus, the cost of vials vs pens depends on dosage.
Detemir vs NPH. In a trial in patients with inadequately controlled type 2 diabetes who had never taken insulin before and who were taking one or more oral hypoglycemic drugs, the addition of detemir insulin once daily or NPH at bedtime resulted in similar improvements in hemoglobin A1c (a decrease of about 1.5%).10
Detemir had several advantages over NPH. First, the incidence of nocturnal hypoglycemia was 50% lower with detemir at bedtime than with NPH at bedtime, and 87% lower with detemir in the morning than with bedtime NPH.10 In another trial,11 the risk of hypoglycemia at any time of day was 47% lower with insulin detemir than with NPH, and the risk of nocturnal hypoglycemia was 55% lower.
The risk of nocturnal hypoglycemia is lower if detemir is taken in the morning than at bedtime, although the total frequency of hypoglycemic episodes is the same.10 Therefore, another decision after starting basal insulin, based on the patient’s glucose trends and frequency of hypoglycemic events, would be whether insulin should be taken in the morning or at bedtime.
The second advantage of detemir is that it causes less weight gain: 0.7 kg at 20 weeks with detemir at bedtime vs 1.6 kg with NPH at bedtime.10
Further, detemir insulin was associated with less within-subject variability in the fasting glucose level than with NPH when these insulins were used in a basal-bolus regimen.12
Hermansen et al11 found that if the dosage of basal insulin was aggressively increased, 70% of patients achieved a hemoglobin A1c target of less than 7% with either NPH or detemir insulin, with fewer hypoglycemic episodes in patients treated with detemir.
Therefore, adding basal insulin to oral therapy is adequate for many patients who are new to insulin. Many patients would need more, such as the addition of insulin before meals.
Glargine vs NPH. Compared with adding NPH, adding glargine to a regimen of oral hypoglycemic agents controls blood glucose levels better and with less fluctuation in glucose levels, a lower risk of hypoglycemia, and less weight gain.13–15 These results were the same when using glargine with either metformin13 or glimeperide (Amaryl).14
Glargine is usually given once daily at bedtime. One study suggested that giving it in the morning is more effective.14
Detemir vs glargine. Studies that compared detemir and glargine revealed more similarities than differences in their clinical benefits.16,17 Both preparations effectively lower glucose levels and improve quality of life.18
Titrating the insulin regimen is a key in achieving adequate glycemic control. This includes teaching patients how to adjust their insulin, for example by increasing the dosage of glargine or detemir by 2 units every 4 to 7 days until adequate glycemic control is achieved, unless hypoglycemia becomes a barrier.
BASAL VS PRANDIAL INSULIN
Once-daily insulin injection is relatively convenient, but it comes with a limitation: it does not adequately control postprandial hyperglycemia. A solution is insulin before meals, ie, prandial insulin.
Kazda et al19 compared three regimens in patients not taking oral hypoglycemic agents: rapid-acting insulin lispro (Humalog) before each meal, a mix of 50% lispro and 50% protamine lispro (Humalog Mix 50/50) (the protamine delays its release) before each meal, and glargine at bedtime. The absolute change in hemoglobin A1c was −0.3% in the glargine group, −1.1% in the lispro group, and −1.2% in the lispro mix group. The glargine group had better control of fasting glucose.
Similar advantages of better glycemic control and fewer nocturnal hypoglycemic episodes were seen in trials of a mixture of 25% lispro and 75% protamine lispro before meals compared with glargine insulin in patients on simultaneous treatment with oral hypoglycemic agents.20,21 Buse et al21 reported that more patients achieved a hemoglobin A1c level below 7% with this lispro mix (47%) than with glargine (40%). The absolute difference in mean hemoglobin A1c between the two groups was minimal, although it reached statistical significance. As expected, weight gain was less in the glargine group.21
Kann et al22 reported that glycemic control was also better with a mixture of 30% aspart and 70% protamine aspart (NovoLog Mix 70/30) twice a day along with metformin than with glargine insulin once a day along with oral glimepiride, a sulfonylurea. Further, in this study, weight gain was noted in the glargine-glimepiride group only.22 Therefore, the advantage of less weight gain has not been always reproducible in glargine studies.
Comment. These studies point to the contribution of postprandial glucose to hemoglobin A1c.23–25 In patients with satisfactory glycemic control, the postprandial glucose level seems to be the major contributor to hemoglobin A1c. When glycemic control worsens, the contribution of fasting glucose to hemoglobin A1c increases.23
Premixed insulins (lispro mix and aspart mix) provide basal coverage and control postprandial hyperglycemia. Therefore, prandial premixed insulin therapy is expected to be superior to basal insulin therapy. Premixed insulin could be considered as a simplified basal-bolus regimen (see below).
The superiority of prandial (rapid-acting) insulin alone over basal insulin therapy, as seen in the study by Kazda et al,19 has not been reproducible in other studies. For example, in one study, once-daily glargine resulted in a similar improvement in hemoglobin A1c, a lower rate of hypoglycemic episodes, and greater patient satisfaction with treatment compared with lispro insulin before meals.26 This issue remains debatable because all the trials have been open-label and thus are subject to limitations.
The main lesson is that either glargine or lispro monotherapy is a reasonable option and results in better glycemic control in patients for whom two oral hypoglycemic agents have failed. Further, both fasting and postprandial hyperglycemia are important to address. In patients with severe hyperglycemia, a combination of prandial and basal insulin may be indicated. One would expect neither basal nor prandial (bolus) insulin to be adequate in this situation.
In conclusion, adding basal insulin to oral hypoglycemic agents is a reasonable option in the advancement of diabetes therapy and has become a common way to introduce insulin. It is simple and less labor-intensive for patients and medical groups than a basal-bolus regimen. Patients usually find it acceptable. The future availability of an easy-to-deliver, safe, and effective prandial insulin may change the current treatment paradigm; several newer prandial insulins are under investigation.
In advanced diabetes, both prandial and fasting glucose levels are crucial to address. Some patients may need to be started on both basal and prandial insulin simultaneously, depending on their degree of hyperglycemia, the duration of diabetes, coexisting medical conditions, and the goal of glycemic control.
BASAL-BOLUS INSULIN REGIMENS
In the advanced stages of type 2 diabetes, as insulin deficiency worsens, patients need to start giving themselves injections of a rapid-acting insulin—regular, lispro, aspart, or glulisine (Apidra) before meals, in addition to once- or twice-daily basal insulin injections. Such a “basal-bolus” regimen could also be used for newly diagnosed patients presenting with severe hyperglycemia. In addition, some patients on basal insulin plus oral hypoglycemic drugs may develop contraindications to their oral drugs. Adding bolus insulin becomes the main option for these patients too.
For others, a basal-bolus regimen might be chosen purely because of cost. For example, a regimen of NPH and regular insulin (multiple daily injections or premixed) would be significantly less expensive than multiple oral hypoglycemic agents.
Currently, only a few classes of oral hypoglycemic drugs are available in generic formulations. For example, generic glimeperide and metformin cost as little as $4 to $12 per month, while the costs of brand-name oral hypoglycemic agents are in the range of $170 to $200 per month. In contrast, premixed NPH plus regular insulin such as Novolin 70/30 and Humulin 70/30 cost between $22 and $70 per vial.
A basal-bolus regimen should provide 50% of the total daily insulin in the form of basal insulin. A regimen of 50% basal and 50% bolus seemed to provide better glycemic control than a regimen of 35% basal and 65% bolus in several studies.27,28
In patients already taking a single daily dose of basal insulin along with oral hypoglycemic agents, the dosage of basal insulin is usually raised gradually until adequate glycemic control is achieved. A main question is when to add prandial insulin. There is no clear cutoff for a basal insulin dosage at which prandial insulin should be added.
In the Treat-to-Target Trial,29 almost 60% of patients achieved a hemoglobin A1c level of 7% or less with the addition of either glargine or NPH insulin (basal insulin only) to oral hypoglycemic agents during 24 weeks of follow-up. As expected, glargine caused less nocturnal hypoglycemia. Fewer than half the patients who achieved a hemoglobin A1c level less than 7% had no documented nocturnal hypoglycemia (33% of glargine-treated patients and 27% of NPH-treated patients).
Type 2 diabetes is progressive1; over time, patients treated with once-daily basal insulin often require multiple daily injections.
Adding prandial to basal insulin clearly results in better glycemic control and less glucose variability.19,20,22,30–33 Two major factors in deciding to start prandial insulin are the degree of hyperglycemia and the patient’s acceptance of multiple daily injections. The higher the blood glucose levels, the sooner prandial insulin should be added, especially if hyperglycemia is influencing the prognosis of a coexisting condition or a diabetic complication (eg, an infected foot ulcer).
Adding prandial insulin should be also considered if the dosage of basal insulin has progressively been increased and the hemoglobin A1c level is not improving, especially if a patient has both inadequate glycemic control and frequent hypoglycemia, or if the morning glucose level is within the desired range (indicating there is no room for a further increase in the basal insulin dose) in association with inadequate control of hemoglobin A1c.
What is the best basal insulin for a basal-bolus regimen?
Glargine and detemir were shown to be equally effective as the basal component of a basal-bolus regimen.34,35 Findings were similar to those of studies comparing NPH, detemir, and glargine added, by themselves, to oral hypoglycemic agents. When possible, either glargine or detemir is favored because of less hypoglycemia and less weight gain than with NPH. Weight gain is the least with detemir.
Adding prandial insulin to a basal regimen
In general, whether to add prandial insulin can be decided on the basis of the patient’s record of blood glucose monitoring. Insulin could be added before breakfast if the pre-lunch glucose level is elevated, or before lunch if the dinnertime blood glucose level is elevated, or before dinner if the bedtime blood glucose level is elevated—or a combination of these. Prandial insulin can be started at a low dose (4–6 units) and increased gradually.
Figure 1.For patients taking NPH at bedtime, adding another dose of NPH in the morning is a reasonable option for managing pre-dinner hyperglycemia (Figure 1).2
In the case of poor glycemic control on a high dosage of basal insulin, a reasonable first step would be to change the regimen to a basal-bolus regimen (about 50% basal and 50% bolus) with no change or a small decrease in the total daily dosage of insulin to avoid hypoglycemia. For example, in a patient on 80 units of glargine or detemir insulin who has inadequate control, the regimen could be changed to 35 units of either glargine or detemir and 10 to 12 units of lispro, aspart, or glulisine before each meal as the bolus component.
Further adjustments of the insulin dosage can be made according to the results of glucose monitoring before each meal and at bedtime. In all case scenarios, the insulin regimen should be re-evaluated routinely during the advancement of therapy from single daily injection of basal insulin to multiple daily injections. Redistribution of total insulin dosage to 50% basal and 50% bolus (divided into three doses before meals) should be considered for patients who continue to have fluctuations of glucose levels, inadequate control, or frequent hypoglycemia. This ratio seems to provide better control for most patients.27,28
Starting with a basal-bolus regimen
For patients new to insulin who are starting a basal-bolus regimen, a dosage based on total body weight could be considered. The requirements vary significantly based on dietary management, level of physical activity, stress (especially illnesses), use of oral hypoglycemic agents, and degree of hyperglycemia.
A lower dosage of insulin (0.2 units per kg) should be considered for people with mild stress, with milder hyperglycemia, or on treatment with oral hypoglycemic agents. Elderly patients and patients with renal or liver failure are at higher risk of hypoglycemia and should also receive a lower dosage of insulin, at least to start with.
Others could be started on a dosage of 0.3 to 0.5 units/kg. Fifty percent of the calculated dosage could be given as basal insulin and 50% given as bolus (divided into three doses, before meals). Subsequently, the dosage would need to be titrated on the basis of the record of glucose monitoring.
Choosing a prandial insulin
Rapid-acting insulin analogues (lispro, aspart, and glulisine) control postprandial glucose levels better than regular insulin and cause less hypoglycemia. Their pharmacokinetics enable them to be taken within a few minutes of the start of a meal, or even after the meal if the patient forgets to take an injection before the meal.
For example, in one study,36 taking aspart immediately before the meal provided better glycemic control than taking regular insulin 30 minutes before meals. In a basal-bolus regimen, the use of aspart along with detemir resulted in glycemic control similar to that provided by twice-daily NPH and regular insulin, with less hypoglycemia.37
The dosage of prandial insulin can be adjusted according to the amount of carbohydrates in each meal (the insulin-to-carbohydrate ratio), as in patients with type 1 diabetes. This approach was associated with less weight gain.38
IS THERE STILL A ROLE FOR PREMIXED INSULIN PREPARATIONS?
Basal-bolus insulin regimens have gained popularity because the prandial doses can easily be adjusted according to carbohydrate intake, glucose level (on a sliding scale), variations in meal time, missed meals (eg, when having a procedure), and exercise. For example, the dose of prandial insulin can be reduced if the patient expects to exercise within 2 or 3 hours after the meal.
Some patients may not accept giving themselves four or five injections per day with a basal-bolus regimen. They may accept a simpler regimen, ie, giving themselves three injections of a premixed insulin per day, one before each meal.
Compared with a basal-bolus regimen, the possibility of achieving adequate glycemic control using lispro mix (50% lispro, 50% lispro protamine suspension) before meals seemed to depend on the goal of glycemic control. Its use in one study showed similar ability to achieve hemoglobin A1c less than 7.5% compared with a basal-bolus regimen of glargine and lispro. For a goal hemoglobin A1c level of less than 7%, the use of glargine and lispro was superior. The rate of hypoglycemia was similar with both strategies.39 These findings imply that the goal hemoglobin A1c should be more relaxed (< 7.5%) when using lispro mix (50% lispro) three times daily before meals.
Biphasic insulin aspart (a mix of aspart and protamine aspart) given three times daily provided similar improvement in glycemic control with no difference in the frequency of hypoglycemia compared with a basal-bolus regimen of NPH and aspart.40 Further, the use of biphasic insulin aspart seemed to provide better glycemic control with less weight gain compared with premixed human insulin (70% NPH, 30% regular insulin).41
Therefore, simpler premixed insulin regimens remain reasonable options for selected patients who do not accept a more complex insulin regimen (basal-bolus) or cannot adhere to it for any reason, especially if premixed insulin is given before meals three times daily. In fact, recent studies have focused on comparing premixed insulin three times daily with basal-bolus regimens (detemir or glargine as basal insulin along with pre-meal insulin analogue).
Glycemic control is harder to achieve with premixed insulin twice daily, mainly because of a higher frequency of hypoglycemia.42 In Europe, the use of premixed insulin three times daily is a popular option, whereas in the United States, a twice-daily schedule has been more common.
COST VS CONTROL
Newer insulin analogues make insulin treatment safer and more accepted by patients. The availability of several options for insulin regimens allows individualization of the treatment according to the patient’s acceptance, the safety profile, and the cost.
Patient selection and insulin titration are key issues in ensuring the achievement of adequate control with the fewest side effects. Lifestyle management (diet and physical activity) enhances the efficacy of insulin therapy and reduces the chances of side effects, namely fluctuation of glucose levels, hypoglycemic episodes, and weight gain.
Human insulins (NPH and regular) remain the least expensive, especially when using premixed NPH-regular insulin 70/30. Their use should be considered when the cost of medication is a major concern for the patient. A more relaxed goal of glycemic control may be considered in order to avoid hypoglycemia when using those insulin preparations, such as a hemoglobin A1c level less than 7.5% or even in the range of 7.5% to 8.5%, depending on the expected seasonal variation of hemoglobin A1c (which is higher in winter43), individual factors, and whether the premixed insulin is used twice or three times daily.
RE-EVALUATE THE REGIMEN ROUTINELY
The insulin regimen should be re-evaluated routinely. It might need to be changed in response to the dynamic multifactorial process of progression of diabetes, change in stress level, presence or resolution of intercurrent illnesses, risk of hypoglycemia, concerns about weight gain, and cost.
Finally, adjustment of the regimen should be considered in response to improvement of glycemic control related to improvement of dietary management, exercising, weight loss, and medical therapies.
Many patients with type 2 diabetes eventually need insulin, as their ability to produce their own insulin from pancreatic beta cells declines progressively.1 The questions remain as to when insulin therapy should be started, and which regimen is the most appropriate.
Guidelines from professional societies differ on these points,2,3 as do individual clinicians. Moreover, antidiabetic treatment is an evolving topic. Many new drugs—oral agents as well as injectable analogues of glucagon-like peptide-1 (GLP1) and insulin formulations—have become available in the last 15 years.
In this paper, I advocate an individualized approach and review the indications for insulin treatment, the available preparations, the pros and cons of each regimen, and how the properties of each type of insulin influence attempts to intensify the regimen.
Coexisting physiologic and medical conditions such as pregnancy and chronic renal failure and drugs such as glucocorticoids may alter insulin requirements. I will not cover these special situations, as they deserve separate, detailed discussions.
WHEN SHOULD INSULIN BE STARTED? TWO VIEWS
Early on, patients can be adequately managed with lifestyle modifications and oral hypoglycemic agents or injections of a GLP1 analogue, either alone or in combination with oral medication. Later, some patients reach a point at which insulin therapy becomes the main treatment, similar to patients with type 1 diabetes.
The American Diabetes Association (ADA), in a consensus statement,2 has called for using insulin early in the disease if lifestyle management and monotherapy with metformin (Glucophage) fail to control glucose or if lifestyle management is not adequate and metformin is contraindicated. The ADA’s goal hemoglobin A1c level is less than 7% for most patients.
The American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE), in another consensus statement, use an algorithm stratified by hemoglobin A1c level, in which insulin is mostly reserved for when combination therapy fails.3 Their goal hemoglobin A1c level is 6.5% or less for most patients.
Comment. Both consensus statements make exceptions for patients presenting with very high blood glucose and hemoglobin A1c levels and those who have contraindications to drugs other than insulin. These patients should start insulin immediately, along with lifestyle management.2,3
Both consensus statements give priority to safety. The AACE/ACE statement gives more weight to the risk of hypoglycemia with insulin treatment, whereas the ADA gives more weight to the risk of edema and congestive heart failure with thiazolidinedione drugs (although both insulin and thiazolidinediones cause weight gain) and to adequate validation of treatments in clinical trials.
Ongoing clinical trials may add insight to this issue. For example, the Outcome Reduction With Initial Glargine Intervention (ORIGIN) study is investigating the effects of the long-acting insulin glargine (Lantus) in early diabetes with regard to glycemic control, safety, and cardiovascular outcomes.4 This study is expected to end this year (2011). The safety of alternative treatment options is also under investigation and scrutiny. In the interim, individualized treatment should be considered, as we will see below.
MY VIEW: AN INDIVIDUALIZED APPROACH
The decision to start insulin therapy should be made individually, based on several factors:
Whether the patient is willing to try it
The degree of hyperglycemia
How relevant the potential side effects of insulin are to the patient compared with those of other hypoglycemic agents
Whether oral hypoglycemic agents with or without GLP1 analogues are expected to provide the desired benefit
The patient’s work schedule and lifestyle factors
Cost
The availability of nurses, diabetes educators, and others to implement and follow the insulin treatment.
Will patients accept insulin?
Factors that affect whether patients comply with a treatment include the number of pills or injections they must take per day, how often they must check their blood glucose, adverse effects, lifestyle limitations caused by the treatment (especially insulin), and cost. Most patients feel better when their glucose levels are under good control, which is a major motivation for initiating and adhering to insulin. The anticipated reduction of diabetic complications further enhances compliance.
Education promotes compliance. Patients need to know that type 2 diabetes tends to progress and that in time their treatment will have to be intensified, with higher doses of their current drugs and new drugs added or substituted, possibly including insulin. This information is best given early, ie, when the diagnosis is made, even if hyperglycemia is mild at that time.
With newer insulin preparations and delivery devices available, more patients are finding insulin treatment acceptable.
The glycemic goal should be individualized
The key issue is glycemic control. If glycemic control is worsening or if the hemoglobin A1c level remains above the goal, then the treatment strategy should be readdressed.
In general, one should try to achieve the best possible glycemic control with the few est adverse effects. Adequate dietary management with a regular meal schedule and predictable carbohydrate intake for each meal helps to avoid or at least minimize the two most important adverse effects of insulin, ie, weight gain and hypoglycemia.
For most patients, I believe a goal hemoglobin A1c level of less than 7% is reasonable.2 For others, a less stringent goal might be more appropriate, such as 7.5%. Several factors affect this decision, including whether the patient is willing to follow a complex insulin regimen (such as a basal-bolus regimen), his or her work schedule, other lifestyle factors, the duration of diabetes, the type or types of insulin used, coexisting medical conditions, the frequency of hypoglycemia, unawareness of hypoglycemia, age, prognosis, life expectancy, and cost.5
If hyperglycemia is severe (Table 1),2 the goal might not be clear when insulin therapy is started. It should become obvious with ongoing follow-up.
Previously untreated patients presenting with severe hyperglycemia are a heterogeneous group. Many of them have had diabetes for a relatively short time and were recently diagnosed. These patients are likely to safely achieve near-normal glycemic control. Some of them might be adequately treated with oral hypoglycemic agents; if insulin is used, transitioning from insulin to oral hypoglycemic agents may be feasible.2
Some untreated patients may have had diabetes for several years and have advanced disease and therefore might be more difficult to treat. Only 21 (57%) of 37 previously untreated patients intensively treated with insulin reached the goal fasting glucose level of less than 126 mg/dL in one study.6 The only way to evaluate the feasibility of achieving near-normal glycemia safely is by following the patient’s progress over time.
The patient’s glycemic goal should be reevaluated periodically and may need to be adjusted over time, based on changes in any of the factors discussed above.
Risk of hypoglycemia
The goal should be looser in difficult-to-treat patients, ie, those with frequent hypoglycemia and decreased awareness of hypoglycemia.
Patients with advanced diabetes whose glucose levels continue to fluctuate widely after lifestyle management and the insulin regimen have been addressed should also have a looser goal. These fluctuations of glucose levels are surrogate markers for the degree of insulin deficiency. Attempting to achieve near-normal glycemic levels in this situation would be associated with a higher risk of hypoglycemia.
A higher risk of hypoglycemia and its complications (eg, falling and accidents, especially among operators of heavy machinery, construction workers, and drivers) is another reason for adopting a relaxed goal of glycemic control.
Table 2 summarizes risk factors for hypoglycemia.5,7–9 Relationships between insulin dosage, hemoglobin A1c level, and the risk of hypoglycemia have not been consistent among studies.8 Several important risk factors for hypoglycemia are not reported in prospective clinical studies because of exclusion criteria in those studies.
ADDING BASAL INSULIN TO ORAL HYPOGLYCEMIC THERAPY
When glycemic control worsens or is not adequate despite the use of oral hypoglycemic agents, often the next step is to add basal insulin therapy, ie, once-daily doses of a long-acting insulin.
NPH, detemir, or glargine?
Most often, glargine or detemir (Levemir) insulin is used. Detemir can also be given twice daily if needed. If cost is a concern, neutral protamine Hagedorn (NPH, Humulin N, Novolin N) insulin once daily at bedtime or twice daily is a reasonable alternative.
Costs of basal insulins are $22 to $50 per 1,000-unit vial for NPH, $70 to $90 per 1,000-unit vial for detemir and glargine, and $170 to $200 for a box of five detemir or glargine pens (containing 1,500 units total). Complicating this issue, vials should not be used for more than 1 month, and thus, the cost of vials vs pens depends on dosage.
Detemir vs NPH. In a trial in patients with inadequately controlled type 2 diabetes who had never taken insulin before and who were taking one or more oral hypoglycemic drugs, the addition of detemir insulin once daily or NPH at bedtime resulted in similar improvements in hemoglobin A1c (a decrease of about 1.5%).10
Detemir had several advantages over NPH. First, the incidence of nocturnal hypoglycemia was 50% lower with detemir at bedtime than with NPH at bedtime, and 87% lower with detemir in the morning than with bedtime NPH.10 In another trial,11 the risk of hypoglycemia at any time of day was 47% lower with insulin detemir than with NPH, and the risk of nocturnal hypoglycemia was 55% lower.
The risk of nocturnal hypoglycemia is lower if detemir is taken in the morning than at bedtime, although the total frequency of hypoglycemic episodes is the same.10 Therefore, another decision after starting basal insulin, based on the patient’s glucose trends and frequency of hypoglycemic events, would be whether insulin should be taken in the morning or at bedtime.
The second advantage of detemir is that it causes less weight gain: 0.7 kg at 20 weeks with detemir at bedtime vs 1.6 kg with NPH at bedtime.10
Further, detemir insulin was associated with less within-subject variability in the fasting glucose level than with NPH when these insulins were used in a basal-bolus regimen.12
Hermansen et al11 found that if the dosage of basal insulin was aggressively increased, 70% of patients achieved a hemoglobin A1c target of less than 7% with either NPH or detemir insulin, with fewer hypoglycemic episodes in patients treated with detemir.
Therefore, adding basal insulin to oral therapy is adequate for many patients who are new to insulin. Many patients would need more, such as the addition of insulin before meals.
Glargine vs NPH. Compared with adding NPH, adding glargine to a regimen of oral hypoglycemic agents controls blood glucose levels better and with less fluctuation in glucose levels, a lower risk of hypoglycemia, and less weight gain.13–15 These results were the same when using glargine with either metformin13 or glimeperide (Amaryl).14
Glargine is usually given once daily at bedtime. One study suggested that giving it in the morning is more effective.14
Detemir vs glargine. Studies that compared detemir and glargine revealed more similarities than differences in their clinical benefits.16,17 Both preparations effectively lower glucose levels and improve quality of life.18
Titrating the insulin regimen is a key in achieving adequate glycemic control. This includes teaching patients how to adjust their insulin, for example by increasing the dosage of glargine or detemir by 2 units every 4 to 7 days until adequate glycemic control is achieved, unless hypoglycemia becomes a barrier.
BASAL VS PRANDIAL INSULIN
Once-daily insulin injection is relatively convenient, but it comes with a limitation: it does not adequately control postprandial hyperglycemia. A solution is insulin before meals, ie, prandial insulin.
Kazda et al19 compared three regimens in patients not taking oral hypoglycemic agents: rapid-acting insulin lispro (Humalog) before each meal, a mix of 50% lispro and 50% protamine lispro (Humalog Mix 50/50) (the protamine delays its release) before each meal, and glargine at bedtime. The absolute change in hemoglobin A1c was −0.3% in the glargine group, −1.1% in the lispro group, and −1.2% in the lispro mix group. The glargine group had better control of fasting glucose.
Similar advantages of better glycemic control and fewer nocturnal hypoglycemic episodes were seen in trials of a mixture of 25% lispro and 75% protamine lispro before meals compared with glargine insulin in patients on simultaneous treatment with oral hypoglycemic agents.20,21 Buse et al21 reported that more patients achieved a hemoglobin A1c level below 7% with this lispro mix (47%) than with glargine (40%). The absolute difference in mean hemoglobin A1c between the two groups was minimal, although it reached statistical significance. As expected, weight gain was less in the glargine group.21
Kann et al22 reported that glycemic control was also better with a mixture of 30% aspart and 70% protamine aspart (NovoLog Mix 70/30) twice a day along with metformin than with glargine insulin once a day along with oral glimepiride, a sulfonylurea. Further, in this study, weight gain was noted in the glargine-glimepiride group only.22 Therefore, the advantage of less weight gain has not been always reproducible in glargine studies.
Comment. These studies point to the contribution of postprandial glucose to hemoglobin A1c.23–25 In patients with satisfactory glycemic control, the postprandial glucose level seems to be the major contributor to hemoglobin A1c. When glycemic control worsens, the contribution of fasting glucose to hemoglobin A1c increases.23
Premixed insulins (lispro mix and aspart mix) provide basal coverage and control postprandial hyperglycemia. Therefore, prandial premixed insulin therapy is expected to be superior to basal insulin therapy. Premixed insulin could be considered as a simplified basal-bolus regimen (see below).
The superiority of prandial (rapid-acting) insulin alone over basal insulin therapy, as seen in the study by Kazda et al,19 has not been reproducible in other studies. For example, in one study, once-daily glargine resulted in a similar improvement in hemoglobin A1c, a lower rate of hypoglycemic episodes, and greater patient satisfaction with treatment compared with lispro insulin before meals.26 This issue remains debatable because all the trials have been open-label and thus are subject to limitations.
The main lesson is that either glargine or lispro monotherapy is a reasonable option and results in better glycemic control in patients for whom two oral hypoglycemic agents have failed. Further, both fasting and postprandial hyperglycemia are important to address. In patients with severe hyperglycemia, a combination of prandial and basal insulin may be indicated. One would expect neither basal nor prandial (bolus) insulin to be adequate in this situation.
In conclusion, adding basal insulin to oral hypoglycemic agents is a reasonable option in the advancement of diabetes therapy and has become a common way to introduce insulin. It is simple and less labor-intensive for patients and medical groups than a basal-bolus regimen. Patients usually find it acceptable. The future availability of an easy-to-deliver, safe, and effective prandial insulin may change the current treatment paradigm; several newer prandial insulins are under investigation.
In advanced diabetes, both prandial and fasting glucose levels are crucial to address. Some patients may need to be started on both basal and prandial insulin simultaneously, depending on their degree of hyperglycemia, the duration of diabetes, coexisting medical conditions, and the goal of glycemic control.
BASAL-BOLUS INSULIN REGIMENS
In the advanced stages of type 2 diabetes, as insulin deficiency worsens, patients need to start giving themselves injections of a rapid-acting insulin—regular, lispro, aspart, or glulisine (Apidra) before meals, in addition to once- or twice-daily basal insulin injections. Such a “basal-bolus” regimen could also be used for newly diagnosed patients presenting with severe hyperglycemia. In addition, some patients on basal insulin plus oral hypoglycemic drugs may develop contraindications to their oral drugs. Adding bolus insulin becomes the main option for these patients too.
For others, a basal-bolus regimen might be chosen purely because of cost. For example, a regimen of NPH and regular insulin (multiple daily injections or premixed) would be significantly less expensive than multiple oral hypoglycemic agents.
Currently, only a few classes of oral hypoglycemic drugs are available in generic formulations. For example, generic glimeperide and metformin cost as little as $4 to $12 per month, while the costs of brand-name oral hypoglycemic agents are in the range of $170 to $200 per month. In contrast, premixed NPH plus regular insulin such as Novolin 70/30 and Humulin 70/30 cost between $22 and $70 per vial.
A basal-bolus regimen should provide 50% of the total daily insulin in the form of basal insulin. A regimen of 50% basal and 50% bolus seemed to provide better glycemic control than a regimen of 35% basal and 65% bolus in several studies.27,28
In patients already taking a single daily dose of basal insulin along with oral hypoglycemic agents, the dosage of basal insulin is usually raised gradually until adequate glycemic control is achieved. A main question is when to add prandial insulin. There is no clear cutoff for a basal insulin dosage at which prandial insulin should be added.
In the Treat-to-Target Trial,29 almost 60% of patients achieved a hemoglobin A1c level of 7% or less with the addition of either glargine or NPH insulin (basal insulin only) to oral hypoglycemic agents during 24 weeks of follow-up. As expected, glargine caused less nocturnal hypoglycemia. Fewer than half the patients who achieved a hemoglobin A1c level less than 7% had no documented nocturnal hypoglycemia (33% of glargine-treated patients and 27% of NPH-treated patients).
Type 2 diabetes is progressive1; over time, patients treated with once-daily basal insulin often require multiple daily injections.
Adding prandial to basal insulin clearly results in better glycemic control and less glucose variability.19,20,22,30–33 Two major factors in deciding to start prandial insulin are the degree of hyperglycemia and the patient’s acceptance of multiple daily injections. The higher the blood glucose levels, the sooner prandial insulin should be added, especially if hyperglycemia is influencing the prognosis of a coexisting condition or a diabetic complication (eg, an infected foot ulcer).
Adding prandial insulin should be also considered if the dosage of basal insulin has progressively been increased and the hemoglobin A1c level is not improving, especially if a patient has both inadequate glycemic control and frequent hypoglycemia, or if the morning glucose level is within the desired range (indicating there is no room for a further increase in the basal insulin dose) in association with inadequate control of hemoglobin A1c.
What is the best basal insulin for a basal-bolus regimen?
Glargine and detemir were shown to be equally effective as the basal component of a basal-bolus regimen.34,35 Findings were similar to those of studies comparing NPH, detemir, and glargine added, by themselves, to oral hypoglycemic agents. When possible, either glargine or detemir is favored because of less hypoglycemia and less weight gain than with NPH. Weight gain is the least with detemir.
Adding prandial insulin to a basal regimen
In general, whether to add prandial insulin can be decided on the basis of the patient’s record of blood glucose monitoring. Insulin could be added before breakfast if the pre-lunch glucose level is elevated, or before lunch if the dinnertime blood glucose level is elevated, or before dinner if the bedtime blood glucose level is elevated—or a combination of these. Prandial insulin can be started at a low dose (4–6 units) and increased gradually.
Figure 1.For patients taking NPH at bedtime, adding another dose of NPH in the morning is a reasonable option for managing pre-dinner hyperglycemia (Figure 1).2
In the case of poor glycemic control on a high dosage of basal insulin, a reasonable first step would be to change the regimen to a basal-bolus regimen (about 50% basal and 50% bolus) with no change or a small decrease in the total daily dosage of insulin to avoid hypoglycemia. For example, in a patient on 80 units of glargine or detemir insulin who has inadequate control, the regimen could be changed to 35 units of either glargine or detemir and 10 to 12 units of lispro, aspart, or glulisine before each meal as the bolus component.
Further adjustments of the insulin dosage can be made according to the results of glucose monitoring before each meal and at bedtime. In all case scenarios, the insulin regimen should be re-evaluated routinely during the advancement of therapy from single daily injection of basal insulin to multiple daily injections. Redistribution of total insulin dosage to 50% basal and 50% bolus (divided into three doses before meals) should be considered for patients who continue to have fluctuations of glucose levels, inadequate control, or frequent hypoglycemia. This ratio seems to provide better control for most patients.27,28
Starting with a basal-bolus regimen
For patients new to insulin who are starting a basal-bolus regimen, a dosage based on total body weight could be considered. The requirements vary significantly based on dietary management, level of physical activity, stress (especially illnesses), use of oral hypoglycemic agents, and degree of hyperglycemia.
A lower dosage of insulin (0.2 units per kg) should be considered for people with mild stress, with milder hyperglycemia, or on treatment with oral hypoglycemic agents. Elderly patients and patients with renal or liver failure are at higher risk of hypoglycemia and should also receive a lower dosage of insulin, at least to start with.
Others could be started on a dosage of 0.3 to 0.5 units/kg. Fifty percent of the calculated dosage could be given as basal insulin and 50% given as bolus (divided into three doses, before meals). Subsequently, the dosage would need to be titrated on the basis of the record of glucose monitoring.
Choosing a prandial insulin
Rapid-acting insulin analogues (lispro, aspart, and glulisine) control postprandial glucose levels better than regular insulin and cause less hypoglycemia. Their pharmacokinetics enable them to be taken within a few minutes of the start of a meal, or even after the meal if the patient forgets to take an injection before the meal.
For example, in one study,36 taking aspart immediately before the meal provided better glycemic control than taking regular insulin 30 minutes before meals. In a basal-bolus regimen, the use of aspart along with detemir resulted in glycemic control similar to that provided by twice-daily NPH and regular insulin, with less hypoglycemia.37
The dosage of prandial insulin can be adjusted according to the amount of carbohydrates in each meal (the insulin-to-carbohydrate ratio), as in patients with type 1 diabetes. This approach was associated with less weight gain.38
IS THERE STILL A ROLE FOR PREMIXED INSULIN PREPARATIONS?
Basal-bolus insulin regimens have gained popularity because the prandial doses can easily be adjusted according to carbohydrate intake, glucose level (on a sliding scale), variations in meal time, missed meals (eg, when having a procedure), and exercise. For example, the dose of prandial insulin can be reduced if the patient expects to exercise within 2 or 3 hours after the meal.
Some patients may not accept giving themselves four or five injections per day with a basal-bolus regimen. They may accept a simpler regimen, ie, giving themselves three injections of a premixed insulin per day, one before each meal.
Compared with a basal-bolus regimen, the possibility of achieving adequate glycemic control using lispro mix (50% lispro, 50% lispro protamine suspension) before meals seemed to depend on the goal of glycemic control. Its use in one study showed similar ability to achieve hemoglobin A1c less than 7.5% compared with a basal-bolus regimen of glargine and lispro. For a goal hemoglobin A1c level of less than 7%, the use of glargine and lispro was superior. The rate of hypoglycemia was similar with both strategies.39 These findings imply that the goal hemoglobin A1c should be more relaxed (< 7.5%) when using lispro mix (50% lispro) three times daily before meals.
Biphasic insulin aspart (a mix of aspart and protamine aspart) given three times daily provided similar improvement in glycemic control with no difference in the frequency of hypoglycemia compared with a basal-bolus regimen of NPH and aspart.40 Further, the use of biphasic insulin aspart seemed to provide better glycemic control with less weight gain compared with premixed human insulin (70% NPH, 30% regular insulin).41
Therefore, simpler premixed insulin regimens remain reasonable options for selected patients who do not accept a more complex insulin regimen (basal-bolus) or cannot adhere to it for any reason, especially if premixed insulin is given before meals three times daily. In fact, recent studies have focused on comparing premixed insulin three times daily with basal-bolus regimens (detemir or glargine as basal insulin along with pre-meal insulin analogue).
Glycemic control is harder to achieve with premixed insulin twice daily, mainly because of a higher frequency of hypoglycemia.42 In Europe, the use of premixed insulin three times daily is a popular option, whereas in the United States, a twice-daily schedule has been more common.
COST VS CONTROL
Newer insulin analogues make insulin treatment safer and more accepted by patients. The availability of several options for insulin regimens allows individualization of the treatment according to the patient’s acceptance, the safety profile, and the cost.
Patient selection and insulin titration are key issues in ensuring the achievement of adequate control with the fewest side effects. Lifestyle management (diet and physical activity) enhances the efficacy of insulin therapy and reduces the chances of side effects, namely fluctuation of glucose levels, hypoglycemic episodes, and weight gain.
Human insulins (NPH and regular) remain the least expensive, especially when using premixed NPH-regular insulin 70/30. Their use should be considered when the cost of medication is a major concern for the patient. A more relaxed goal of glycemic control may be considered in order to avoid hypoglycemia when using those insulin preparations, such as a hemoglobin A1c level less than 7.5% or even in the range of 7.5% to 8.5%, depending on the expected seasonal variation of hemoglobin A1c (which is higher in winter43), individual factors, and whether the premixed insulin is used twice or three times daily.
RE-EVALUATE THE REGIMEN ROUTINELY
The insulin regimen should be re-evaluated routinely. It might need to be changed in response to the dynamic multifactorial process of progression of diabetes, change in stress level, presence or resolution of intercurrent illnesses, risk of hypoglycemia, concerns about weight gain, and cost.
Finally, adjustment of the regimen should be considered in response to improvement of glycemic control related to improvement of dietary management, exercising, weight loss, and medical therapies.
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Umpierrez GE, Hor T, Smiley D, et al. Comparison of inpatient insulin regimens with detemir plus aspart versus neutral protamine hagedorn plus regular in medical patients with type 2 diabetes. J Clin Endocrinol Metab2009; 94:564–569.
Bergenstal RM, Johnson M, Powers MA, et al. Adjust to target in type 2 diabetes: comparison of a simple algorithm with carbohydrate counting for adjustment of mealtime insulin glulisine. Diabetes Care2008; 31:1305–1310.
Rosenstock J, Ahmann AJ, Colon G, Scism-Bacon J, Jiang H, Martin S. Advancing insulin therapy in type 2 diabetes previously treated with glargine plus oral agents: prandial premixed (insulin lispro protamine suspension/lispro) versus basal/bolus (glargine/lispro) therapy. Diabetes Care2008; 31:20–25.
Ligthelm RJ, Mouritzen U, Lynggaard H, et al. Biphasic insulin aspart given thrice daily is as efficacious as a basal-bolus insulin regimen with four daily injections: a randomised open-label parallel group four months comparison in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes2006; 114:511–519.
Velojic-Golubovic M, Mikic D, Pesic M, Dimic D, Radenkovic S, Antic S. Biphasic insulin aspart 30: better glycemic control than with premixed human insulin 30 in obese patients with type 2 diabetes. J Endocrinol Invest2009; 32:23–27.
Holman RR, Farmer AJ, Davies MJ, et al; 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl Med2009; 361:1736–1747.
Tseng CL, Brimacombe M, Xie M, et al. Seasonal patterns in monthly hemoglobin A1c values. Am J Epidemiol2005; 161:565–574.
References
UK Prospective Diabetes Study 16. Overview of 6 years’ therapy of type II diabetes: a progressive disease. UK Prospective Diabetes Study Group. Diabetes1995; 44:1249–1258.
Nathan DM, Buse JB, Davidson MB, et al; American Diabetes Association. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care2009; 32:193–203.
Rodbard HW, Jellinger PS, Davidson JA, et al. Statement by an American Association of Clinical Endocrinologists/American College of Endocrinology consensus panel on type 2 diabetes mellitus: an algorithm for glycemic control. Endocr Pract2009; 15:540–558.
American Diabetes Association. Standards of medical care in diabetes—2010. Diabetes Care2010; 33(suppl 1):S11–S61.
Retnakaran R, Qi Y, Opsteen C, Vivero E, Zinman B. Initial short-term intensive insulin therapy as a strategy for evaluating the preservation of beta-cell function with oral antidiabetic medications: a pilot study with sitagliptin. Diabetes Obes Metab2010; 12:909–915.
Zoungas S, Patel A, Chalmers J, et al; ADVANCE Collaborative Group. Severe hypoglycemia and risks of vascular events and death. N Engl J Med2010; 363:1410–1418.
Akram K, Pedersen-Bjergaard U, Borch-Johnsen K, Thorsteinsson B. Frequency and risk factors of severe hypoglycemia in insulin-treated type 2 diabetes: a literature survey. J Diabetes Complications2006; 20:402–408.
Philis-Tsimikas A, Charpentier G, Clauson P, Ravn GM, Roberts VL, Thorsteinsson B. Comparison of once-daily insulin detemir with NPH insulin added to a regimen of oral antidiabetic drugs in poorly controlled type 2 diabetes. Clin Ther2006; 28:1569–1581. Erratum in: Clin Ther 2006; 28:1967.
Hermansen K, Davies M, Derezinski T, Martinez Ravn G, Clauson P, Home P. A 26-week, randomized, parallel, treat-to-target trial comparing insulin detemir with NPH insulin as add-on therapy to oral glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetes Care2006; 29:1269–1274. Erratum in: Diabetes Care 2007; 30:1035.
Haak T, Tiengo A, Draeger E, Suntum M, Waldhäusl W. Lower within-subject variability of fasting blood glucose and reduced weight gain with insulin detemir compared to NPH insulin in patients with type 2 diabetes. Diabetes Obes Metab2005; 7:56–64.
Yki-Järvinen H, Kauppinen-Mäkelin R, Tiikkainen M, et al. Insulin glargine or NPH combined with metformin in type 2 diabetes: the LANMET study. Diabetalogia2006; 49:442–451.
Fritsche A, Schweitzer MA, Häring HU; 4001 Study Group. Glimepiride combined with morning insulin glargine, bedtime neutral protamine hagedorn insulin, or bedtime insulin glargine in patients with type 2 diabetes. A randomized, controlled trial. Ann Intern Med2003; 138:952–959.
Rosenstock J, Schwartz SL, Clark CM, Park GD, Donley DW, Edwards MB. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care2001; 24:631–636.
Rosenstock J, Davies M, Home PD, Larsen J, Koenen C, Schernthaner G. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia2008; 51:408–416.
King AB. Once-daily insulin detemir is comparable to once-daily insulin glargine in providing glycaemic control over 24 h in patients with type 2 diabetes: a double-blind, randomized, crossover study. Diabetes Obes Metab2009; 11:69–71.
Swinnen SG, Snoek FJ, Dain MP, DeVries JH, Hoekstra JB, Holleman F. Rationale, design, and baseline data of the insulin glargine (Lantus) versus insulin detemir (Levemir) Treat-To-Target (L2T3) study: a multinational, randomized noninferiority trial of basal insulin initiation in type 2 diabetes. Diabetes Technol Ther2009; 11:739–743.
Kazda C, Hülstrunk H, Helsberg K, Langer F, Forst T, Hanefeld M. Prandial insulin substitution with insulin lispro or insulin lispro mid mixture vs. basal therapy with insulin glargine: a randomized controlled trial in patients with type 2 diabetes beginning insulin therapy. J Diabetes Complications2006; 20:145–152.
Malone JK, Bai S, Campaigne BN, Reviriego J, Augendre-Ferrante B. Twice-daily pre-mixed insulin rather than basal insulin therapy alone results in better overall glycaemic control in patients with type 2 diabetes. Diabet Med2005; 22:374–381.
Buse JB, Wolffenbuttel BH, Herman WH, et al. DURAbility of basal versus lispro mix 75/25 insulin efficacy (DURABLE) trial 24-week results: safety and efficacy of insulin lispro mix 75/25 versus insulin glargine added to oral antihyperglycemic drugs in patients with type 2 diabetes. Diabetes Care2009; 32:1007–1013.
Kann PH, Wascher T, Zackova V, et al. Starting insulin therapy in type 2 diabetes: twice-daily biphasic insulin Aspart 30 plus metformin versus once-daily insulin glargine plus glimepiride. Exp Clin Endocrinol Diabetes2006; 114:527–532.
Monnier L, Colette C, Monnier L, Colette C. Contributions of fasting and postprandial glucose to hemoglobin A1c. Endocr Pract2006; 12(suppl 1):42–46.
Woerle HJ, Pimenta WP, Meyer C, et al. Diagnostic and therapeutic implications of relationships between fasting, 2-hour postchallenge plasma glucose and hemoglobin A1c values. Arch Intern Med2004; 164:1627–1632.
Bretzel RG, Nuber U, Landgraf W, Owens DR, Bradley C, Linn T. Once-daily basal insulin glargine versus thrice-daily prandial insulin lispro in people with type 2 diabetes on oral hypoglycaemic agents (APOLLO): an open randomised controlled trial. Lancet2008; 371:1073–1084.
Tamaki M, Shimizu T, Kanazawa A, Fujitani Y, Watada H, Kawamori R, Hirose T. Effects of changes in basal/total daily insulin ratio in type 2 diabetes patients on intensive insulin therapy including insulin glargine (JUN-LAN Study 6). Diabetes Res Clin Pract2008; 81:e1–e3.
Yokoyama H, Tada J, Kamikawa F, Kanno S, Yokota Y, Kuramitsu M. Efficacy of conversion from bedtime NPH insulin to morning insulin glargine in type 2 diabetic patients on basal-prandial insulin therapy. Diabetes Res Clin Pract2006; 73:35–40.
Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators. The Treat-To-Target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care2003; 26:3080–3086.
Davies M, Sinnassamy P, Storms F, Gomis R; ATLANTUS Study Group. Insulin glargine-based therapy improves glycemic control in patients with type 2 diabetes sub-optimally controlled on premixed insulin therapies. Diabetes Res Clin Pract2008; 79:368–375.
Jacober SJ, Scism-Bacon JL, Zagar AJ. A comparison of intensive mixture therapy with basal insulin therapy in insulin-naïve patients with type 2 diabetes receiving oral antidiabetes agents. Diabetes Obes Metab2006; 8:448–455.
Hirsch IB, Yuan H, Campaigne BN, Tan MH. Impact of prandial plus basal vs basal insulin on glycemic variability in type 2 diabetic patients. Endocr Pract2009; 15:343–348.
Robbins DC, Beisswenger PJ, Ceriello A, et al. Mealtime 50/50 basal + prandial insulin analogue mixture with a basal insulin analogue, both plus metformin, in the achievement of target HbA1c and pre- and postprandial blood glucose levels in patients with type 2 diabetes: a multinational, 24-week, randomized, open-label, parallel-group comparison. Clin Ther2007; 29:2349–2364.
Hollander P, Cooper J, Bregnhøj J, Pedersen CB. A 52-week, multinational, open-label, parallel-group, noninferiority, treat-to-target trial comparing insulin detemir with insulin glargine in a basal-bolus regimen with mealtime insulin aspart in patients with type 2 diabetes. Clin Ther2008; 30:1976–1987.
Raskin P, Gylvin T, Weng W, Chaykin L. Comparison of insulin detemir and insulin glargine using a basal-bolus regimen in a randomized, controlled clinical study in patients with type 2 diabetes. Diabetes Metab Res Rev2009; 25:542–548.
Perriello G, Pampanelli S, Porcellati F, et al. Insulin aspart improves meal time glycaemic control in patients with type 2 diabetes: a randomized, stratified, double-blind and cross-over trial. Diabet Med2005; 22:606–611.
Umpierrez GE, Hor T, Smiley D, et al. Comparison of inpatient insulin regimens with detemir plus aspart versus neutral protamine hagedorn plus regular in medical patients with type 2 diabetes. J Clin Endocrinol Metab2009; 94:564–569.
Bergenstal RM, Johnson M, Powers MA, et al. Adjust to target in type 2 diabetes: comparison of a simple algorithm with carbohydrate counting for adjustment of mealtime insulin glulisine. Diabetes Care2008; 31:1305–1310.
Rosenstock J, Ahmann AJ, Colon G, Scism-Bacon J, Jiang H, Martin S. Advancing insulin therapy in type 2 diabetes previously treated with glargine plus oral agents: prandial premixed (insulin lispro protamine suspension/lispro) versus basal/bolus (glargine/lispro) therapy. Diabetes Care2008; 31:20–25.
Ligthelm RJ, Mouritzen U, Lynggaard H, et al. Biphasic insulin aspart given thrice daily is as efficacious as a basal-bolus insulin regimen with four daily injections: a randomised open-label parallel group four months comparison in patients with type 2 diabetes. Exp Clin Endocrinol Diabetes2006; 114:511–519.
Velojic-Golubovic M, Mikic D, Pesic M, Dimic D, Radenkovic S, Antic S. Biphasic insulin aspart 30: better glycemic control than with premixed human insulin 30 in obese patients with type 2 diabetes. J Endocrinol Invest2009; 32:23–27.
Holman RR, Farmer AJ, Davies MJ, et al; 4-T Study Group. Three-year efficacy of complex insulin regimens in type 2 diabetes. N Engl Med2009; 361:1736–1747.
Tseng CL, Brimacombe M, Xie M, et al. Seasonal patterns in monthly hemoglobin A1c values. Am J Epidemiol2005; 161:565–574.
Whether to start insulin therapy and which regimen to use depend on a number of factors, including the patient’s acceptance and willingness to adhere to the therapy.
A common way to start is to add a once-daily dose of a long-acting insulin at bedtime (basal insulin) to the patient’s antidiabetic regimen.
Basal regimens do not control postprandial hyperglycemia very well. Another option is to take a long-acting (basal) insulin along with a rapid-acting (prandial or bolus) insulin before meals. Multiple formulations of premixed insulins are available and are convenient to use among new users.
Basal-bolus regimens, which involve injections of rapid-acting insulin before meals and long-acting insulin at bedtime, are gaining popularity. Their cost and the number of injections may affect patient acceptance of this treatment.
Prostate cancer screening, diagnosis, and treatment present challenges to internists, urologists, and oncologists. For the internist, there is the ongoing debate about when and how often to screen with prostate-specific antigen (PSA) testing, as well as about how to interpret the results. For urologists and oncologists, there is no consensus on how to treat prostate cancer with the growing array of options, from surgery to cryoablation. Most therapies have not been compared in head-to-head trials, and anxious patients often approach their internist for help in navigating the maze of options.
This review summarizes current American Urological Association (AUA) guidelines,1 as well as current practice patterns at the Glickman Urological and Kidney Institute of Cleveland Clinic regarding screening, diagnosis, risk assessment, treatment, and posttreatment management of prostate cancer. We try to explain the approved and the experimental treatments, outlining what we know about their advantages and disadvantages.
SCREENING: WHEN AND HOW
Screening for prostate cancer should involve both a digital rectal examination (DRE) and measurement of the serum PSA level. But when should screening start?
The AUA recommends annual screening with DRE and serum PSA test starting at age 40 for all men with a life expectancy of more than 10 years.1
The American Cancer Society2 and the American College of Physicians,3 in contrast, recommend that men who choose to undergo screening should begin at age 50, or at age 45 if they are black or have a family history of prostate cancer in a primary relative diagnosed before age 65. They also recommend that screening with PSA and DRE be stopped at age 75, given the low likelihood of death from de novo prostate cancer after this age. The AUA recommends that screening be stopped at age 75, but may be continued beyond age 75 if the patient has a life expectancy of 10 years or more.
Before being screened, patients should understand the benefits and the risks of testing. While a small subset of prostate cancers behave aggressively, the majority are slow-growing and pose minimal risk for the development of fatal disease.
A discussion of the rationale for these guidelines and their differences is beyond the scope of this review. Differences stem from the observation that most men treated for prostate cancer will likely not die from prostate cancer, but rather from another condition.
Digital rectal examination’s role and limitations
The utility of DRE is limited to the detection of nodules, gross asymmetry, and gland fixation. DRE is not highly specific: only 40% to 50% of men who have abnormal findings on DRE have prostate cancer on biopsy.5 Anyone who has an abnormal finding on DRE should undergo prostate biopsy. However, if a rectal mass is palpated or if the prostate is exquisitely sensitive, biopsy is not indicated.
Although DRE is not considered very sensitive, it remains an essential element of the clinical staging system for prostate cancer because it can detect cancers that produce little or no PSA (Table 1). Up to 23% of men with prostate cancer in one large cohort study had PSA levels of 4.0 μg/L or less (traditionally deemed normal) and were diagnosed on the basis of a positive DRE alone.4,5
DRE is highly inaccurate for estimating gland volume; it should not be used to gauge cancer risk.
Prostate-specific antigen: Caveats
PSA measurement was introduced as a clinical screening test for prostate cancer in the early 1990s, and it serves as the foundation for early detection.
PSA, a protein involved in seminal coagulation, is produced by the prostate epithelium and is mostly confined within the prostatic ducts. Cancer cells secrete PSA into the bloodstream at increased levels via a disrupted basement membrane in tumor-affected areas of the gland. Elevated PSA can also result from benign prostatic hypertrophy, prostatitis, and prostate biopsy.
PSA levels represent a continuum of prostate cancer risk, and no single PSA value is sensitive and specific enough to predict the presence of cancer.6 Abnormal PSA cutoffs have been defined from 2.5 μg/L to 4 μg/L, and much debate surrounds this topic. Men who present with an elevated PSA (ie, > 2.5 μg/L) should be tested again. If the value remains high, then prostate biopsy should be considered. An elevated PSA level in older men with benign prostatic hypertrophy is not unexpected, and in these patients observation of the PSA value over time may prove valuable to assess the need for biopsy.
A useful adjunct in men with elevated PSA and benign prostatic hypertrophy is the percentage of serum PSA that is free rather than bound.7 PSA produced by prostate cancer binds more avidly with serum proteins (alpha-1 chymotrypsin and alpha-2 macroglobulin), resulting in a lower percentage of free PSA. In men with an elevated PSA (ie, 4.1–10.0 μg/L), the percentage of free PSA provides an indication of whether the elevation is due to benign prostatic hypertrophy or to cancer: the lower the percent free PSA, the more likely an elevated total PSA represents cancer and not benign prostatic hypertrophy. The sensitivity of a free PSA less than 15% to detect prostate cancer is about 85%, and its use as a screening tool is under study.
Much attention has also been given to other PSA indices, namely, the PSA density (the PSA level divided by the prostate volume), the PSA velocity (the rate of increase in the PSA level over time), and the PSA doubling time. While these nuanced PSA measures are useful to predict disease severity and behavior, they are not routinely used in screening.
BIOPSY IS INDICATED IF EITHER TEST IS ABNORMAL
In the past, imaging of the prostate with transrectal ultrasonography was used as a screening tool to detect prostate cancer. Further research showed that only 15% to 20% of hypoechoic lesions detected on ultrasonography contained cancer.8 Because of its low sensitivity and specificity, primary ultrasonographic screening (ie, transrectal ultrasonography alone) is not acceptable for screening or for diagnosis. Its main role is in guiding prostate biopsy.
Biopsy of the prostate with transrectal ultrasonographic guidance is indicated if either the DRE or the PSA level is abnormal. The standard of care is to use an 18-gauge biopsy needle-gun to obtain two to three tissue samples from each of six regions of the prostate, focusing on the outer peripheral zone, specifically the right and left bases, the mid-gland, and the apex.
Pathologic analysis of each tissue core takes into consideration the presence or absence of cancer, the Gleason score, and the percentage of the tissue sample volume that is occupied by cancer.
The Gleason grading system is based on the histologic appearance and reflects the degree of differentiation and aggressiveness of the cancer. The two most prominent tumor grades present are added to give a final Gleason score. For instance, a Gleason grade of 4+3=7 indicates a tumor with predominant Gleason grade 4 disease with a lesser amount of grade 3 disease. The number of positive core samples and the volume of cancer provide information on the severity of the cancer.
If the PSA is high but biopsy is negative
Prostate biopsy misses up to 30% of small cancers. Many of these are clinically insignificant, but about 20% of those missed cancers can be high-risk and thus merit identification. There should be a low threshold for repeating biopsy 1 year later in men who have a persistently high PSA or a rising PSA.
High-grade prostatic intraepithelial neoplasia is a common finding on biopsy. The incidence of de novo prostate cancer at 5 years in men with this finding is 22% to 26%.9 Patients with multifocal high-grade prostatic intraepithelial neoplasia should be monitored with PSA testing and DRE every 6 to 12 months and should be considered for repeat “saturation” biopsy (ie, obtaining as many as 36 core samples).
IF CANCER IS FOUND, HOW RISKY IS IT?
Patients with a new diagnosis of prostate cancer must decide on a treatment plan. This decision is highly individualized, based on the patient’s personal preferences, lifestyle, performance status (ie, his general well-being), disease severity, continence status, and sexual function.
When counseling patients about their disease and the treatment options, we consider three main factors:
The severity of disease on biopsy
The patient’s current state of health and performance status
The patient’s understanding of and willingness to accept the adverse effects of the various treatments.
Pathologic features, the PSA level, and clinical stage determined by DRE are used to predict the severity of disease. Most data on the efficacy of treatments for prostate cancer are based on the incidence of biochemical recurrence, ie, a rise in PSA level after primary therapy. The AUA and the D’Amico risk criteria use biopsy pathology, clinical stage, and the pretreatment PSA level to predict the likelihood of biochemical recurrence (Table 1).10,11
DISCUSSING TREATMENT OPTIONS WITH THE PATIENT
Risk stratification helps guide discussions with patients about which treatment will likely afford the most benefit. When counseling patients about the severity of their disease, it is helpful to use a nomogram to show the likelihood of cure with the different treatment options (Table 2).6,12–16
Important to the consideration of treatment options are the patient’s baseline performance status and life expectancy. Use of the Charlson Comorbidity Index and life expectancy nomograms can help make these assessments less subjective (Table 3).17–20
In our practice, we usually do not recommend treatment in men with low-risk or intermediate-risk prostate cancer who have a life expectancy of less than 10 years, as most of them will likely die of a cause other than prostate cancer. For patients with poor baseline performance status, surveillance or radiation therapy may be preferable to surgery. In younger patients, surgery may confer a more durable benefit.
Figure 1.Treatment options for prostate cancer (Figure 1) include active surveillance, radical prostatectomy, interstitial prostatic brachytherapy, external beam radiotherapy, cryotherapy, and, if the patient is enrolled in a research protocol, high-intensity focused ultrasound (HIFU). Level 1 data show that radical prostatectomy and external beam radiotherapy confer longer overall survival and cancer-specific survival compared with no treatment.21,22 However, no such data exist to prove the superior efficacy of prostatectomy vs brachytherapy vs radiotherapy, for several reasons:
No prospective, randomized clinical trials have directly compared these treatments
Prostate cancer progresses slowly
Definitions of treatment failure used in various studies have been inconsistent
Clinical studies have been subject to selection bias.
ACTIVE SURVEILLANCE IS ACCEPTABLE FOR LOW-RISK PROSTATE CANCER
Active surveillance is an acceptable option for patients with low-risk prostate cancer (ie, if the Gleason score is ≤ 6, the tumor stage is T1c or T2a, and the PSA level is ≤ 10 μg/L). To rule out high-risk disease before starting a program of surveillance, repeat biopsy is advisable, although optional.
Active surveillance consists of PSA testing and DRE every 6 to 12 months, followed by repeat biopsy if significant changes are noted in either test. Some centers advocate biopsy with transrectal ultrasonographic guidance every year regardless of the PSA or DRE findings.
Whether a change in the PSA level is significant is subjective, but a recent phase 2 study in 453 patients23 on a program of active surveillance used a PSA doubling time of less than 3 years as a criterion for repeat biopsy. Thirty-eight percent of the men had to undergo radiation therapy or surgery within 10 years, and 5 patients (1%) died of prostate cancer. The authors concluded that active surveillance did not put these patients at undue risk, and that this approach prevented overtreatment of clinically insignificant prostate cancer.23
The risks of surveillance include the chance that cancer could progress to an incurable state during the surveillance period, greater anxiety for the patient, and, if prostatectomy becomes necessary, greater technical difficulty due to scarring from repeat biopsies. The benefit is postponement or complete avoidance of the adverse effects of treatment.
Debate continues over the potential dangers of deferred treatment of prostate cancer, but in certain patients it is an acceptable option. Patient education, accurate disease assessment, and compliance with monitoring are critical considerations.
RADICAL PROSTATECTOMY: SEVERAL OPTIONS, EQUIVALENT EFFICACY
Radical prostatectomy is widely used for treating prostate cancer of any risk level. The operation entails removing the prostate and seminal vesicles, as well as the pelvic lymph nodes in patients with intermediate or high-risk cancer.
This procedure was increasingly used in the 1990s with the introduction of PSA screening and nerve-sparing surgical techniques that preserve continence and erectile function.
Radical prostatectomy can be done via a standard open approach or a minimally invasive laparoscopic approach with or without robotic assistance. Open surgery, laparoscopic surgery, and robotic prostatectomy offer equivalent rates of oncologic efficacy, continence, and potency.24 The more experienced the surgeon, the better the outcome is likely to be.
The average biochemical recurrence rate at 5 years after radical prostatectomy is approximately 6% for patients with low-risk cancer, 23% for those with intermediate-risk cancer, and 45% for those with high-risk cancer.25 The rate of death from prostate cancer at 10 years is about 1% for patients with low-risk cancer, 4% for those with intermediate-risk cancer, and 8% for those with high-risk cancer.12
Secondary therapy
Pathologic staging of the surgical specimen after radical prostatectomy yields information that can be beneficial in terms of initiating early secondary therapy.
Patients with node-positive disease should immediately undergo androgen deprivation treatment.26
Evidence of positive surgical margins, seminal vesicle invasion, bladder neck invasion, and extracapsular extension also increase the risk of recurrence. This additional risk can be ascertained via the use of a postoperative nomogram. Patients at high risk of recurrence should be considered for early adjuvant external beam radiotherapy to the surgical field 3 to 6 months after surgery.
Advantages and disadvantages of radical prostatectomy
Advantages of radical prostatectomy include the ability to accurately stage the cancer with the surgical specimen and the ability to remove the pelvic lymph nodes in patients at intermediate and high risk. Another advantage is that postoperative surveillance is straightforward: PSA should become undetectable after surgery, and a measurable increase in PSA represents disease recurrence.
Disadvantages include:
The risk of surgical complications (reported in 3% to 17% of cases)24
An average hospital stay of 1 to 3 days (and a typical 3 to 6 weeks before returning to work)
The need for a Foley catheter for 10 to 14 days
The risk of incontinence and impotence, which are very distressing to patients.
Postoperative incontinence is typically defined as the need for any type of protective pad for leakage. Up to 70% of patients have incontinence in the first 3 months after surgery, but 82% to 94% of patients regain continence by 12 months.24 A small percentage of patients (3% to 5%) have significant permanent incontinence.
Counseling about postoperative erectile dysfunction
All patients should be counseled about the risk of a postoperative decrease in erectile function, especially those with pre-existing erectile dysfunction. Potency is defined as the ability to have an erection suitable for intercourse (with or without phosphodiesterase type 5 inhibitors) more than 50% of the time. In men with bilateral nerve-sparing open prostatectomy, potency rates at 12 months have been reported between 63% and 81%.13
Data on potency rates vary widely because of differences in how potency was defined, selection bias, and the multifactorial nature of erectile dysfunction. Also, because single-institution, single-surgeon reports and advertisements tend to underestimate rates of impotence after radical prostatectomy by any approach, many patients have false expectations.
INTERSTITIAL BRACHYTHERAPY FOR LOW-RISK CANCERS
Interstitial brachytherapy delivers a localized, high dose (125 to 145 Gy) of radiation to the prostate, with minimal radiation dosing to the bladder, rectum, or other adjacent organs and tissues. “Seeds” or small pellets containing a radioisotope (iodine 125 or palladium 103) are stereotactically implanted through the perineum into the prostate under ultrasonographic guidance. Computerized mapping done before or during surgery helps determine the optimal placement of the seeds, the object being to cover at least 90% of the prostate with 100% of the radiation dose.
In permanent brachytherapy, the implants give off radiation at a low dose rate over weeks to months and are left in place permanently. In temporary brachytherapy, seeds are implanted to deliver a low or high dose rate for a specified period, and then they are removed.
“Implant quality,” ie, delivery of more than 90% of the radiation dose, is a major predictor of success and can depend on both the available instrumentation and the skill of the operator.
Caveats about brachytherapy
The evidence in support of combining androgen deprivation therapy and interstitial brachytherapy is poor, and there is some evidence of increased rates of irritative voiding symptoms,27 so this is generally not recommended.
Interstitial brachytherapy as monotherapy has usually been reserved for patients with low-risk cancer with a low likelihood of extracapsular disease extension or pelvic lymph node involvement. No randomized controlled clinical trial has compared brachytherapy with radical prostatectomy or external beam radiotherapy. One large long-term study reported an 8-year biochemical recurrence rate of 18% in patients with low-risk cancer and 30% in patients with intermediate-risk cancer.28 The long-term efficacy of brachytherapy for intermediate- and high-risk prostate cancer is still under investigation.
Advantages and disadvantages of interstitial brachytherapy
Advantages. Interstitial brachytherapy is done as a single outpatient procedure. It can deliver a targeted high dose of radiation. And it is associated with a lower rate of posttreatment incontinence than radical prostatectomy, and a lower cost.
Disadvantages. There are limited data to support long-term cancer control in intermediate- and high-risk disease. Short-term adverse effects include dysuria, hematuria, urinary urgency, and urinary frequency in up to 80% of patients.29 Voiding symptoms typically peak 1 to 3 months after the procedure and subside after 8 to 12 months. Erectile dysfunction has been reported in 30% to 35% of men at 5 years after the procedure. Other possible adverse effects include urethral stricture, incontinence, recurrent hematuria, rectal bleeding, proctitis, and the development of bladder cancer and other secondary cancers.
EXTERNAL BEAM RADIOTHERAPY
In external beam radiotherapy, radiation is delivered to the prostate and surrounding tissues via an external energy source. Electrons, protons, or neutrons are used, and although each has theoretical advantages over the others, all appear to have similar clinical efficacy.
As with brachytherapy, the object—and the challenge—is to deliver an effective dose of radiation to the tumor while sparing adjacent organs. Intensity-modulated delivery is a radiotherapy technique that delivers more of the radiation dose where we want it to go—and less where we don’t want it to go. For prostate cancer, the target dose with intensity-modulated delivery is typically 75 to 85 Gy, in doses of 2 to 2.25 Gy for 30 to 36 days.
Androgen deprivation therapy before or after external beam radiotherapy augments the effects of the radiotherapy, particularly in patients with high-risk disease.30
The oncologic efficacy of intensity-modulated radiotherapy in patients at low and intermediate risk appears commensurate with that of radical prostatectomy. In one study,31 in low-risk cases, biochemical disease-free survival rates were 85% for radiotherapy vs 93% for prostatectomy; in intermediate-risk cases, 82% for radiotherapy and 87% for prostatectomy; and in high-risk cases, 62% for combined androgen deprivation and radiotherapy vs 38% for prostatectomy.31
Advantages and disadvantages of external beam radiotherapy
Advantages. External beam radiotherapy is noninvasive. It can treat the prostate as well as areas outside the prostate in patients with intermediate- and high-risk disease, and it is proven effective for high-risk cancer when used in combination with androgen deprivation.
Disadvantages. On the other hand, radiotherapy requires a series of daily treatments, which can be inconvenient and burdensome to the patient. Its adverse effects are similar to those of brachytherapy, and it is expensive. Long-term adverse effects include irritative voiding symptoms (frequency, urgency, nocturia), hemorrhagic cystitis, bowel symptoms (pain with defecation, tenesmus, bleeding), and a significantly higher lifetime risk of a secondary malignancy, particularly of the bladder and rectum.32
External beam radiotherapy also induces tissue changes in the pelvis that make salvage surgery more difficult. Patients in whom radiotherapy is ineffective as monotherapy and who require salvage prostatectomy typically have poor outcomes in terms of disease control, continence, and potency.
COMBINED RADIATION THERAPY: BETTER, OR OVERTREATMENT?
Many patients are offered a combination of external beam radiotherapy and interstitial brachytherapy. The rationale is that the combination can boost the dose of radiation to the prostate and at the same time treat cancer that has extended beyond the prostate or to the pelvic lymph nodes.
The radiation dose in the combined approach is 45 to 50 Gy (vs 70 to 80 Gy in monotherapy), thereby minimizing toxicity.
This combination has not been shown to improve overall survival or cancer-specific survival compared with either therapy alone, and it likely constitutes overtreatment.33 Adverse effects of combination therapy include erectile dysfunction, rectal and bladder toxicity, and secondary malignancy.
A serious complication associated more often with the combination of external beam radiotherapy and brachytherapy than other treatments is rectoprostatic fistula, a condition that requires complex reconstructive surgery and often requires permanent urinary and fecal diversion.34
CRYOTHERAPY: MORE STUDY NEEDED
Refinements in cryoablative therapy to destroy prostate tissue have improved the safety and efficacy of this procedure significantly over the past decade. The AUA consensus guidelines recognize cryotherapy as a viable primary cancer monotherapy, but it is most commonly used as a salvage therapy after failure of radiation therapy.
The procedure involves ultrasonographically guided stereotactic placement of cryoprobes into the prostate via a transperineal approach. Argon is pumped through the probes under pressure to initiate ice formation, and repeated freeze-thaw cycles cause tissue damage and necrosis.
Rates of biochemical recurrence at 5 years in patients at low, intermediate, and high risk have been reported at 16%, 27%, and 25%, respectively.35 The presence of viable cancer on biopsy specimens after primary cryoablation has been reported at 15%, compared with 25% after definitive radiation therapy.35
Advantages and disadvantages of cryotherapy
Cryotherapy can destroy cancer tissue in a minimally invasive way. It has no long-term delayed adverse effects, and it is a low-cost and convenient outpatient procedure.
On the other hand, we lack long-term data on its oncologic efficacy, acute complications, and late adverse effects. Acute complications occur in up to 16% of patients and include acute urinary retention requiring prolonged catheterization, hematuria, urethral sloughing, perineal pain, and incontinence.36 Potential late effects include rectoprostatic fistula (< 1%), incontinence (< 5%), persistent hematuria, and chronic pelvic pain.36
Cryoablation therapy appears to have a more significant negative impact on sexual function than does brachytherapy.37
More study of the complications and efficacy of cryotherapy is needed before the procedure can be adopted as routine primary monotherapy.
HIGH-INTENSITY FOCUSED ULTRASOUND: NOT YET FDA-APPROVED
High-intensity focused ultrasound (HIFU) is not yet approved by the US Food and Drug Administration (other than in an approved research protocol) but is used in Canada and in certain countries of Europe and Asia. It involves the insertion of a transducer into the rectum that generates a high-intensity, focused beam that heats target tissue in the prostate to a high temperature. This temperature triggers a heat-shock response that leads to cellular apoptosis and tissue necrosis. The procedure can be done with or without magnetic resonance imaging (MRI) guidance.
Biochemical recurrence rates at 2 years after the procedure have been reported between 23% and 50%, but long-term efficacy data are lacking.38,39
Advantages and disadvantages of ultrasound
HIFU is a minimally invasive, low-cost, outpatient procedure that offers trackless delivery of energy to the prostate: ie, there is no direct mechanical penetration into the tissue.
Complications include rectal-wall injury, fistula, acute urinary retention, hematuria, and urethral stricture.
FOCAL ABLATION: GETTING ATTENTION, BUT STILL UNDER DEVELOPMENT
Focal ablation for prostate cancer has been receiving much attention. This treatment uses heat energy to destroy tumor cells, guided by high-resolution endorectal-coil MRI. The procedure is in the developmental stages and is available only in research protocols.
The procedure has several major hurdles to overcome before becoming acceptable for clinical practice. First, prostate cancer is multifocal, and microscopic tumor foci are likely present that are invisible even to MRI, so ablation of only part of the prostate leaves the rest of the gland at risk of continued or de novo tumor growth.
Second, a wide range of sensitivities and specificities have been reported for endorectal coil MRI for detecting prostate cancer: its sensitivity has ranged from 27% to 100%, and its specificity has ranged from 32% to 99%.40
ANDROGEN DEPRIVATION, AN ADJUVANT THERAPY
Androgen deprivation therapy (medical castration) is not effective as a monotherapy for prostate cancer. A large population-based study in men with localized prostate cancer showed no higher rate of overall survival at 10 years with primary androgen deprivation therapy than with conservative management.41
Androgen deprivation is achieved with a leutinizing hormone-releasing hormone agonist such as leuprolide (Lupron) or goserelin (Zoladex), or an antiandrogen drug such as flutamide or bicalutamide (Casodex), or a combination of each.
Adverse effects include hot flashes, gynecomastia, decreased libido, erectile dysfunction, weight gain, and hyperlipidemia. Long-term effects include osteoporosis and a significantly higher risk of cardiac events, new-onset type 2 diabetes mellitus, and stroke.
Currently, the only recognized role for androgen deprivation therapy in prostate cancer is as an adjunct to external beam radiotherapy or as a treatment of metastatic prostate cancer.
Orchiectomy
The other way to eliminate testicular production of testosterone is surgical castration. Bilateral orchiectomy has advantages over medical androgen deprivation therapy in that it costs less, is highly reliable, and is done as a single treatment on an outpatient basis. Disadvantages include surgery-related morbidity and the irreversible nature of the procedure. The adverse effects are similar to those of androgen deprivation therapy.
POSTTREATMENT MONITORING
The management of patients with recurrent prostate cancer can be complex, and these patients should be referred to a medical or urologic oncologist.42,43
Often, a rise in PSA after primary therapy represents a regrowth of cancer; 30% to 60% of patients with a recurrence have metastasis, and nearly 20% will die from the disease. The average time from documentation of biochemical recurrence to metastatic progression is 8 years. The average time from metastatic progression to death is 5 years.44,45
After radical prostatectomy, the PSA level should be checked every 6 to 12 months for the first 2 years, then annually until the patient’s life expectancy is only 10 years even without prostate cancer. PSA should reach undetectable levels within 4 to 6 weeks after surgery. Biochemical recurrence after surgery is defined as a PSA level of 0.2 μg/L or higher in two serial studies.
After radiation therapy or cryotherapy, monitoring is complicated by the presence of viable prostatic epithelium that continues to produce PSA. During the first 1 to 2 years after radiation therapy, a PSA “bounce” phenomenon is observed whereby PSA levels rise or fluctuate significantly. This bounce should not be mistaken for a recurrence of cancer. The most widely accepted definition of biochemical recurrence is based on the American Society for Therapeutic Radiology and Oncology “Phoenix” criteria, defined as the nadir PSA level plus 2.0 μg/L.46
References
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Stephenson AJ, Scardino PT, Eastham JA, et al. Preoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Natl Cancer Inst2006; 98:715–717.
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Prostate cancer screening, diagnosis, and treatment present challenges to internists, urologists, and oncologists. For the internist, there is the ongoing debate about when and how often to screen with prostate-specific antigen (PSA) testing, as well as about how to interpret the results. For urologists and oncologists, there is no consensus on how to treat prostate cancer with the growing array of options, from surgery to cryoablation. Most therapies have not been compared in head-to-head trials, and anxious patients often approach their internist for help in navigating the maze of options.
This review summarizes current American Urological Association (AUA) guidelines,1 as well as current practice patterns at the Glickman Urological and Kidney Institute of Cleveland Clinic regarding screening, diagnosis, risk assessment, treatment, and posttreatment management of prostate cancer. We try to explain the approved and the experimental treatments, outlining what we know about their advantages and disadvantages.
SCREENING: WHEN AND HOW
Screening for prostate cancer should involve both a digital rectal examination (DRE) and measurement of the serum PSA level. But when should screening start?
The AUA recommends annual screening with DRE and serum PSA test starting at age 40 for all men with a life expectancy of more than 10 years.1
The American Cancer Society2 and the American College of Physicians,3 in contrast, recommend that men who choose to undergo screening should begin at age 50, or at age 45 if they are black or have a family history of prostate cancer in a primary relative diagnosed before age 65. They also recommend that screening with PSA and DRE be stopped at age 75, given the low likelihood of death from de novo prostate cancer after this age. The AUA recommends that screening be stopped at age 75, but may be continued beyond age 75 if the patient has a life expectancy of 10 years or more.
Before being screened, patients should understand the benefits and the risks of testing. While a small subset of prostate cancers behave aggressively, the majority are slow-growing and pose minimal risk for the development of fatal disease.
A discussion of the rationale for these guidelines and their differences is beyond the scope of this review. Differences stem from the observation that most men treated for prostate cancer will likely not die from prostate cancer, but rather from another condition.
Digital rectal examination’s role and limitations
The utility of DRE is limited to the detection of nodules, gross asymmetry, and gland fixation. DRE is not highly specific: only 40% to 50% of men who have abnormal findings on DRE have prostate cancer on biopsy.5 Anyone who has an abnormal finding on DRE should undergo prostate biopsy. However, if a rectal mass is palpated or if the prostate is exquisitely sensitive, biopsy is not indicated.
Although DRE is not considered very sensitive, it remains an essential element of the clinical staging system for prostate cancer because it can detect cancers that produce little or no PSA (Table 1). Up to 23% of men with prostate cancer in one large cohort study had PSA levels of 4.0 μg/L or less (traditionally deemed normal) and were diagnosed on the basis of a positive DRE alone.4,5
DRE is highly inaccurate for estimating gland volume; it should not be used to gauge cancer risk.
Prostate-specific antigen: Caveats
PSA measurement was introduced as a clinical screening test for prostate cancer in the early 1990s, and it serves as the foundation for early detection.
PSA, a protein involved in seminal coagulation, is produced by the prostate epithelium and is mostly confined within the prostatic ducts. Cancer cells secrete PSA into the bloodstream at increased levels via a disrupted basement membrane in tumor-affected areas of the gland. Elevated PSA can also result from benign prostatic hypertrophy, prostatitis, and prostate biopsy.
PSA levels represent a continuum of prostate cancer risk, and no single PSA value is sensitive and specific enough to predict the presence of cancer.6 Abnormal PSA cutoffs have been defined from 2.5 μg/L to 4 μg/L, and much debate surrounds this topic. Men who present with an elevated PSA (ie, > 2.5 μg/L) should be tested again. If the value remains high, then prostate biopsy should be considered. An elevated PSA level in older men with benign prostatic hypertrophy is not unexpected, and in these patients observation of the PSA value over time may prove valuable to assess the need for biopsy.
A useful adjunct in men with elevated PSA and benign prostatic hypertrophy is the percentage of serum PSA that is free rather than bound.7 PSA produced by prostate cancer binds more avidly with serum proteins (alpha-1 chymotrypsin and alpha-2 macroglobulin), resulting in a lower percentage of free PSA. In men with an elevated PSA (ie, 4.1–10.0 μg/L), the percentage of free PSA provides an indication of whether the elevation is due to benign prostatic hypertrophy or to cancer: the lower the percent free PSA, the more likely an elevated total PSA represents cancer and not benign prostatic hypertrophy. The sensitivity of a free PSA less than 15% to detect prostate cancer is about 85%, and its use as a screening tool is under study.
Much attention has also been given to other PSA indices, namely, the PSA density (the PSA level divided by the prostate volume), the PSA velocity (the rate of increase in the PSA level over time), and the PSA doubling time. While these nuanced PSA measures are useful to predict disease severity and behavior, they are not routinely used in screening.
BIOPSY IS INDICATED IF EITHER TEST IS ABNORMAL
In the past, imaging of the prostate with transrectal ultrasonography was used as a screening tool to detect prostate cancer. Further research showed that only 15% to 20% of hypoechoic lesions detected on ultrasonography contained cancer.8 Because of its low sensitivity and specificity, primary ultrasonographic screening (ie, transrectal ultrasonography alone) is not acceptable for screening or for diagnosis. Its main role is in guiding prostate biopsy.
Biopsy of the prostate with transrectal ultrasonographic guidance is indicated if either the DRE or the PSA level is abnormal. The standard of care is to use an 18-gauge biopsy needle-gun to obtain two to three tissue samples from each of six regions of the prostate, focusing on the outer peripheral zone, specifically the right and left bases, the mid-gland, and the apex.
Pathologic analysis of each tissue core takes into consideration the presence or absence of cancer, the Gleason score, and the percentage of the tissue sample volume that is occupied by cancer.
The Gleason grading system is based on the histologic appearance and reflects the degree of differentiation and aggressiveness of the cancer. The two most prominent tumor grades present are added to give a final Gleason score. For instance, a Gleason grade of 4+3=7 indicates a tumor with predominant Gleason grade 4 disease with a lesser amount of grade 3 disease. The number of positive core samples and the volume of cancer provide information on the severity of the cancer.
If the PSA is high but biopsy is negative
Prostate biopsy misses up to 30% of small cancers. Many of these are clinically insignificant, but about 20% of those missed cancers can be high-risk and thus merit identification. There should be a low threshold for repeating biopsy 1 year later in men who have a persistently high PSA or a rising PSA.
High-grade prostatic intraepithelial neoplasia is a common finding on biopsy. The incidence of de novo prostate cancer at 5 years in men with this finding is 22% to 26%.9 Patients with multifocal high-grade prostatic intraepithelial neoplasia should be monitored with PSA testing and DRE every 6 to 12 months and should be considered for repeat “saturation” biopsy (ie, obtaining as many as 36 core samples).
IF CANCER IS FOUND, HOW RISKY IS IT?
Patients with a new diagnosis of prostate cancer must decide on a treatment plan. This decision is highly individualized, based on the patient’s personal preferences, lifestyle, performance status (ie, his general well-being), disease severity, continence status, and sexual function.
When counseling patients about their disease and the treatment options, we consider three main factors:
The severity of disease on biopsy
The patient’s current state of health and performance status
The patient’s understanding of and willingness to accept the adverse effects of the various treatments.
Pathologic features, the PSA level, and clinical stage determined by DRE are used to predict the severity of disease. Most data on the efficacy of treatments for prostate cancer are based on the incidence of biochemical recurrence, ie, a rise in PSA level after primary therapy. The AUA and the D’Amico risk criteria use biopsy pathology, clinical stage, and the pretreatment PSA level to predict the likelihood of biochemical recurrence (Table 1).10,11
DISCUSSING TREATMENT OPTIONS WITH THE PATIENT
Risk stratification helps guide discussions with patients about which treatment will likely afford the most benefit. When counseling patients about the severity of their disease, it is helpful to use a nomogram to show the likelihood of cure with the different treatment options (Table 2).6,12–16
Important to the consideration of treatment options are the patient’s baseline performance status and life expectancy. Use of the Charlson Comorbidity Index and life expectancy nomograms can help make these assessments less subjective (Table 3).17–20
In our practice, we usually do not recommend treatment in men with low-risk or intermediate-risk prostate cancer who have a life expectancy of less than 10 years, as most of them will likely die of a cause other than prostate cancer. For patients with poor baseline performance status, surveillance or radiation therapy may be preferable to surgery. In younger patients, surgery may confer a more durable benefit.
Figure 1.Treatment options for prostate cancer (Figure 1) include active surveillance, radical prostatectomy, interstitial prostatic brachytherapy, external beam radiotherapy, cryotherapy, and, if the patient is enrolled in a research protocol, high-intensity focused ultrasound (HIFU). Level 1 data show that radical prostatectomy and external beam radiotherapy confer longer overall survival and cancer-specific survival compared with no treatment.21,22 However, no such data exist to prove the superior efficacy of prostatectomy vs brachytherapy vs radiotherapy, for several reasons:
No prospective, randomized clinical trials have directly compared these treatments
Prostate cancer progresses slowly
Definitions of treatment failure used in various studies have been inconsistent
Clinical studies have been subject to selection bias.
ACTIVE SURVEILLANCE IS ACCEPTABLE FOR LOW-RISK PROSTATE CANCER
Active surveillance is an acceptable option for patients with low-risk prostate cancer (ie, if the Gleason score is ≤ 6, the tumor stage is T1c or T2a, and the PSA level is ≤ 10 μg/L). To rule out high-risk disease before starting a program of surveillance, repeat biopsy is advisable, although optional.
Active surveillance consists of PSA testing and DRE every 6 to 12 months, followed by repeat biopsy if significant changes are noted in either test. Some centers advocate biopsy with transrectal ultrasonographic guidance every year regardless of the PSA or DRE findings.
Whether a change in the PSA level is significant is subjective, but a recent phase 2 study in 453 patients23 on a program of active surveillance used a PSA doubling time of less than 3 years as a criterion for repeat biopsy. Thirty-eight percent of the men had to undergo radiation therapy or surgery within 10 years, and 5 patients (1%) died of prostate cancer. The authors concluded that active surveillance did not put these patients at undue risk, and that this approach prevented overtreatment of clinically insignificant prostate cancer.23
The risks of surveillance include the chance that cancer could progress to an incurable state during the surveillance period, greater anxiety for the patient, and, if prostatectomy becomes necessary, greater technical difficulty due to scarring from repeat biopsies. The benefit is postponement or complete avoidance of the adverse effects of treatment.
Debate continues over the potential dangers of deferred treatment of prostate cancer, but in certain patients it is an acceptable option. Patient education, accurate disease assessment, and compliance with monitoring are critical considerations.
RADICAL PROSTATECTOMY: SEVERAL OPTIONS, EQUIVALENT EFFICACY
Radical prostatectomy is widely used for treating prostate cancer of any risk level. The operation entails removing the prostate and seminal vesicles, as well as the pelvic lymph nodes in patients with intermediate or high-risk cancer.
This procedure was increasingly used in the 1990s with the introduction of PSA screening and nerve-sparing surgical techniques that preserve continence and erectile function.
Radical prostatectomy can be done via a standard open approach or a minimally invasive laparoscopic approach with or without robotic assistance. Open surgery, laparoscopic surgery, and robotic prostatectomy offer equivalent rates of oncologic efficacy, continence, and potency.24 The more experienced the surgeon, the better the outcome is likely to be.
The average biochemical recurrence rate at 5 years after radical prostatectomy is approximately 6% for patients with low-risk cancer, 23% for those with intermediate-risk cancer, and 45% for those with high-risk cancer.25 The rate of death from prostate cancer at 10 years is about 1% for patients with low-risk cancer, 4% for those with intermediate-risk cancer, and 8% for those with high-risk cancer.12
Secondary therapy
Pathologic staging of the surgical specimen after radical prostatectomy yields information that can be beneficial in terms of initiating early secondary therapy.
Patients with node-positive disease should immediately undergo androgen deprivation treatment.26
Evidence of positive surgical margins, seminal vesicle invasion, bladder neck invasion, and extracapsular extension also increase the risk of recurrence. This additional risk can be ascertained via the use of a postoperative nomogram. Patients at high risk of recurrence should be considered for early adjuvant external beam radiotherapy to the surgical field 3 to 6 months after surgery.
Advantages and disadvantages of radical prostatectomy
Advantages of radical prostatectomy include the ability to accurately stage the cancer with the surgical specimen and the ability to remove the pelvic lymph nodes in patients at intermediate and high risk. Another advantage is that postoperative surveillance is straightforward: PSA should become undetectable after surgery, and a measurable increase in PSA represents disease recurrence.
Disadvantages include:
The risk of surgical complications (reported in 3% to 17% of cases)24
An average hospital stay of 1 to 3 days (and a typical 3 to 6 weeks before returning to work)
The need for a Foley catheter for 10 to 14 days
The risk of incontinence and impotence, which are very distressing to patients.
Postoperative incontinence is typically defined as the need for any type of protective pad for leakage. Up to 70% of patients have incontinence in the first 3 months after surgery, but 82% to 94% of patients regain continence by 12 months.24 A small percentage of patients (3% to 5%) have significant permanent incontinence.
Counseling about postoperative erectile dysfunction
All patients should be counseled about the risk of a postoperative decrease in erectile function, especially those with pre-existing erectile dysfunction. Potency is defined as the ability to have an erection suitable for intercourse (with or without phosphodiesterase type 5 inhibitors) more than 50% of the time. In men with bilateral nerve-sparing open prostatectomy, potency rates at 12 months have been reported between 63% and 81%.13
Data on potency rates vary widely because of differences in how potency was defined, selection bias, and the multifactorial nature of erectile dysfunction. Also, because single-institution, single-surgeon reports and advertisements tend to underestimate rates of impotence after radical prostatectomy by any approach, many patients have false expectations.
INTERSTITIAL BRACHYTHERAPY FOR LOW-RISK CANCERS
Interstitial brachytherapy delivers a localized, high dose (125 to 145 Gy) of radiation to the prostate, with minimal radiation dosing to the bladder, rectum, or other adjacent organs and tissues. “Seeds” or small pellets containing a radioisotope (iodine 125 or palladium 103) are stereotactically implanted through the perineum into the prostate under ultrasonographic guidance. Computerized mapping done before or during surgery helps determine the optimal placement of the seeds, the object being to cover at least 90% of the prostate with 100% of the radiation dose.
In permanent brachytherapy, the implants give off radiation at a low dose rate over weeks to months and are left in place permanently. In temporary brachytherapy, seeds are implanted to deliver a low or high dose rate for a specified period, and then they are removed.
“Implant quality,” ie, delivery of more than 90% of the radiation dose, is a major predictor of success and can depend on both the available instrumentation and the skill of the operator.
Caveats about brachytherapy
The evidence in support of combining androgen deprivation therapy and interstitial brachytherapy is poor, and there is some evidence of increased rates of irritative voiding symptoms,27 so this is generally not recommended.
Interstitial brachytherapy as monotherapy has usually been reserved for patients with low-risk cancer with a low likelihood of extracapsular disease extension or pelvic lymph node involvement. No randomized controlled clinical trial has compared brachytherapy with radical prostatectomy or external beam radiotherapy. One large long-term study reported an 8-year biochemical recurrence rate of 18% in patients with low-risk cancer and 30% in patients with intermediate-risk cancer.28 The long-term efficacy of brachytherapy for intermediate- and high-risk prostate cancer is still under investigation.
Advantages and disadvantages of interstitial brachytherapy
Advantages. Interstitial brachytherapy is done as a single outpatient procedure. It can deliver a targeted high dose of radiation. And it is associated with a lower rate of posttreatment incontinence than radical prostatectomy, and a lower cost.
Disadvantages. There are limited data to support long-term cancer control in intermediate- and high-risk disease. Short-term adverse effects include dysuria, hematuria, urinary urgency, and urinary frequency in up to 80% of patients.29 Voiding symptoms typically peak 1 to 3 months after the procedure and subside after 8 to 12 months. Erectile dysfunction has been reported in 30% to 35% of men at 5 years after the procedure. Other possible adverse effects include urethral stricture, incontinence, recurrent hematuria, rectal bleeding, proctitis, and the development of bladder cancer and other secondary cancers.
EXTERNAL BEAM RADIOTHERAPY
In external beam radiotherapy, radiation is delivered to the prostate and surrounding tissues via an external energy source. Electrons, protons, or neutrons are used, and although each has theoretical advantages over the others, all appear to have similar clinical efficacy.
As with brachytherapy, the object—and the challenge—is to deliver an effective dose of radiation to the tumor while sparing adjacent organs. Intensity-modulated delivery is a radiotherapy technique that delivers more of the radiation dose where we want it to go—and less where we don’t want it to go. For prostate cancer, the target dose with intensity-modulated delivery is typically 75 to 85 Gy, in doses of 2 to 2.25 Gy for 30 to 36 days.
Androgen deprivation therapy before or after external beam radiotherapy augments the effects of the radiotherapy, particularly in patients with high-risk disease.30
The oncologic efficacy of intensity-modulated radiotherapy in patients at low and intermediate risk appears commensurate with that of radical prostatectomy. In one study,31 in low-risk cases, biochemical disease-free survival rates were 85% for radiotherapy vs 93% for prostatectomy; in intermediate-risk cases, 82% for radiotherapy and 87% for prostatectomy; and in high-risk cases, 62% for combined androgen deprivation and radiotherapy vs 38% for prostatectomy.31
Advantages and disadvantages of external beam radiotherapy
Advantages. External beam radiotherapy is noninvasive. It can treat the prostate as well as areas outside the prostate in patients with intermediate- and high-risk disease, and it is proven effective for high-risk cancer when used in combination with androgen deprivation.
Disadvantages. On the other hand, radiotherapy requires a series of daily treatments, which can be inconvenient and burdensome to the patient. Its adverse effects are similar to those of brachytherapy, and it is expensive. Long-term adverse effects include irritative voiding symptoms (frequency, urgency, nocturia), hemorrhagic cystitis, bowel symptoms (pain with defecation, tenesmus, bleeding), and a significantly higher lifetime risk of a secondary malignancy, particularly of the bladder and rectum.32
External beam radiotherapy also induces tissue changes in the pelvis that make salvage surgery more difficult. Patients in whom radiotherapy is ineffective as monotherapy and who require salvage prostatectomy typically have poor outcomes in terms of disease control, continence, and potency.
COMBINED RADIATION THERAPY: BETTER, OR OVERTREATMENT?
Many patients are offered a combination of external beam radiotherapy and interstitial brachytherapy. The rationale is that the combination can boost the dose of radiation to the prostate and at the same time treat cancer that has extended beyond the prostate or to the pelvic lymph nodes.
The radiation dose in the combined approach is 45 to 50 Gy (vs 70 to 80 Gy in monotherapy), thereby minimizing toxicity.
This combination has not been shown to improve overall survival or cancer-specific survival compared with either therapy alone, and it likely constitutes overtreatment.33 Adverse effects of combination therapy include erectile dysfunction, rectal and bladder toxicity, and secondary malignancy.
A serious complication associated more often with the combination of external beam radiotherapy and brachytherapy than other treatments is rectoprostatic fistula, a condition that requires complex reconstructive surgery and often requires permanent urinary and fecal diversion.34
CRYOTHERAPY: MORE STUDY NEEDED
Refinements in cryoablative therapy to destroy prostate tissue have improved the safety and efficacy of this procedure significantly over the past decade. The AUA consensus guidelines recognize cryotherapy as a viable primary cancer monotherapy, but it is most commonly used as a salvage therapy after failure of radiation therapy.
The procedure involves ultrasonographically guided stereotactic placement of cryoprobes into the prostate via a transperineal approach. Argon is pumped through the probes under pressure to initiate ice formation, and repeated freeze-thaw cycles cause tissue damage and necrosis.
Rates of biochemical recurrence at 5 years in patients at low, intermediate, and high risk have been reported at 16%, 27%, and 25%, respectively.35 The presence of viable cancer on biopsy specimens after primary cryoablation has been reported at 15%, compared with 25% after definitive radiation therapy.35
Advantages and disadvantages of cryotherapy
Cryotherapy can destroy cancer tissue in a minimally invasive way. It has no long-term delayed adverse effects, and it is a low-cost and convenient outpatient procedure.
On the other hand, we lack long-term data on its oncologic efficacy, acute complications, and late adverse effects. Acute complications occur in up to 16% of patients and include acute urinary retention requiring prolonged catheterization, hematuria, urethral sloughing, perineal pain, and incontinence.36 Potential late effects include rectoprostatic fistula (< 1%), incontinence (< 5%), persistent hematuria, and chronic pelvic pain.36
Cryoablation therapy appears to have a more significant negative impact on sexual function than does brachytherapy.37
More study of the complications and efficacy of cryotherapy is needed before the procedure can be adopted as routine primary monotherapy.
HIGH-INTENSITY FOCUSED ULTRASOUND: NOT YET FDA-APPROVED
High-intensity focused ultrasound (HIFU) is not yet approved by the US Food and Drug Administration (other than in an approved research protocol) but is used in Canada and in certain countries of Europe and Asia. It involves the insertion of a transducer into the rectum that generates a high-intensity, focused beam that heats target tissue in the prostate to a high temperature. This temperature triggers a heat-shock response that leads to cellular apoptosis and tissue necrosis. The procedure can be done with or without magnetic resonance imaging (MRI) guidance.
Biochemical recurrence rates at 2 years after the procedure have been reported between 23% and 50%, but long-term efficacy data are lacking.38,39
Advantages and disadvantages of ultrasound
HIFU is a minimally invasive, low-cost, outpatient procedure that offers trackless delivery of energy to the prostate: ie, there is no direct mechanical penetration into the tissue.
Complications include rectal-wall injury, fistula, acute urinary retention, hematuria, and urethral stricture.
FOCAL ABLATION: GETTING ATTENTION, BUT STILL UNDER DEVELOPMENT
Focal ablation for prostate cancer has been receiving much attention. This treatment uses heat energy to destroy tumor cells, guided by high-resolution endorectal-coil MRI. The procedure is in the developmental stages and is available only in research protocols.
The procedure has several major hurdles to overcome before becoming acceptable for clinical practice. First, prostate cancer is multifocal, and microscopic tumor foci are likely present that are invisible even to MRI, so ablation of only part of the prostate leaves the rest of the gland at risk of continued or de novo tumor growth.
Second, a wide range of sensitivities and specificities have been reported for endorectal coil MRI for detecting prostate cancer: its sensitivity has ranged from 27% to 100%, and its specificity has ranged from 32% to 99%.40
ANDROGEN DEPRIVATION, AN ADJUVANT THERAPY
Androgen deprivation therapy (medical castration) is not effective as a monotherapy for prostate cancer. A large population-based study in men with localized prostate cancer showed no higher rate of overall survival at 10 years with primary androgen deprivation therapy than with conservative management.41
Androgen deprivation is achieved with a leutinizing hormone-releasing hormone agonist such as leuprolide (Lupron) or goserelin (Zoladex), or an antiandrogen drug such as flutamide or bicalutamide (Casodex), or a combination of each.
Adverse effects include hot flashes, gynecomastia, decreased libido, erectile dysfunction, weight gain, and hyperlipidemia. Long-term effects include osteoporosis and a significantly higher risk of cardiac events, new-onset type 2 diabetes mellitus, and stroke.
Currently, the only recognized role for androgen deprivation therapy in prostate cancer is as an adjunct to external beam radiotherapy or as a treatment of metastatic prostate cancer.
Orchiectomy
The other way to eliminate testicular production of testosterone is surgical castration. Bilateral orchiectomy has advantages over medical androgen deprivation therapy in that it costs less, is highly reliable, and is done as a single treatment on an outpatient basis. Disadvantages include surgery-related morbidity and the irreversible nature of the procedure. The adverse effects are similar to those of androgen deprivation therapy.
POSTTREATMENT MONITORING
The management of patients with recurrent prostate cancer can be complex, and these patients should be referred to a medical or urologic oncologist.42,43
Often, a rise in PSA after primary therapy represents a regrowth of cancer; 30% to 60% of patients with a recurrence have metastasis, and nearly 20% will die from the disease. The average time from documentation of biochemical recurrence to metastatic progression is 8 years. The average time from metastatic progression to death is 5 years.44,45
After radical prostatectomy, the PSA level should be checked every 6 to 12 months for the first 2 years, then annually until the patient’s life expectancy is only 10 years even without prostate cancer. PSA should reach undetectable levels within 4 to 6 weeks after surgery. Biochemical recurrence after surgery is defined as a PSA level of 0.2 μg/L or higher in two serial studies.
After radiation therapy or cryotherapy, monitoring is complicated by the presence of viable prostatic epithelium that continues to produce PSA. During the first 1 to 2 years after radiation therapy, a PSA “bounce” phenomenon is observed whereby PSA levels rise or fluctuate significantly. This bounce should not be mistaken for a recurrence of cancer. The most widely accepted definition of biochemical recurrence is based on the American Society for Therapeutic Radiology and Oncology “Phoenix” criteria, defined as the nadir PSA level plus 2.0 μg/L.46
Prostate cancer screening, diagnosis, and treatment present challenges to internists, urologists, and oncologists. For the internist, there is the ongoing debate about when and how often to screen with prostate-specific antigen (PSA) testing, as well as about how to interpret the results. For urologists and oncologists, there is no consensus on how to treat prostate cancer with the growing array of options, from surgery to cryoablation. Most therapies have not been compared in head-to-head trials, and anxious patients often approach their internist for help in navigating the maze of options.
This review summarizes current American Urological Association (AUA) guidelines,1 as well as current practice patterns at the Glickman Urological and Kidney Institute of Cleveland Clinic regarding screening, diagnosis, risk assessment, treatment, and posttreatment management of prostate cancer. We try to explain the approved and the experimental treatments, outlining what we know about their advantages and disadvantages.
SCREENING: WHEN AND HOW
Screening for prostate cancer should involve both a digital rectal examination (DRE) and measurement of the serum PSA level. But when should screening start?
The AUA recommends annual screening with DRE and serum PSA test starting at age 40 for all men with a life expectancy of more than 10 years.1
The American Cancer Society2 and the American College of Physicians,3 in contrast, recommend that men who choose to undergo screening should begin at age 50, or at age 45 if they are black or have a family history of prostate cancer in a primary relative diagnosed before age 65. They also recommend that screening with PSA and DRE be stopped at age 75, given the low likelihood of death from de novo prostate cancer after this age. The AUA recommends that screening be stopped at age 75, but may be continued beyond age 75 if the patient has a life expectancy of 10 years or more.
Before being screened, patients should understand the benefits and the risks of testing. While a small subset of prostate cancers behave aggressively, the majority are slow-growing and pose minimal risk for the development of fatal disease.
A discussion of the rationale for these guidelines and their differences is beyond the scope of this review. Differences stem from the observation that most men treated for prostate cancer will likely not die from prostate cancer, but rather from another condition.
Digital rectal examination’s role and limitations
The utility of DRE is limited to the detection of nodules, gross asymmetry, and gland fixation. DRE is not highly specific: only 40% to 50% of men who have abnormal findings on DRE have prostate cancer on biopsy.5 Anyone who has an abnormal finding on DRE should undergo prostate biopsy. However, if a rectal mass is palpated or if the prostate is exquisitely sensitive, biopsy is not indicated.
Although DRE is not considered very sensitive, it remains an essential element of the clinical staging system for prostate cancer because it can detect cancers that produce little or no PSA (Table 1). Up to 23% of men with prostate cancer in one large cohort study had PSA levels of 4.0 μg/L or less (traditionally deemed normal) and were diagnosed on the basis of a positive DRE alone.4,5
DRE is highly inaccurate for estimating gland volume; it should not be used to gauge cancer risk.
Prostate-specific antigen: Caveats
PSA measurement was introduced as a clinical screening test for prostate cancer in the early 1990s, and it serves as the foundation for early detection.
PSA, a protein involved in seminal coagulation, is produced by the prostate epithelium and is mostly confined within the prostatic ducts. Cancer cells secrete PSA into the bloodstream at increased levels via a disrupted basement membrane in tumor-affected areas of the gland. Elevated PSA can also result from benign prostatic hypertrophy, prostatitis, and prostate biopsy.
PSA levels represent a continuum of prostate cancer risk, and no single PSA value is sensitive and specific enough to predict the presence of cancer.6 Abnormal PSA cutoffs have been defined from 2.5 μg/L to 4 μg/L, and much debate surrounds this topic. Men who present with an elevated PSA (ie, > 2.5 μg/L) should be tested again. If the value remains high, then prostate biopsy should be considered. An elevated PSA level in older men with benign prostatic hypertrophy is not unexpected, and in these patients observation of the PSA value over time may prove valuable to assess the need for biopsy.
A useful adjunct in men with elevated PSA and benign prostatic hypertrophy is the percentage of serum PSA that is free rather than bound.7 PSA produced by prostate cancer binds more avidly with serum proteins (alpha-1 chymotrypsin and alpha-2 macroglobulin), resulting in a lower percentage of free PSA. In men with an elevated PSA (ie, 4.1–10.0 μg/L), the percentage of free PSA provides an indication of whether the elevation is due to benign prostatic hypertrophy or to cancer: the lower the percent free PSA, the more likely an elevated total PSA represents cancer and not benign prostatic hypertrophy. The sensitivity of a free PSA less than 15% to detect prostate cancer is about 85%, and its use as a screening tool is under study.
Much attention has also been given to other PSA indices, namely, the PSA density (the PSA level divided by the prostate volume), the PSA velocity (the rate of increase in the PSA level over time), and the PSA doubling time. While these nuanced PSA measures are useful to predict disease severity and behavior, they are not routinely used in screening.
BIOPSY IS INDICATED IF EITHER TEST IS ABNORMAL
In the past, imaging of the prostate with transrectal ultrasonography was used as a screening tool to detect prostate cancer. Further research showed that only 15% to 20% of hypoechoic lesions detected on ultrasonography contained cancer.8 Because of its low sensitivity and specificity, primary ultrasonographic screening (ie, transrectal ultrasonography alone) is not acceptable for screening or for diagnosis. Its main role is in guiding prostate biopsy.
Biopsy of the prostate with transrectal ultrasonographic guidance is indicated if either the DRE or the PSA level is abnormal. The standard of care is to use an 18-gauge biopsy needle-gun to obtain two to three tissue samples from each of six regions of the prostate, focusing on the outer peripheral zone, specifically the right and left bases, the mid-gland, and the apex.
Pathologic analysis of each tissue core takes into consideration the presence or absence of cancer, the Gleason score, and the percentage of the tissue sample volume that is occupied by cancer.
The Gleason grading system is based on the histologic appearance and reflects the degree of differentiation and aggressiveness of the cancer. The two most prominent tumor grades present are added to give a final Gleason score. For instance, a Gleason grade of 4+3=7 indicates a tumor with predominant Gleason grade 4 disease with a lesser amount of grade 3 disease. The number of positive core samples and the volume of cancer provide information on the severity of the cancer.
If the PSA is high but biopsy is negative
Prostate biopsy misses up to 30% of small cancers. Many of these are clinically insignificant, but about 20% of those missed cancers can be high-risk and thus merit identification. There should be a low threshold for repeating biopsy 1 year later in men who have a persistently high PSA or a rising PSA.
High-grade prostatic intraepithelial neoplasia is a common finding on biopsy. The incidence of de novo prostate cancer at 5 years in men with this finding is 22% to 26%.9 Patients with multifocal high-grade prostatic intraepithelial neoplasia should be monitored with PSA testing and DRE every 6 to 12 months and should be considered for repeat “saturation” biopsy (ie, obtaining as many as 36 core samples).
IF CANCER IS FOUND, HOW RISKY IS IT?
Patients with a new diagnosis of prostate cancer must decide on a treatment plan. This decision is highly individualized, based on the patient’s personal preferences, lifestyle, performance status (ie, his general well-being), disease severity, continence status, and sexual function.
When counseling patients about their disease and the treatment options, we consider three main factors:
The severity of disease on biopsy
The patient’s current state of health and performance status
The patient’s understanding of and willingness to accept the adverse effects of the various treatments.
Pathologic features, the PSA level, and clinical stage determined by DRE are used to predict the severity of disease. Most data on the efficacy of treatments for prostate cancer are based on the incidence of biochemical recurrence, ie, a rise in PSA level after primary therapy. The AUA and the D’Amico risk criteria use biopsy pathology, clinical stage, and the pretreatment PSA level to predict the likelihood of biochemical recurrence (Table 1).10,11
DISCUSSING TREATMENT OPTIONS WITH THE PATIENT
Risk stratification helps guide discussions with patients about which treatment will likely afford the most benefit. When counseling patients about the severity of their disease, it is helpful to use a nomogram to show the likelihood of cure with the different treatment options (Table 2).6,12–16
Important to the consideration of treatment options are the patient’s baseline performance status and life expectancy. Use of the Charlson Comorbidity Index and life expectancy nomograms can help make these assessments less subjective (Table 3).17–20
In our practice, we usually do not recommend treatment in men with low-risk or intermediate-risk prostate cancer who have a life expectancy of less than 10 years, as most of them will likely die of a cause other than prostate cancer. For patients with poor baseline performance status, surveillance or radiation therapy may be preferable to surgery. In younger patients, surgery may confer a more durable benefit.
Figure 1.Treatment options for prostate cancer (Figure 1) include active surveillance, radical prostatectomy, interstitial prostatic brachytherapy, external beam radiotherapy, cryotherapy, and, if the patient is enrolled in a research protocol, high-intensity focused ultrasound (HIFU). Level 1 data show that radical prostatectomy and external beam radiotherapy confer longer overall survival and cancer-specific survival compared with no treatment.21,22 However, no such data exist to prove the superior efficacy of prostatectomy vs brachytherapy vs radiotherapy, for several reasons:
No prospective, randomized clinical trials have directly compared these treatments
Prostate cancer progresses slowly
Definitions of treatment failure used in various studies have been inconsistent
Clinical studies have been subject to selection bias.
ACTIVE SURVEILLANCE IS ACCEPTABLE FOR LOW-RISK PROSTATE CANCER
Active surveillance is an acceptable option for patients with low-risk prostate cancer (ie, if the Gleason score is ≤ 6, the tumor stage is T1c or T2a, and the PSA level is ≤ 10 μg/L). To rule out high-risk disease before starting a program of surveillance, repeat biopsy is advisable, although optional.
Active surveillance consists of PSA testing and DRE every 6 to 12 months, followed by repeat biopsy if significant changes are noted in either test. Some centers advocate biopsy with transrectal ultrasonographic guidance every year regardless of the PSA or DRE findings.
Whether a change in the PSA level is significant is subjective, but a recent phase 2 study in 453 patients23 on a program of active surveillance used a PSA doubling time of less than 3 years as a criterion for repeat biopsy. Thirty-eight percent of the men had to undergo radiation therapy or surgery within 10 years, and 5 patients (1%) died of prostate cancer. The authors concluded that active surveillance did not put these patients at undue risk, and that this approach prevented overtreatment of clinically insignificant prostate cancer.23
The risks of surveillance include the chance that cancer could progress to an incurable state during the surveillance period, greater anxiety for the patient, and, if prostatectomy becomes necessary, greater technical difficulty due to scarring from repeat biopsies. The benefit is postponement or complete avoidance of the adverse effects of treatment.
Debate continues over the potential dangers of deferred treatment of prostate cancer, but in certain patients it is an acceptable option. Patient education, accurate disease assessment, and compliance with monitoring are critical considerations.
RADICAL PROSTATECTOMY: SEVERAL OPTIONS, EQUIVALENT EFFICACY
Radical prostatectomy is widely used for treating prostate cancer of any risk level. The operation entails removing the prostate and seminal vesicles, as well as the pelvic lymph nodes in patients with intermediate or high-risk cancer.
This procedure was increasingly used in the 1990s with the introduction of PSA screening and nerve-sparing surgical techniques that preserve continence and erectile function.
Radical prostatectomy can be done via a standard open approach or a minimally invasive laparoscopic approach with or without robotic assistance. Open surgery, laparoscopic surgery, and robotic prostatectomy offer equivalent rates of oncologic efficacy, continence, and potency.24 The more experienced the surgeon, the better the outcome is likely to be.
The average biochemical recurrence rate at 5 years after radical prostatectomy is approximately 6% for patients with low-risk cancer, 23% for those with intermediate-risk cancer, and 45% for those with high-risk cancer.25 The rate of death from prostate cancer at 10 years is about 1% for patients with low-risk cancer, 4% for those with intermediate-risk cancer, and 8% for those with high-risk cancer.12
Secondary therapy
Pathologic staging of the surgical specimen after radical prostatectomy yields information that can be beneficial in terms of initiating early secondary therapy.
Patients with node-positive disease should immediately undergo androgen deprivation treatment.26
Evidence of positive surgical margins, seminal vesicle invasion, bladder neck invasion, and extracapsular extension also increase the risk of recurrence. This additional risk can be ascertained via the use of a postoperative nomogram. Patients at high risk of recurrence should be considered for early adjuvant external beam radiotherapy to the surgical field 3 to 6 months after surgery.
Advantages and disadvantages of radical prostatectomy
Advantages of radical prostatectomy include the ability to accurately stage the cancer with the surgical specimen and the ability to remove the pelvic lymph nodes in patients at intermediate and high risk. Another advantage is that postoperative surveillance is straightforward: PSA should become undetectable after surgery, and a measurable increase in PSA represents disease recurrence.
Disadvantages include:
The risk of surgical complications (reported in 3% to 17% of cases)24
An average hospital stay of 1 to 3 days (and a typical 3 to 6 weeks before returning to work)
The need for a Foley catheter for 10 to 14 days
The risk of incontinence and impotence, which are very distressing to patients.
Postoperative incontinence is typically defined as the need for any type of protective pad for leakage. Up to 70% of patients have incontinence in the first 3 months after surgery, but 82% to 94% of patients regain continence by 12 months.24 A small percentage of patients (3% to 5%) have significant permanent incontinence.
Counseling about postoperative erectile dysfunction
All patients should be counseled about the risk of a postoperative decrease in erectile function, especially those with pre-existing erectile dysfunction. Potency is defined as the ability to have an erection suitable for intercourse (with or without phosphodiesterase type 5 inhibitors) more than 50% of the time. In men with bilateral nerve-sparing open prostatectomy, potency rates at 12 months have been reported between 63% and 81%.13
Data on potency rates vary widely because of differences in how potency was defined, selection bias, and the multifactorial nature of erectile dysfunction. Also, because single-institution, single-surgeon reports and advertisements tend to underestimate rates of impotence after radical prostatectomy by any approach, many patients have false expectations.
INTERSTITIAL BRACHYTHERAPY FOR LOW-RISK CANCERS
Interstitial brachytherapy delivers a localized, high dose (125 to 145 Gy) of radiation to the prostate, with minimal radiation dosing to the bladder, rectum, or other adjacent organs and tissues. “Seeds” or small pellets containing a radioisotope (iodine 125 or palladium 103) are stereotactically implanted through the perineum into the prostate under ultrasonographic guidance. Computerized mapping done before or during surgery helps determine the optimal placement of the seeds, the object being to cover at least 90% of the prostate with 100% of the radiation dose.
In permanent brachytherapy, the implants give off radiation at a low dose rate over weeks to months and are left in place permanently. In temporary brachytherapy, seeds are implanted to deliver a low or high dose rate for a specified period, and then they are removed.
“Implant quality,” ie, delivery of more than 90% of the radiation dose, is a major predictor of success and can depend on both the available instrumentation and the skill of the operator.
Caveats about brachytherapy
The evidence in support of combining androgen deprivation therapy and interstitial brachytherapy is poor, and there is some evidence of increased rates of irritative voiding symptoms,27 so this is generally not recommended.
Interstitial brachytherapy as monotherapy has usually been reserved for patients with low-risk cancer with a low likelihood of extracapsular disease extension or pelvic lymph node involvement. No randomized controlled clinical trial has compared brachytherapy with radical prostatectomy or external beam radiotherapy. One large long-term study reported an 8-year biochemical recurrence rate of 18% in patients with low-risk cancer and 30% in patients with intermediate-risk cancer.28 The long-term efficacy of brachytherapy for intermediate- and high-risk prostate cancer is still under investigation.
Advantages and disadvantages of interstitial brachytherapy
Advantages. Interstitial brachytherapy is done as a single outpatient procedure. It can deliver a targeted high dose of radiation. And it is associated with a lower rate of posttreatment incontinence than radical prostatectomy, and a lower cost.
Disadvantages. There are limited data to support long-term cancer control in intermediate- and high-risk disease. Short-term adverse effects include dysuria, hematuria, urinary urgency, and urinary frequency in up to 80% of patients.29 Voiding symptoms typically peak 1 to 3 months after the procedure and subside after 8 to 12 months. Erectile dysfunction has been reported in 30% to 35% of men at 5 years after the procedure. Other possible adverse effects include urethral stricture, incontinence, recurrent hematuria, rectal bleeding, proctitis, and the development of bladder cancer and other secondary cancers.
EXTERNAL BEAM RADIOTHERAPY
In external beam radiotherapy, radiation is delivered to the prostate and surrounding tissues via an external energy source. Electrons, protons, or neutrons are used, and although each has theoretical advantages over the others, all appear to have similar clinical efficacy.
As with brachytherapy, the object—and the challenge—is to deliver an effective dose of radiation to the tumor while sparing adjacent organs. Intensity-modulated delivery is a radiotherapy technique that delivers more of the radiation dose where we want it to go—and less where we don’t want it to go. For prostate cancer, the target dose with intensity-modulated delivery is typically 75 to 85 Gy, in doses of 2 to 2.25 Gy for 30 to 36 days.
Androgen deprivation therapy before or after external beam radiotherapy augments the effects of the radiotherapy, particularly in patients with high-risk disease.30
The oncologic efficacy of intensity-modulated radiotherapy in patients at low and intermediate risk appears commensurate with that of radical prostatectomy. In one study,31 in low-risk cases, biochemical disease-free survival rates were 85% for radiotherapy vs 93% for prostatectomy; in intermediate-risk cases, 82% for radiotherapy and 87% for prostatectomy; and in high-risk cases, 62% for combined androgen deprivation and radiotherapy vs 38% for prostatectomy.31
Advantages and disadvantages of external beam radiotherapy
Advantages. External beam radiotherapy is noninvasive. It can treat the prostate as well as areas outside the prostate in patients with intermediate- and high-risk disease, and it is proven effective for high-risk cancer when used in combination with androgen deprivation.
Disadvantages. On the other hand, radiotherapy requires a series of daily treatments, which can be inconvenient and burdensome to the patient. Its adverse effects are similar to those of brachytherapy, and it is expensive. Long-term adverse effects include irritative voiding symptoms (frequency, urgency, nocturia), hemorrhagic cystitis, bowel symptoms (pain with defecation, tenesmus, bleeding), and a significantly higher lifetime risk of a secondary malignancy, particularly of the bladder and rectum.32
External beam radiotherapy also induces tissue changes in the pelvis that make salvage surgery more difficult. Patients in whom radiotherapy is ineffective as monotherapy and who require salvage prostatectomy typically have poor outcomes in terms of disease control, continence, and potency.
COMBINED RADIATION THERAPY: BETTER, OR OVERTREATMENT?
Many patients are offered a combination of external beam radiotherapy and interstitial brachytherapy. The rationale is that the combination can boost the dose of radiation to the prostate and at the same time treat cancer that has extended beyond the prostate or to the pelvic lymph nodes.
The radiation dose in the combined approach is 45 to 50 Gy (vs 70 to 80 Gy in monotherapy), thereby minimizing toxicity.
This combination has not been shown to improve overall survival or cancer-specific survival compared with either therapy alone, and it likely constitutes overtreatment.33 Adverse effects of combination therapy include erectile dysfunction, rectal and bladder toxicity, and secondary malignancy.
A serious complication associated more often with the combination of external beam radiotherapy and brachytherapy than other treatments is rectoprostatic fistula, a condition that requires complex reconstructive surgery and often requires permanent urinary and fecal diversion.34
CRYOTHERAPY: MORE STUDY NEEDED
Refinements in cryoablative therapy to destroy prostate tissue have improved the safety and efficacy of this procedure significantly over the past decade. The AUA consensus guidelines recognize cryotherapy as a viable primary cancer monotherapy, but it is most commonly used as a salvage therapy after failure of radiation therapy.
The procedure involves ultrasonographically guided stereotactic placement of cryoprobes into the prostate via a transperineal approach. Argon is pumped through the probes under pressure to initiate ice formation, and repeated freeze-thaw cycles cause tissue damage and necrosis.
Rates of biochemical recurrence at 5 years in patients at low, intermediate, and high risk have been reported at 16%, 27%, and 25%, respectively.35 The presence of viable cancer on biopsy specimens after primary cryoablation has been reported at 15%, compared with 25% after definitive radiation therapy.35
Advantages and disadvantages of cryotherapy
Cryotherapy can destroy cancer tissue in a minimally invasive way. It has no long-term delayed adverse effects, and it is a low-cost and convenient outpatient procedure.
On the other hand, we lack long-term data on its oncologic efficacy, acute complications, and late adverse effects. Acute complications occur in up to 16% of patients and include acute urinary retention requiring prolonged catheterization, hematuria, urethral sloughing, perineal pain, and incontinence.36 Potential late effects include rectoprostatic fistula (< 1%), incontinence (< 5%), persistent hematuria, and chronic pelvic pain.36
Cryoablation therapy appears to have a more significant negative impact on sexual function than does brachytherapy.37
More study of the complications and efficacy of cryotherapy is needed before the procedure can be adopted as routine primary monotherapy.
HIGH-INTENSITY FOCUSED ULTRASOUND: NOT YET FDA-APPROVED
High-intensity focused ultrasound (HIFU) is not yet approved by the US Food and Drug Administration (other than in an approved research protocol) but is used in Canada and in certain countries of Europe and Asia. It involves the insertion of a transducer into the rectum that generates a high-intensity, focused beam that heats target tissue in the prostate to a high temperature. This temperature triggers a heat-shock response that leads to cellular apoptosis and tissue necrosis. The procedure can be done with or without magnetic resonance imaging (MRI) guidance.
Biochemical recurrence rates at 2 years after the procedure have been reported between 23% and 50%, but long-term efficacy data are lacking.38,39
Advantages and disadvantages of ultrasound
HIFU is a minimally invasive, low-cost, outpatient procedure that offers trackless delivery of energy to the prostate: ie, there is no direct mechanical penetration into the tissue.
Complications include rectal-wall injury, fistula, acute urinary retention, hematuria, and urethral stricture.
FOCAL ABLATION: GETTING ATTENTION, BUT STILL UNDER DEVELOPMENT
Focal ablation for prostate cancer has been receiving much attention. This treatment uses heat energy to destroy tumor cells, guided by high-resolution endorectal-coil MRI. The procedure is in the developmental stages and is available only in research protocols.
The procedure has several major hurdles to overcome before becoming acceptable for clinical practice. First, prostate cancer is multifocal, and microscopic tumor foci are likely present that are invisible even to MRI, so ablation of only part of the prostate leaves the rest of the gland at risk of continued or de novo tumor growth.
Second, a wide range of sensitivities and specificities have been reported for endorectal coil MRI for detecting prostate cancer: its sensitivity has ranged from 27% to 100%, and its specificity has ranged from 32% to 99%.40
ANDROGEN DEPRIVATION, AN ADJUVANT THERAPY
Androgen deprivation therapy (medical castration) is not effective as a monotherapy for prostate cancer. A large population-based study in men with localized prostate cancer showed no higher rate of overall survival at 10 years with primary androgen deprivation therapy than with conservative management.41
Androgen deprivation is achieved with a leutinizing hormone-releasing hormone agonist such as leuprolide (Lupron) or goserelin (Zoladex), or an antiandrogen drug such as flutamide or bicalutamide (Casodex), or a combination of each.
Adverse effects include hot flashes, gynecomastia, decreased libido, erectile dysfunction, weight gain, and hyperlipidemia. Long-term effects include osteoporosis and a significantly higher risk of cardiac events, new-onset type 2 diabetes mellitus, and stroke.
Currently, the only recognized role for androgen deprivation therapy in prostate cancer is as an adjunct to external beam radiotherapy or as a treatment of metastatic prostate cancer.
Orchiectomy
The other way to eliminate testicular production of testosterone is surgical castration. Bilateral orchiectomy has advantages over medical androgen deprivation therapy in that it costs less, is highly reliable, and is done as a single treatment on an outpatient basis. Disadvantages include surgery-related morbidity and the irreversible nature of the procedure. The adverse effects are similar to those of androgen deprivation therapy.
POSTTREATMENT MONITORING
The management of patients with recurrent prostate cancer can be complex, and these patients should be referred to a medical or urologic oncologist.42,43
Often, a rise in PSA after primary therapy represents a regrowth of cancer; 30% to 60% of patients with a recurrence have metastasis, and nearly 20% will die from the disease. The average time from documentation of biochemical recurrence to metastatic progression is 8 years. The average time from metastatic progression to death is 5 years.44,45
After radical prostatectomy, the PSA level should be checked every 6 to 12 months for the first 2 years, then annually until the patient’s life expectancy is only 10 years even without prostate cancer. PSA should reach undetectable levels within 4 to 6 weeks after surgery. Biochemical recurrence after surgery is defined as a PSA level of 0.2 μg/L or higher in two serial studies.
After radiation therapy or cryotherapy, monitoring is complicated by the presence of viable prostatic epithelium that continues to produce PSA. During the first 1 to 2 years after radiation therapy, a PSA “bounce” phenomenon is observed whereby PSA levels rise or fluctuate significantly. This bounce should not be mistaken for a recurrence of cancer. The most widely accepted definition of biochemical recurrence is based on the American Society for Therapeutic Radiology and Oncology “Phoenix” criteria, defined as the nadir PSA level plus 2.0 μg/L.46
References
Thompson I, Thrasher JB, Aus G, et al; AUA Prostate Cancer Clinical Guideline Update Panel. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol2007; 177:2106–2131.
Brooks DD, Wolf A, Smith RA, Dash C, Guessous I. Prostate cancer screening 2010: updated recommendations from the American Cancer Society. J Natl Med Assoc2010; 102:423–429.
US Preventive Services Task Force. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med2008; 149:185–191.
Okotie OT, Roehl KA, Han M, Loeb S, Gashti SN, Catalona WJ. Characteristics of prostate cancer detected by digital rectal examination only. Urology2007; 70:1117–1120.
Philip J, Dutta Roy S, Ballal M, Foster CS, Javlé P. Is a digital rectal examination necessary in the diagnosis and clinical staging of early prostate cancer?BJU Int2005; 95:969–971.
Thompson IM, Ankerst DP, Chi C, et al. Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst2006; 98:529–534.
Catalona WJ, Partin AW, Slawin KM, et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA1998; 279:1542–1547.
Terris MK, Freiha FS, McNeal JE, Stamey TA. Efficacy of transrectal ultrasound for identification of clinically undetected prostate cancer. J Urol1991; 146:78–83.
Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol2006Mar; 175( 3 Pt1):820–34.
D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA1998; 280:969–974.
Greene FL. American Joint Committee on Cancer. American Cancer Society. AJCC cancer staging manual. 6th ed. New York, NY: Springer-Verlag; 2002.
Stephenson AJ, Kattan MW, Eastham JA, et al. Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. J Clin Oncol2009; 27:4300–4305.
Eastham JA, Scardino PT, Kattan MW. Predicting an optimal outcome after radical prostatectomy: the trifecta nomogram. J Urol2008; 179:2207–2210.
Stephenson AJ, Scardino PT, Eastham JA, et al. Preoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Natl Cancer Inst2006; 98:715–717.
Potters L, Roach M, Davis BJ, et al. Postoperative nomogram predicting the 9-year probability of prostate cancer recurrence after permanent prostate brachytherapy using radiation dose as a prognostic variable. Int J Radiat Oncol Biol Phys2010; 76:1061–1065.
Zelefsky MJ, Kattan MW, Fearn P, et al. Pretreatment nomogram predicting ten-year biochemical outcome of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for prostate cancer. Urology2007; 70:283–287.
Walz J, Gallina A, Saad F, et al. A nomogram predicting 10-year life expectancy in candidates for radical prostatectomy or radiotherapy for prostate cancer. J Clin Oncol2007; 25:3576–3581.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis1987; 40:373–383.
Hall WH, Ramachandran R, Narayan S, Jani AB, Vijayakumar S. An electronic application for rapidly calculating Charlson comorbidity score. BMC Cancer2004; 4:94.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol1982; 5:649–655.
Bill-Axelson A, Holmberg L, Ruutu M, et al; Scandinavian Prostate Cancer Group Study No. 4. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med2005; 352:1977–1984.
Widmark A, Klepp O, Solberg A, et al; Scandinavian Prostate Cancer Group Study 7. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet2009; 373:301–308.
Krakowsky Y, Loblaw A, Klotz L. Prostate cancer death of men treated with initial active surveillance: clinical and biochemical characteristics. J Urol2010; 184:131–135.
Ficarra V, Novara G, Artibani W, et al. Retropubic, laparoscopic, and robot-assisted radical prostatectomy: a systematic review and cumulative analysis of comparative studies. Eur Urol2009; 55:1037–1063.
Hernandez DJ, Nielsen ME, Han M, Partin AW. Contemporary evaluation of the D’amico risk classification of prostate cancer. Urology2007; 70:931–935.
Messing EM, Manola J, Yao J, et al; Eastern Cooperative Oncology Group study EST 3886. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol2006; 7:472–479.
Beyer DC, McKeough T, Thomas T. Impact of short course hormonal therapy on overall and cancer specific survival after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys2005; 61:1299–1305.
Zelefsky MJ, Kuban DA, Levy LB, et al. Multi-institutional analysis of long-term outcome for stages T1-T2 prostate cancer treated with permanent seed implantation. Int J Radiat Oncol Biol Phys2007; 67:327–333.
Gelblum DY, Potters L, Ashley R, Waldbaum R, Wang XH, Leibel S. Urinary morbidity following ultrasound-guided transperineal prostate seed implantation. Int J Radiat Oncol Biol Phys1999; 45:59–67.
Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet2002; 360:103–106.
Aizer AA, Yu JB, Colberg JW, McKeon AM, Decker RH, Peschel RE. Radical prostatectomy vs intensity-modulated radiation therapy in the management of localized prostate adenocarcinoma. Radiother Oncol2009; 93:185–191.
Moon K, Stukenborg GJ, Keim J, Theodorescu D. Cancer incidence after localized therapy for prostate cancer. Cancer2006; 107:991–998.
Terakedis BE, Rossi PJ, Liauw SL, Johnstone PA, Jani AB. A surveillance, epidemiology, and end results registry analysis of prostate cancer modality time trends by age. Am J Clin Oncol2010; 33:619–623.
Lane BR, Stein DE, Remzi FH, Strong SA, Fazio VW, Angermeier KW. Management of radiotherapy induced rectourethral fistula. J Urol2006; 175:1382–1387.
Jones JS, Rewcastle JC, Donnelly BJ, Lugnani FM, Pisters LL, Katz AE. Whole gland primary prostate cryoablation: initial results from the cryo on-line data registry. J Urol2008; 180:554–558.
Hubosky SG, Fabrizio MD, Schellhammer PF, Barone BB, Tepera CM, Given RW. Single center experience with third-generation cryosurgery for management of organ-confined prostate cancer: critical evaluation of short-term outcomes, complications, and patient quality of life. J Endourol2007; 21:1521–1531.
Malcolm JB, Fabrizio MD, Barone BB, et al. Quality of life after open or robotic prostatectomy, cryoablation or brachytherapy for localized prostate cancer. J Urol2010; 183:1822–1828.
Ficarra V, Antoniolli SZ, Novara G, et al. Short-term outcome after high-intensity focused ultrasound in the treatment of patients with high-risk prostate cancer. BJU Int2006; 98:1193–1198.
Challacombe BJ, Murphy DG, Zakri R, Cahill DJ. High-intensity focused ultrasound for localized prostate cancer: initial experience with a 2-year follow-up. BJU Int2009; 104:200–204.
Bouchelouche K, Turkbey B, Choyke P, Capala J. Imaging prostate cancer: an update on positron emission tomography and magnetic resonance imaging. Curr Urol Rep2010; 11:180–190.
Lu-Yao GL, Albertsen PC, Moore DF, et al. Survival following primary androgen deprivation therapy among men with localized prostate cancer. JAMA2008; 300:173–181.
Simmons MN, Stephenson AJ, Klein EA. Natural history of biochemical recurrence after radical prostatectomy: risk assessment for secondary therapy. Eur Urol2007; 51:1175–1184.
Boukaram C, Hannoun-Levi JM. Management of prostate cancer recurrence after definitive radiation therapy. Cancer Treat Rev2010; 36:91–100.
Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA1999; 281:1591–1597.
Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA2005; 294:433–439.
Roach M, Hanks G, Thames H, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys2006; 65:965–974.
References
Thompson I, Thrasher JB, Aus G, et al; AUA Prostate Cancer Clinical Guideline Update Panel. Guideline for the management of clinically localized prostate cancer: 2007 update. J Urol2007; 177:2106–2131.
Brooks DD, Wolf A, Smith RA, Dash C, Guessous I. Prostate cancer screening 2010: updated recommendations from the American Cancer Society. J Natl Med Assoc2010; 102:423–429.
US Preventive Services Task Force. Screening for prostate cancer: US Preventive Services Task Force recommendation statement. Ann Intern Med2008; 149:185–191.
Okotie OT, Roehl KA, Han M, Loeb S, Gashti SN, Catalona WJ. Characteristics of prostate cancer detected by digital rectal examination only. Urology2007; 70:1117–1120.
Philip J, Dutta Roy S, Ballal M, Foster CS, Javlé P. Is a digital rectal examination necessary in the diagnosis and clinical staging of early prostate cancer?BJU Int2005; 95:969–971.
Thompson IM, Ankerst DP, Chi C, et al. Assessing prostate cancer risk: results from the Prostate Cancer Prevention Trial. J Natl Cancer Inst2006; 98:529–534.
Catalona WJ, Partin AW, Slawin KM, et al. Use of the percentage of free prostate-specific antigen to enhance differentiation of prostate cancer from benign prostatic disease: a prospective multicenter clinical trial. JAMA1998; 279:1542–1547.
Terris MK, Freiha FS, McNeal JE, Stamey TA. Efficacy of transrectal ultrasound for identification of clinically undetected prostate cancer. J Urol1991; 146:78–83.
Epstein JI, Herawi M. Prostate needle biopsies containing prostatic intraepithelial neoplasia or atypical foci suspicious for carcinoma: implications for patient care. J Urol2006Mar; 175( 3 Pt1):820–34.
D’Amico AV, Whittington R, Malkowicz SB, et al. Biochemical outcome after radical prostatectomy, external beam radiation therapy, or interstitial radiation therapy for clinically localized prostate cancer. JAMA1998; 280:969–974.
Greene FL. American Joint Committee on Cancer. American Cancer Society. AJCC cancer staging manual. 6th ed. New York, NY: Springer-Verlag; 2002.
Stephenson AJ, Kattan MW, Eastham JA, et al. Prostate cancer-specific mortality after radical prostatectomy for patients treated in the prostate-specific antigen era. J Clin Oncol2009; 27:4300–4305.
Eastham JA, Scardino PT, Kattan MW. Predicting an optimal outcome after radical prostatectomy: the trifecta nomogram. J Urol2008; 179:2207–2210.
Stephenson AJ, Scardino PT, Eastham JA, et al. Preoperative nomogram predicting the 10-year probability of prostate cancer recurrence after radical prostatectomy. J Natl Cancer Inst2006; 98:715–717.
Potters L, Roach M, Davis BJ, et al. Postoperative nomogram predicting the 9-year probability of prostate cancer recurrence after permanent prostate brachytherapy using radiation dose as a prognostic variable. Int J Radiat Oncol Biol Phys2010; 76:1061–1065.
Zelefsky MJ, Kattan MW, Fearn P, et al. Pretreatment nomogram predicting ten-year biochemical outcome of three-dimensional conformal radiotherapy and intensity-modulated radiotherapy for prostate cancer. Urology2007; 70:283–287.
Walz J, Gallina A, Saad F, et al. A nomogram predicting 10-year life expectancy in candidates for radical prostatectomy or radiotherapy for prostate cancer. J Clin Oncol2007; 25:3576–3581.
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis1987; 40:373–383.
Hall WH, Ramachandran R, Narayan S, Jani AB, Vijayakumar S. An electronic application for rapidly calculating Charlson comorbidity score. BMC Cancer2004; 4:94.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol1982; 5:649–655.
Bill-Axelson A, Holmberg L, Ruutu M, et al; Scandinavian Prostate Cancer Group Study No. 4. Radical prostatectomy versus watchful waiting in early prostate cancer. N Engl J Med2005; 352:1977–1984.
Widmark A, Klepp O, Solberg A, et al; Scandinavian Prostate Cancer Group Study 7. Endocrine treatment, with or without radiotherapy, in locally advanced prostate cancer (SPCG-7/SFUO-3): an open randomised phase III trial. Lancet2009; 373:301–308.
Krakowsky Y, Loblaw A, Klotz L. Prostate cancer death of men treated with initial active surveillance: clinical and biochemical characteristics. J Urol2010; 184:131–135.
Ficarra V, Novara G, Artibani W, et al. Retropubic, laparoscopic, and robot-assisted radical prostatectomy: a systematic review and cumulative analysis of comparative studies. Eur Urol2009; 55:1037–1063.
Hernandez DJ, Nielsen ME, Han M, Partin AW. Contemporary evaluation of the D’amico risk classification of prostate cancer. Urology2007; 70:931–935.
Messing EM, Manola J, Yao J, et al; Eastern Cooperative Oncology Group study EST 3886. Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy. Lancet Oncol2006; 7:472–479.
Beyer DC, McKeough T, Thomas T. Impact of short course hormonal therapy on overall and cancer specific survival after permanent prostate brachytherapy. Int J Radiat Oncol Biol Phys2005; 61:1299–1305.
Zelefsky MJ, Kuban DA, Levy LB, et al. Multi-institutional analysis of long-term outcome for stages T1-T2 prostate cancer treated with permanent seed implantation. Int J Radiat Oncol Biol Phys2007; 67:327–333.
Gelblum DY, Potters L, Ashley R, Waldbaum R, Wang XH, Leibel S. Urinary morbidity following ultrasound-guided transperineal prostate seed implantation. Int J Radiat Oncol Biol Phys1999; 45:59–67.
Bolla M, Collette L, Blank L, et al. Long-term results with immediate androgen suppression and external irradiation in patients with locally advanced prostate cancer (an EORTC study): a phase III randomised trial. Lancet2002; 360:103–106.
Aizer AA, Yu JB, Colberg JW, McKeon AM, Decker RH, Peschel RE. Radical prostatectomy vs intensity-modulated radiation therapy in the management of localized prostate adenocarcinoma. Radiother Oncol2009; 93:185–191.
Moon K, Stukenborg GJ, Keim J, Theodorescu D. Cancer incidence after localized therapy for prostate cancer. Cancer2006; 107:991–998.
Terakedis BE, Rossi PJ, Liauw SL, Johnstone PA, Jani AB. A surveillance, epidemiology, and end results registry analysis of prostate cancer modality time trends by age. Am J Clin Oncol2010; 33:619–623.
Lane BR, Stein DE, Remzi FH, Strong SA, Fazio VW, Angermeier KW. Management of radiotherapy induced rectourethral fistula. J Urol2006; 175:1382–1387.
Jones JS, Rewcastle JC, Donnelly BJ, Lugnani FM, Pisters LL, Katz AE. Whole gland primary prostate cryoablation: initial results from the cryo on-line data registry. J Urol2008; 180:554–558.
Hubosky SG, Fabrizio MD, Schellhammer PF, Barone BB, Tepera CM, Given RW. Single center experience with third-generation cryosurgery for management of organ-confined prostate cancer: critical evaluation of short-term outcomes, complications, and patient quality of life. J Endourol2007; 21:1521–1531.
Malcolm JB, Fabrizio MD, Barone BB, et al. Quality of life after open or robotic prostatectomy, cryoablation or brachytherapy for localized prostate cancer. J Urol2010; 183:1822–1828.
Ficarra V, Antoniolli SZ, Novara G, et al. Short-term outcome after high-intensity focused ultrasound in the treatment of patients with high-risk prostate cancer. BJU Int2006; 98:1193–1198.
Challacombe BJ, Murphy DG, Zakri R, Cahill DJ. High-intensity focused ultrasound for localized prostate cancer: initial experience with a 2-year follow-up. BJU Int2009; 104:200–204.
Bouchelouche K, Turkbey B, Choyke P, Capala J. Imaging prostate cancer: an update on positron emission tomography and magnetic resonance imaging. Curr Urol Rep2010; 11:180–190.
Lu-Yao GL, Albertsen PC, Moore DF, et al. Survival following primary androgen deprivation therapy among men with localized prostate cancer. JAMA2008; 300:173–181.
Simmons MN, Stephenson AJ, Klein EA. Natural history of biochemical recurrence after radical prostatectomy: risk assessment for secondary therapy. Eur Urol2007; 51:1175–1184.
Boukaram C, Hannoun-Levi JM. Management of prostate cancer recurrence after definitive radiation therapy. Cancer Treat Rev2010; 36:91–100.
Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA1999; 281:1591–1597.
Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA2005; 294:433–439.
Roach M, Hanks G, Thames H, et al. Defining biochemical failure following radiotherapy with or without hormonal therapy in men with clinically localized prostate cancer: recommendations of the RTOG-ASTRO Phoenix Consensus Conference. Int J Radiat Oncol Biol Phys2006; 65:965–974.
The AUA recommends annual screening with both digital rectal examination (DRE) and prostate-specific antigen (PSA) testing starting at age 40 for all men whose life expectancy is more than 10 years. Guidelines from other organizations differ somewhat.
If the DRE is abnormal or if the PSA level is persistently higher than 2.5 μg/L, then biopsy should be considered.
In low-risk cases, active surveillance may be acceptable in lieu of immediate treatment. Patient education, accurate disease assessment, and compliance with monitoring are critical considerations.
The most common primary treatments are active surveillance, prostatectomy, interstitial brachytherapy, external beam radiotherapy, and cryotherapy. Newer ablative and focal therapies may offer an advantage in select patients. Which treatment to use is highly patient-dependent.
Single-institution, single-surgeon reports and advertisements tend to underestimate rates of impotence after prostatectomy, and as a result patients may have false expectations.
Unfortunately, physicians often tell patients with tinnitus (the perception of noises in the ear, head, or both without an external acoustic source) to simply “learn to live with it.” This type of advice can result in missing the diagnosis of a potentially serious medical condition or, at the very least, in dismissing the patient’s complaints and hence failing to provide any hope of relief—increasing the negative impact on the patient’s quality of life.
The disabling effects of tinnitus resemble those of chronic pain.1 Specifically, its consequences may include:
Loss of sleep
Interference with concentration
Difficulties functioning at work, at home, and in social relationships
Negative emotional reactions, including despair, frustration, depression, and suicidal ideation.2,3
Chronic tinnitus affects 42 million Americans and is considered “clinically significant” in 10 million adults, and the numbers are increasing.4–7
Because primary care physicians may serve as the gatekeepers for tinnitus sufferers, as they do for patients with other chronic health issues, it is important that they understand the underlying mechanisms responsible for tinnitus, its impact, and its management options.
The goal of this article is to provide a basic understanding of tinnitus and its treatment so that physicians can provide hope to its sufferers and know when to initiate appropriate referrals for management.
WHAT CAUSES TINNITUS?
The precise cause of tinnitus is unknown. However, substantial evidence indicates that it is the result of plastic changes in the auditory system that cause auditory neurons to become hyperactive and to fire more synchronously.
If the auditory system is injured, eg, if outer hair cells have been lost because of noise exposure or ototoxicity, then neurons that normally have low levels of activity in silence begin to fire at a higher rate and more synchronously. Therefore, reduced neural activity from the peripheral system (ie, the cochlea) may result in increased spontaneous neural activity in the central auditory nervous system.8
Although most investigators of the neurobiology of tinnitus subscribe to this theory, more than one system must be involved, either simultaneously or interactively, since tinnitus has both auditory and nonauditory components.9
Evidence is accumulating that the perception of tinnitus is multimodal and may arise from complex interactions among different sensory and motor systems.10 For example, some patients with tinnitus can modulate its pitch, loudness, or both by forcefully contracting the muscles in the head, neck, or limbs; by moving the eyes in the horizontal or vertical axis; by placing pressure on myofacial trigger points; by moving the face or mouth; or by applying pressure to the temporomandibular joint.11,12 Although somatic tinnitus modulation is not yet well understood, it may reflect the interaction between the auditory system and other sensory systems.
Because the underlying mechanisms of tinnitus are complex and may involve more than the auditory system, a multidisciplinary approach to management should be considered.
RULING OUT HEALTH-THREATENING DISEASE
The complaint of tinnitus should not be taken lightly. True, it may be just a nuisance the patient can learn to ignore. On the other hand, it may negatively affect the patient’s quality of life. Worst of all, it could be a symptom of a potentially health-threatening disease.
Primary care physicians should know the red flags (Table 1) for otologic diseases such as vestibular schwannoma, Meniere disease, cholesteotoma, glomus jugulare tumor, and temporal bone trauma and, if these are present, refer patients to an otolaryngologist for a complete cochleovestibular examination.
At the same time, the physician should avoid heightening the patient’s preoccupation with the tinnitus by creating unnecessary fear about an underlying cause. This may create further anxiety and exacerbate the patient’s perception of tinnitus and emotional reaction to it.13
WHAT IS THE IMPACT OF TINNITUS ON QUALITY OF LIFE?
Figure 1.Exploring the impact of tinnitus on the patient’s quality of life is important to determine the course of action.
A quick method is simply to ask, “How much of a problem is your tinnitus?” If the patient considers it a small problem, minimum counseling may suffice (Figure 1). But if the response suggests a greater impact, an in-depth history should be taken (Table 2) to determine the appropriate treatment plan.
Another approach to exploring the impact on quality of life is to ask the patient to list difficulties associated with the tinnitus.3
Still another option is to use a standardized screening tool. The Tinnitus Handicap Inventory-Screening Version (THI-S)14 consists of 10 questions that screen for the psychosocial consequences of tinnitus (Table 3). For each question, the patient answers “yes” (worth 4 points), “sometimes” (2 points), or “no” (0 points). The possible total score thus ranges from 0 to 40 points; the higher the score, the greater the perceived disability (activity limitation) and handicap (participation restriction). A score of more than 6 points indicates a need for an in-depth evaluation (Table 2). Having the patient complete this tool in the waiting room can save precious time and help identify those in need of referral.
SOME PATIENTS MAY NEED TO SEE ONE OR MORE SPECIALISTS
Many patients can manage their tinnitus successfully after receiving reassurance and some simple suggestions about how to manage it at home and at work. Helpful techniques can be listed in an information sheet, such as the one that follows this paper, to give to patients.
Patients whose tinnitus is distressing may need referral. Traditionally, the primary care physician refers the patient to an otolaryngologist. However, the complex nature and etiology of tinnitus may necessitate referring the patient to one or more specialists in addition to an otolaryngologist for further assessment and management. The following sections briefly describe what other specialists offer.
AUDIOLOGY: TESTING, SOUND THERAPY
A patient referred to an audiologist may undergo traditional audiologic testing (pure tone and speech thresholds, word recognition), as well as a battery of special psychoacoustic tests. This includes pitch-matching and loudness-matching, evaluation of residual inhibition (suppression of tinnitus after an external masking stimulus has been turned off), and assessing the minimum masking level. These provide a quantitative estimate of the acoustic attributes of the perceived tinnitus. Questionnaires can be used to assess the impact of tinnitus on everyday life and can provide guidance for treatment.15
Real sounds mask the perceived ones
As treatment, audiologists offer ongoing counseling, encouragement, education, and sound therapy, ie, relieving the tinnitus by maintaining a low level of background noise. Several advantages and benefits have been attributed to sound therapy (Table 4). A variety of devices can be used.15
Environmental enrichment devices such as portable machines that generate pleasant sounds (eg, rain, waterfalls, ocean waves), tabletop water fountains, fans, or even televisions or radios can be used to promote relief, provide distraction, and decrease the patient’s awareness of tinnitus.
Hearing aids amplify ambient sounds, reducing the perception of tinnitus.16,17 They also improve communication.
Sound generators, worn in the ear, produce a stable broadband signal (“white noise”). These devices may be used by patients who have normal or near-normal hearing sensitivity and therefore neither benefit from nor require amplification.
Combination instruments are both hearing aids and white-noise generators. These allow patients who have both hearing loss and tinnitus to use a single device.
Music can distract from the tinnitus and help patients relax. Patients may find benefit listening to their preferred music on a personal listening device such as an MP3 or CD player.
Neuromonics Inc. (Bethlehem, PA) makes a sophisticated device for tinnitus treatment. Resembling an MP3 player, it is used with headphones and plays soothing music (baroque or new age) that contains a tinnitus-masking noise. The music is modified to compensate for the patient’s hearing loss, if present. After approximately 2 months of use, the embedded noise is removed to help desensitize the patient to the tinnitus. Results of small trials have been promising.18,19
DENTISTRY: TREATING TINNITUS BY TREATING TMD
Temporomandibular disorder (TMD), involving the temporomandibular joints, the muscles of mastication, and the teeth, is associated with tinnitus.20,21 The prevalence of tinnitus in a Cleveland Clinic study of 109 patients with TMD was 36%.22
There is also an association between cervical muscle disorders and masticatory muscle function. For example, patients who grind their teeth at night must contract the sternocleidomastoid muscles of the neck to stabilize the head during grinding. Correcting cervical posture, changing the sleep position, and controlling conscious parafunctional habits (eg, clenching the teeth, grinding the teeth together) can decrease many of the symptoms of TMD.
The dental examination for tinnitus patients
The dentist looks for a history of TMD symptoms, use of orthotic devices, and head and neck trauma, and performs a clinical examination.
The clinical examination includes mandibular range of motion, auscultation and palpation of the temporomandibular joints, palpation of masticatory and cervical muscles, and cervical range of motion. The intraoral examination includes identifying occlusal attrition patterns, “load testing” of the temporomandibular joints, and identifying premature tooth contacts. Additionally, attempts to restrict jaw opening and lateral movements may modulate the patient’s tinnitus, thus confirming the role of TMD in the patient’s tinnitus.
How tinnitus is treated by managing TMD
Tinnitus can be treated by managing TMD, specifically through the use of dental orthotics (splints, nightguards) to improve abnormal jaw mechanics and tracking.23–25
Tullberg and Ernberg26 treated patients with TMD and tinnitus using a variety of methods, including occlusal splinting, jaw muscle exercises, and relaxation. They reported that 43% of the patients experienced an improvement in their tinnitus after these interventions.
A home exercise program may help patients maintain muscle strength and harmony. Self-help therapies provide patients with a protocol to recognize daytime parafunctional habits and provide suggestions to decrease clenching and other overloading of the masticatory system.
In addition, management of TMD-related tinnitus often involves physical therapy, which can include soft-tissue mobilization, deep heat, ultrasound, low-current electrical stimulation, myofascial trigger-point release techniques, and posture retraining. Occlusal correction procedures (bite correction) can often provide long-term stability to the masticatory system.
NEUROLOGY: LOOKING FOR AN UNDERLYING CONDITION
The comprehensive neurologic evaluation of the tinnitus patient should include a thorough neurologic history, review of systems, examination, and appropriate imaging. The aim is to identify accompanying symptoms or disorders that may help to localize and ultimately diagnose the underlying condition.
Related disorders could manifest with vestibular symptoms (dizziness, imbalance), various pain syndromes including facial pain and headache (tension or migraine),27 or other cranial nerve disorders such as Bell palsy (facial nerve injury)28 or trigeminal neuralgia.
Medical and surgical interventions for tinnitus-associated neurologic conditions
In cases in which there is a treatable underlying neurologic condition, tinnitus-focused interventions should be deferred until treatment has been completed or discontinued.
At that point, other options including various oral medications (eg, antiarrhythmics, anticonvulsants, benzodiazepines, and antidepressants) and anesthetic blocks (eg, intravenous anesthetic-plus-steroid injections)29 may be considered on a case-by-case basis. Results of randomized clinical trials of the aforementioned drugs have not been promising30; however, drugs that affect the emotional status of the patient by reducing anxiety, depression, and sleep disturbance have been shown to be beneficial.31,32
In addition, some experimental surgical treatments (eg, deep brain stimulation, dural grid stimulation)33,34 are being evaluated and show potential for managing tinnitus.
PHYSICAL THERAPY
A preliminary physical therapy evaluation can identify biomechanical problems of the head, neck, and jaw that can contribute to tinnitus.
Subsequent therapy is designed to restore proper cervical and temporomandibular biomechanics and to educate the patient on proper posture, ergonomics, and exercise techniques that together could help minimize these abnormalities and reduce the severity of tinnitus in some patients.11,24–26,35
PSYCHOLOGY: ADDRESSING DEPRESSION, ANXIETY
Tinnitus exacts an emotional toll on its sufferers. Some estimates suggest that 40% to 50% of tinnitus patients experience significant perceived handicap and psychological distress.36 Consequently, many patients respond to the onset of tinnitus with anxiety or depression, or both. Owing to these responses, the chronicity of the condition, and the patient’s perception that tinnitus is uncontrollable, tinnitus can produce notable distress and impairment in quality of life.
When a patient’s responses include both depression and anxiety, the reduction in quality of life and impairment in coping capacities can be significant.37 Sleep problems, poor concentration, social withdrawal, feelings of helplessness, avoidance behaviors, and upset in interpersonal relationships are common signs that quality of life is compromised.
One of the greatest challenges for the primary care physician when treating tinnitus patients is attending to their emotional suffering and disability. Simple screening tools can be useful in quickly assessing a patient’s emotional response to tinnitus and in helping to enter into a conversation with the patient about this topic. These tools include:
The THI-S (Table 3)14
The Patient Health Questionnaire-9 (PHQ-9)38
The Generalized Anxiety Disorder-7 (GAD-7).39
Suicidal ideas need to be addressed
The final question on the PHQ-9 asks about suicidal ideation. This cannot be overlooked when assessing patients with tinnitus. The questionnaire invites the patient to communicate this rather painful topic to the physician in a direct matter.
The physician should be prepared to address suicidal ideas, plans, means, intentions, and safety measures with the patient. This requires that the physician be comfortable conducting these conversations in a direct and forthright manner; it also requires that the physician have reliable referrals to qualified mental health practitioners at the ready to assist the distressed tinnitus patient.
Asking a patient to commit to calling 911 or going to the nearest emergency room if he or she has any impulse toward self-harm is a simple option that many distressed patients may have never considered.
Treatments for depression and anxiety in tinnitus patients
Some patients may already have been seeing a mental health professional before the onset of tinnitus and may elect to discuss treatment with their current provider. However, many need guidance in selecting appropriate treatment. Their options may include:
Psychotropic drugs such as selective serotonin reuptake inhibitors and benzodiazepines, to provide quick relief from debilitating depression and anxiety.
Cognitive behavioral therapy, designed to provide a more active and durable adjustment to tinnitus. It is the most widely validated psychotherapeutic treatment approach to tinnitus.40
Acceptance and commitment therapy, which emphasizes strategies for acceptance, mindfulness, and cognitive defusion (the process of separating thoughts from emotions that have become fused together). There is some preliminary evidence that it also may be effective in reducing the distress of tinnitus sufferers, as well as those with other chronic medical conditions.41Table 5 contains a sample of the approaches used in cognitive behavioral therapy and acceptance and commitment therapy for tinnitus.
References
Møller AR. The role of neural plasticity in tinnitus. Prog Brain Res2007; 166:37–45.
Dobie RA. Overview: suffering from tinnitus. In:Snow JB, ed. Tinnitus: Theory and Management. Hamilton, Ontario: BC Decker; 2004:1–7.
Henry JA, Dennis KC, Schechter MA. General review of tinnitus: prevalence, mechanisms, effects, and management. J Speech Lang Hear Res2005; 48:1204–1235.
Hoffman HJ, Reed GW. Epidemiology of tinnitus. In:Snow JB, editor. Tinnitus: Theory and Management. Hamilton, Ontario: BC Decker; 2004:16–41.
Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in U.S. Soldiers returning from Iraq. N Engl J Med2008; 358:453–63.
Rauschecker JP, Leaver AM, Mühlau M. Tuning out the noise: limbicauditory interactions in tinnitus. Neuron2010; 66:819–826.
Kaltenbach JA, Zhang J, Finlayson P. Tinnitus as a plastic phenomenon and its possible neural underpinnings in the dorsal cochlear nucleus. Hear Res2005; 206:200–226.
Georgiewa P, Klapp BF, Fischer F, et al. An integrative model of developing tinnitus based on recent neurobiological findings. Med Hypotheses2006; 66:592–600.
Cacace AT. Expanding the biological basis of tinnitus: crossmodal origins and the role of neuroplasticity. Hear Res2003; 175:112–132.
Levine RA. Somatic tinnitus. In:Snow JB, editor. Tinnitus: Theory and Management. Hamilton, Ontario: BC Decker; 2004:108–124.
Sanchez TG, Kii MA. Modulating tinnitus with visual, muscular, and tactile stimulation. Semin Hear2008; 29:350–360.
Schleuning AL, Shi BY, Martin WH. Tinnitus. In:Bailey BJ, Johnson JT, Newlands SD, et al, editors. Head and Neck Surgery—Otolarygnology. 4th ed, vol 2. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:2237–2246.
Newman CW, Sandridge SA, Bolek L. Development and psychometric adequacy of the screening version of the Tinnitus Handicap Inventory. Otol Neurotol2008; 29:276–281.
Kochkin S, Tyler R. Tinnitus treatment and the effectiveness of hearing aids: hearing care professional perceptions. Hearing Review2008; 15:14–18.
Sheldrake JB, Jasterboff MM. Role of hearing aids in management of tinnitus. In:Snow JB, editor. Tinnitus: Theory and Management. Hamilton, Ontario: BC Decker; 2004:310–313.
Davis PB, Paki B, Hanley PJ. Neuromonics Tinnitus Treatment: third clinical trial. Ear Hear2007; 28:242–259.
Davis PB, Wilde RA, Steed LG, Hanley PJ. Treatment of tinnitus with a customized acoustic neural stimulus: a controlled clinical study. Ear Nose Throat J2008; 87:330–339.
Lam DK, Lawrence HP, Tenenbaum HC. Aural symptoms in temporomandibular disorder patients attending a craniofacial pain unit. J Orofac Pain2001; 15:146–157.
Steigerwald DP, Verne SV, Young D. A retrospective evaluation of the impact of temporomandibular joint arthroscopy on the symptoms of headache, neck pain, shoulder pain, dizziness, and tinnitus. Cranio1996; 14:46–54.
Kahn K. Multidisciplinary strategies for managing patients with tinnitus. Poster presented at the American Equilibration Society, Chicago, IL, February 24–25, 2010.
Morgan DH. Tinnitus caused by a temporomandibular disorder. In:Reich GE, Vernon JA, editors. Proceedings of the Fifth International Tinnitus Seminar. Portland, Oregon: American Tinnitus Association; 1996:653–654.
Wright EF, Bifano SL. Tinnitus improvement through TMD therapy. J Am Dent Assoc1997; 128:1424–1432.
Latifpour DH, Grenner J, Sjödahl C. The effect of a new treatment based on somatosensory stimulation in a group of patients with somatically related tinnitus. Int Tinnitus J2009; 15:94–99.
Tullberg M, Ernberg M. Long-term effect on tinnitus by treatment of temporomandibular disorders: a two-year follow-up by questionnaire. Acta Odontol Scand2006; 64:89–96.
Volcy M, Sheftell FD, Tepper SJ, Rapoport AM, Bigal ME. Tinnitus in migraine: an allodynic symptom secondary to abnormal cortical functioning?Headache2005; 45:1083–1087.
Yamamoto E, Nishimura H, Hirono Y. Occurrence of sequelae in Bell’s palsy. Acta Otolaryngol Suppl1988; 446:93–96.
Duckert LG, Rees TS. Treatment of tinnitus with intravenous lidocaine: a double-blind randomized trial. Otolaryngol Head Neck Surg1983; 91:550–555.
Dobie RA. Clinical trials and drug therapy for tinnitus. In:Snow JB, editor. Tinnitus: Theory and Management. Hamilton, Ontario: BC Decker; 2004:266–277.
Johnson RM, Brummett R, Schleuning A. Use of alprazolam for relief of tinnitus. A double-blind study. Arch Otolaryngol Head Neck Surg1993; 119:842–845.
Brummett R. Drugs for and against tinnitus. The Hearing Journal1989; 42:34–37.
Cheung SW, Larson PS. Tinnitus modulation by deep brain stimulation in locus of caudate neurons (area LC). Neuroscience2010; 169:1768–1778.
Friedland DR, Gaggl W, Runge-Samuelson C, Ulmer JL, Kopell BH. Feasibility of auditory cortical stimulation for the treatment of tinnitus. Otol Neurotol2007; 28:1005–1012.
Simmons R, Dambra C, Lobarinas E, Stocking C, Salvi R. Head, neck, and eye movements that modulate tinnitus. Semin Hear2008; 29:361–370.
Bauch CD, Lynn SG, Williams DE, Mellon MW, Weaver AL. Tinnitus impact: three different measurement tools. J Am Acad Audiol2003; 14:181–187.
Bartels H, Middel BL, van der Laan BF, Staal MJ, Albers FW. The additive effect of co-occurring anxiety and depression on health status, quality of life and coping strategies in help-seeking tinnitus sufferers. Ear Hear2008; 29:947–956.
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med2001; 16:606–613.
Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med2006; 166:1092–1097.
Andersson G. Psychological aspects of tinnitus and the application of cognitive-behavioral therapy. Clin Psychol Rev2002; 22:977–990.
Hesser H, Westin V, Hayes SC, Andersson G. Clients’ in-session acceptance and cognitive defusion behaviors in acceptance-based treatment of tinnitus distress. Behav Res Ther2009; 47:523–528.
Craig W. Newman, PhD Head, Section of Audiology, Head and Neck Institute, Cleveland Clinic; Professor, Department of Surgery, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
Sharon A. Sandridge, PhD Director, Clinical Audiology Services, Section of Audiology, Head and Neck Institute, Cleveland Clinic
Scott M. Bea, PsyD Department of Psychiatry and Psychology, Neurological Institute, Cleveland Clinic; Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
Kay Cherian, PT, MPT, Cert MDT Rehabilitation and Sports Therapy, Neurological Institute, Cleveland Clinic
Neil Cherian, MD Neurological Center for Pain, Neurological Institute, Cleveland Clinic
Karyn M. Kahn, DDS Section of Dentistry, Head and Neck Institute, Cleveland Clinic; Assistant Professor, Case Western Reserve School of Dental Medicine
James Kaltenbach, PhD Director, Otology Research, Department of Neurosciences, Head and Neck Institute and Lerner Research Institute, Cleveland Clinic
Address: Craig W. Newman, PhD, Section of Audiology, A71, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]
Craig W. Newman, PhD Head, Section of Audiology, Head and Neck Institute, Cleveland Clinic; Professor, Department of Surgery, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
Sharon A. Sandridge, PhD Director, Clinical Audiology Services, Section of Audiology, Head and Neck Institute, Cleveland Clinic
Scott M. Bea, PsyD Department of Psychiatry and Psychology, Neurological Institute, Cleveland Clinic; Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
Kay Cherian, PT, MPT, Cert MDT Rehabilitation and Sports Therapy, Neurological Institute, Cleveland Clinic
Neil Cherian, MD Neurological Center for Pain, Neurological Institute, Cleveland Clinic
Karyn M. Kahn, DDS Section of Dentistry, Head and Neck Institute, Cleveland Clinic; Assistant Professor, Case Western Reserve School of Dental Medicine
James Kaltenbach, PhD Director, Otology Research, Department of Neurosciences, Head and Neck Institute and Lerner Research Institute, Cleveland Clinic
Address: Craig W. Newman, PhD, Section of Audiology, A71, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]
Author and Disclosure Information
Craig W. Newman, PhD Head, Section of Audiology, Head and Neck Institute, Cleveland Clinic; Professor, Department of Surgery, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
Sharon A. Sandridge, PhD Director, Clinical Audiology Services, Section of Audiology, Head and Neck Institute, Cleveland Clinic
Scott M. Bea, PsyD Department of Psychiatry and Psychology, Neurological Institute, Cleveland Clinic; Assistant Professor of Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University
Kay Cherian, PT, MPT, Cert MDT Rehabilitation and Sports Therapy, Neurological Institute, Cleveland Clinic
Neil Cherian, MD Neurological Center for Pain, Neurological Institute, Cleveland Clinic
Karyn M. Kahn, DDS Section of Dentistry, Head and Neck Institute, Cleveland Clinic; Assistant Professor, Case Western Reserve School of Dental Medicine
James Kaltenbach, PhD Director, Otology Research, Department of Neurosciences, Head and Neck Institute and Lerner Research Institute, Cleveland Clinic
Address: Craig W. Newman, PhD, Section of Audiology, A71, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; e-mail [email protected]
Unfortunately, physicians often tell patients with tinnitus (the perception of noises in the ear, head, or both without an external acoustic source) to simply “learn to live with it.” This type of advice can result in missing the diagnosis of a potentially serious medical condition or, at the very least, in dismissing the patient’s complaints and hence failing to provide any hope of relief—increasing the negative impact on the patient’s quality of life.
The disabling effects of tinnitus resemble those of chronic pain.1 Specifically, its consequences may include:
Loss of sleep
Interference with concentration
Difficulties functioning at work, at home, and in social relationships
Negative emotional reactions, including despair, frustration, depression, and suicidal ideation.2,3
Chronic tinnitus affects 42 million Americans and is considered “clinically significant” in 10 million adults, and the numbers are increasing.4–7
Because primary care physicians may serve as the gatekeepers for tinnitus sufferers, as they do for patients with other chronic health issues, it is important that they understand the underlying mechanisms responsible for tinnitus, its impact, and its management options.
The goal of this article is to provide a basic understanding of tinnitus and its treatment so that physicians can provide hope to its sufferers and know when to initiate appropriate referrals for management.
WHAT CAUSES TINNITUS?
The precise cause of tinnitus is unknown. However, substantial evidence indicates that it is the result of plastic changes in the auditory system that cause auditory neurons to become hyperactive and to fire more synchronously.
If the auditory system is injured, eg, if outer hair cells have been lost because of noise exposure or ototoxicity, then neurons that normally have low levels of activity in silence begin to fire at a higher rate and more synchronously. Therefore, reduced neural activity from the peripheral system (ie, the cochlea) may result in increased spontaneous neural activity in the central auditory nervous system.8
Although most investigators of the neurobiology of tinnitus subscribe to this theory, more than one system must be involved, either simultaneously or interactively, since tinnitus has both auditory and nonauditory components.9
Evidence is accumulating that the perception of tinnitus is multimodal and may arise from complex interactions among different sensory and motor systems.10 For example, some patients with tinnitus can modulate its pitch, loudness, or both by forcefully contracting the muscles in the head, neck, or limbs; by moving the eyes in the horizontal or vertical axis; by placing pressure on myofacial trigger points; by moving the face or mouth; or by applying pressure to the temporomandibular joint.11,12 Although somatic tinnitus modulation is not yet well understood, it may reflect the interaction between the auditory system and other sensory systems.
Because the underlying mechanisms of tinnitus are complex and may involve more than the auditory system, a multidisciplinary approach to management should be considered.
RULING OUT HEALTH-THREATENING DISEASE
The complaint of tinnitus should not be taken lightly. True, it may be just a nuisance the patient can learn to ignore. On the other hand, it may negatively affect the patient’s quality of life. Worst of all, it could be a symptom of a potentially health-threatening disease.
Primary care physicians should know the red flags (Table 1) for otologic diseases such as vestibular schwannoma, Meniere disease, cholesteotoma, glomus jugulare tumor, and temporal bone trauma and, if these are present, refer patients to an otolaryngologist for a complete cochleovestibular examination.
At the same time, the physician should avoid heightening the patient’s preoccupation with the tinnitus by creating unnecessary fear about an underlying cause. This may create further anxiety and exacerbate the patient’s perception of tinnitus and emotional reaction to it.13
WHAT IS THE IMPACT OF TINNITUS ON QUALITY OF LIFE?
Figure 1.Exploring the impact of tinnitus on the patient’s quality of life is important to determine the course of action.
A quick method is simply to ask, “How much of a problem is your tinnitus?” If the patient considers it a small problem, minimum counseling may suffice (Figure 1). But if the response suggests a greater impact, an in-depth history should be taken (Table 2) to determine the appropriate treatment plan.
Another approach to exploring the impact on quality of life is to ask the patient to list difficulties associated with the tinnitus.3
Still another option is to use a standardized screening tool. The Tinnitus Handicap Inventory-Screening Version (THI-S)14 consists of 10 questions that screen for the psychosocial consequences of tinnitus (Table 3). For each question, the patient answers “yes” (worth 4 points), “sometimes” (2 points), or “no” (0 points). The possible total score thus ranges from 0 to 40 points; the higher the score, the greater the perceived disability (activity limitation) and handicap (participation restriction). A score of more than 6 points indicates a need for an in-depth evaluation (Table 2). Having the patient complete this tool in the waiting room can save precious time and help identify those in need of referral.
SOME PATIENTS MAY NEED TO SEE ONE OR MORE SPECIALISTS
Many patients can manage their tinnitus successfully after receiving reassurance and some simple suggestions about how to manage it at home and at work. Helpful techniques can be listed in an information sheet, such as the one that follows this paper, to give to patients.
Patients whose tinnitus is distressing may need referral. Traditionally, the primary care physician refers the patient to an otolaryngologist. However, the complex nature and etiology of tinnitus may necessitate referring the patient to one or more specialists in addition to an otolaryngologist for further assessment and management. The following sections briefly describe what other specialists offer.
AUDIOLOGY: TESTING, SOUND THERAPY
A patient referred to an audiologist may undergo traditional audiologic testing (pure tone and speech thresholds, word recognition), as well as a battery of special psychoacoustic tests. This includes pitch-matching and loudness-matching, evaluation of residual inhibition (suppression of tinnitus after an external masking stimulus has been turned off), and assessing the minimum masking level. These provide a quantitative estimate of the acoustic attributes of the perceived tinnitus. Questionnaires can be used to assess the impact of tinnitus on everyday life and can provide guidance for treatment.15
Real sounds mask the perceived ones
As treatment, audiologists offer ongoing counseling, encouragement, education, and sound therapy, ie, relieving the tinnitus by maintaining a low level of background noise. Several advantages and benefits have been attributed to sound therapy (Table 4). A variety of devices can be used.15
Environmental enrichment devices such as portable machines that generate pleasant sounds (eg, rain, waterfalls, ocean waves), tabletop water fountains, fans, or even televisions or radios can be used to promote relief, provide distraction, and decrease the patient’s awareness of tinnitus.
Hearing aids amplify ambient sounds, reducing the perception of tinnitus.16,17 They also improve communication.
Sound generators, worn in the ear, produce a stable broadband signal (“white noise”). These devices may be used by patients who have normal or near-normal hearing sensitivity and therefore neither benefit from nor require amplification.
Combination instruments are both hearing aids and white-noise generators. These allow patients who have both hearing loss and tinnitus to use a single device.
Music can distract from the tinnitus and help patients relax. Patients may find benefit listening to their preferred music on a personal listening device such as an MP3 or CD player.
Neuromonics Inc. (Bethlehem, PA) makes a sophisticated device for tinnitus treatment. Resembling an MP3 player, it is used with headphones and plays soothing music (baroque or new age) that contains a tinnitus-masking noise. The music is modified to compensate for the patient’s hearing loss, if present. After approximately 2 months of use, the embedded noise is removed to help desensitize the patient to the tinnitus. Results of small trials have been promising.18,19
DENTISTRY: TREATING TINNITUS BY TREATING TMD
Temporomandibular disorder (TMD), involving the temporomandibular joints, the muscles of mastication, and the teeth, is associated with tinnitus.20,21 The prevalence of tinnitus in a Cleveland Clinic study of 109 patients with TMD was 36%.22
There is also an association between cervical muscle disorders and masticatory muscle function. For example, patients who grind their teeth at night must contract the sternocleidomastoid muscles of the neck to stabilize the head during grinding. Correcting cervical posture, changing the sleep position, and controlling conscious parafunctional habits (eg, clenching the teeth, grinding the teeth together) can decrease many of the symptoms of TMD.
The dental examination for tinnitus patients
The dentist looks for a history of TMD symptoms, use of orthotic devices, and head and neck trauma, and performs a clinical examination.
The clinical examination includes mandibular range of motion, auscultation and palpation of the temporomandibular joints, palpation of masticatory and cervical muscles, and cervical range of motion. The intraoral examination includes identifying occlusal attrition patterns, “load testing” of the temporomandibular joints, and identifying premature tooth contacts. Additionally, attempts to restrict jaw opening and lateral movements may modulate the patient’s tinnitus, thus confirming the role of TMD in the patient’s tinnitus.
How tinnitus is treated by managing TMD
Tinnitus can be treated by managing TMD, specifically through the use of dental orthotics (splints, nightguards) to improve abnormal jaw mechanics and tracking.23–25
Tullberg and Ernberg26 treated patients with TMD and tinnitus using a variety of methods, including occlusal splinting, jaw muscle exercises, and relaxation. They reported that 43% of the patients experienced an improvement in their tinnitus after these interventions.
A home exercise program may help patients maintain muscle strength and harmony. Self-help therapies provide patients with a protocol to recognize daytime parafunctional habits and provide suggestions to decrease clenching and other overloading of the masticatory system.
In addition, management of TMD-related tinnitus often involves physical therapy, which can include soft-tissue mobilization, deep heat, ultrasound, low-current electrical stimulation, myofascial trigger-point release techniques, and posture retraining. Occlusal correction procedures (bite correction) can often provide long-term stability to the masticatory system.
NEUROLOGY: LOOKING FOR AN UNDERLYING CONDITION
The comprehensive neurologic evaluation of the tinnitus patient should include a thorough neurologic history, review of systems, examination, and appropriate imaging. The aim is to identify accompanying symptoms or disorders that may help to localize and ultimately diagnose the underlying condition.
Related disorders could manifest with vestibular symptoms (dizziness, imbalance), various pain syndromes including facial pain and headache (tension or migraine),27 or other cranial nerve disorders such as Bell palsy (facial nerve injury)28 or trigeminal neuralgia.
Medical and surgical interventions for tinnitus-associated neurologic conditions
In cases in which there is a treatable underlying neurologic condition, tinnitus-focused interventions should be deferred until treatment has been completed or discontinued.
At that point, other options including various oral medications (eg, antiarrhythmics, anticonvulsants, benzodiazepines, and antidepressants) and anesthetic blocks (eg, intravenous anesthetic-plus-steroid injections)29 may be considered on a case-by-case basis. Results of randomized clinical trials of the aforementioned drugs have not been promising30; however, drugs that affect the emotional status of the patient by reducing anxiety, depression, and sleep disturbance have been shown to be beneficial.31,32
In addition, some experimental surgical treatments (eg, deep brain stimulation, dural grid stimulation)33,34 are being evaluated and show potential for managing tinnitus.
PHYSICAL THERAPY
A preliminary physical therapy evaluation can identify biomechanical problems of the head, neck, and jaw that can contribute to tinnitus.
Subsequent therapy is designed to restore proper cervical and temporomandibular biomechanics and to educate the patient on proper posture, ergonomics, and exercise techniques that together could help minimize these abnormalities and reduce the severity of tinnitus in some patients.11,24–26,35
PSYCHOLOGY: ADDRESSING DEPRESSION, ANXIETY
Tinnitus exacts an emotional toll on its sufferers. Some estimates suggest that 40% to 50% of tinnitus patients experience significant perceived handicap and psychological distress.36 Consequently, many patients respond to the onset of tinnitus with anxiety or depression, or both. Owing to these responses, the chronicity of the condition, and the patient’s perception that tinnitus is uncontrollable, tinnitus can produce notable distress and impairment in quality of life.
When a patient’s responses include both depression and anxiety, the reduction in quality of life and impairment in coping capacities can be significant.37 Sleep problems, poor concentration, social withdrawal, feelings of helplessness, avoidance behaviors, and upset in interpersonal relationships are common signs that quality of life is compromised.
One of the greatest challenges for the primary care physician when treating tinnitus patients is attending to their emotional suffering and disability. Simple screening tools can be useful in quickly assessing a patient’s emotional response to tinnitus and in helping to enter into a conversation with the patient about this topic. These tools include:
The THI-S (Table 3)14
The Patient Health Questionnaire-9 (PHQ-9)38
The Generalized Anxiety Disorder-7 (GAD-7).39
Suicidal ideas need to be addressed
The final question on the PHQ-9 asks about suicidal ideation. This cannot be overlooked when assessing patients with tinnitus. The questionnaire invites the patient to communicate this rather painful topic to the physician in a direct matter.
The physician should be prepared to address suicidal ideas, plans, means, intentions, and safety measures with the patient. This requires that the physician be comfortable conducting these conversations in a direct and forthright manner; it also requires that the physician have reliable referrals to qualified mental health practitioners at the ready to assist the distressed tinnitus patient.
Asking a patient to commit to calling 911 or going to the nearest emergency room if he or she has any impulse toward self-harm is a simple option that many distressed patients may have never considered.
Treatments for depression and anxiety in tinnitus patients
Some patients may already have been seeing a mental health professional before the onset of tinnitus and may elect to discuss treatment with their current provider. However, many need guidance in selecting appropriate treatment. Their options may include:
Psychotropic drugs such as selective serotonin reuptake inhibitors and benzodiazepines, to provide quick relief from debilitating depression and anxiety.
Cognitive behavioral therapy, designed to provide a more active and durable adjustment to tinnitus. It is the most widely validated psychotherapeutic treatment approach to tinnitus.40
Acceptance and commitment therapy, which emphasizes strategies for acceptance, mindfulness, and cognitive defusion (the process of separating thoughts from emotions that have become fused together). There is some preliminary evidence that it also may be effective in reducing the distress of tinnitus sufferers, as well as those with other chronic medical conditions.41Table 5 contains a sample of the approaches used in cognitive behavioral therapy and acceptance and commitment therapy for tinnitus.
Unfortunately, physicians often tell patients with tinnitus (the perception of noises in the ear, head, or both without an external acoustic source) to simply “learn to live with it.” This type of advice can result in missing the diagnosis of a potentially serious medical condition or, at the very least, in dismissing the patient’s complaints and hence failing to provide any hope of relief—increasing the negative impact on the patient’s quality of life.
The disabling effects of tinnitus resemble those of chronic pain.1 Specifically, its consequences may include:
Loss of sleep
Interference with concentration
Difficulties functioning at work, at home, and in social relationships
Negative emotional reactions, including despair, frustration, depression, and suicidal ideation.2,3
Chronic tinnitus affects 42 million Americans and is considered “clinically significant” in 10 million adults, and the numbers are increasing.4–7
Because primary care physicians may serve as the gatekeepers for tinnitus sufferers, as they do for patients with other chronic health issues, it is important that they understand the underlying mechanisms responsible for tinnitus, its impact, and its management options.
The goal of this article is to provide a basic understanding of tinnitus and its treatment so that physicians can provide hope to its sufferers and know when to initiate appropriate referrals for management.
WHAT CAUSES TINNITUS?
The precise cause of tinnitus is unknown. However, substantial evidence indicates that it is the result of plastic changes in the auditory system that cause auditory neurons to become hyperactive and to fire more synchronously.
If the auditory system is injured, eg, if outer hair cells have been lost because of noise exposure or ototoxicity, then neurons that normally have low levels of activity in silence begin to fire at a higher rate and more synchronously. Therefore, reduced neural activity from the peripheral system (ie, the cochlea) may result in increased spontaneous neural activity in the central auditory nervous system.8
Although most investigators of the neurobiology of tinnitus subscribe to this theory, more than one system must be involved, either simultaneously or interactively, since tinnitus has both auditory and nonauditory components.9
Evidence is accumulating that the perception of tinnitus is multimodal and may arise from complex interactions among different sensory and motor systems.10 For example, some patients with tinnitus can modulate its pitch, loudness, or both by forcefully contracting the muscles in the head, neck, or limbs; by moving the eyes in the horizontal or vertical axis; by placing pressure on myofacial trigger points; by moving the face or mouth; or by applying pressure to the temporomandibular joint.11,12 Although somatic tinnitus modulation is not yet well understood, it may reflect the interaction between the auditory system and other sensory systems.
Because the underlying mechanisms of tinnitus are complex and may involve more than the auditory system, a multidisciplinary approach to management should be considered.
RULING OUT HEALTH-THREATENING DISEASE
The complaint of tinnitus should not be taken lightly. True, it may be just a nuisance the patient can learn to ignore. On the other hand, it may negatively affect the patient’s quality of life. Worst of all, it could be a symptom of a potentially health-threatening disease.
Primary care physicians should know the red flags (Table 1) for otologic diseases such as vestibular schwannoma, Meniere disease, cholesteotoma, glomus jugulare tumor, and temporal bone trauma and, if these are present, refer patients to an otolaryngologist for a complete cochleovestibular examination.
At the same time, the physician should avoid heightening the patient’s preoccupation with the tinnitus by creating unnecessary fear about an underlying cause. This may create further anxiety and exacerbate the patient’s perception of tinnitus and emotional reaction to it.13
WHAT IS THE IMPACT OF TINNITUS ON QUALITY OF LIFE?
Figure 1.Exploring the impact of tinnitus on the patient’s quality of life is important to determine the course of action.
A quick method is simply to ask, “How much of a problem is your tinnitus?” If the patient considers it a small problem, minimum counseling may suffice (Figure 1). But if the response suggests a greater impact, an in-depth history should be taken (Table 2) to determine the appropriate treatment plan.
Another approach to exploring the impact on quality of life is to ask the patient to list difficulties associated with the tinnitus.3
Still another option is to use a standardized screening tool. The Tinnitus Handicap Inventory-Screening Version (THI-S)14 consists of 10 questions that screen for the psychosocial consequences of tinnitus (Table 3). For each question, the patient answers “yes” (worth 4 points), “sometimes” (2 points), or “no” (0 points). The possible total score thus ranges from 0 to 40 points; the higher the score, the greater the perceived disability (activity limitation) and handicap (participation restriction). A score of more than 6 points indicates a need for an in-depth evaluation (Table 2). Having the patient complete this tool in the waiting room can save precious time and help identify those in need of referral.
SOME PATIENTS MAY NEED TO SEE ONE OR MORE SPECIALISTS
Many patients can manage their tinnitus successfully after receiving reassurance and some simple suggestions about how to manage it at home and at work. Helpful techniques can be listed in an information sheet, such as the one that follows this paper, to give to patients.
Patients whose tinnitus is distressing may need referral. Traditionally, the primary care physician refers the patient to an otolaryngologist. However, the complex nature and etiology of tinnitus may necessitate referring the patient to one or more specialists in addition to an otolaryngologist for further assessment and management. The following sections briefly describe what other specialists offer.
AUDIOLOGY: TESTING, SOUND THERAPY
A patient referred to an audiologist may undergo traditional audiologic testing (pure tone and speech thresholds, word recognition), as well as a battery of special psychoacoustic tests. This includes pitch-matching and loudness-matching, evaluation of residual inhibition (suppression of tinnitus after an external masking stimulus has been turned off), and assessing the minimum masking level. These provide a quantitative estimate of the acoustic attributes of the perceived tinnitus. Questionnaires can be used to assess the impact of tinnitus on everyday life and can provide guidance for treatment.15
Real sounds mask the perceived ones
As treatment, audiologists offer ongoing counseling, encouragement, education, and sound therapy, ie, relieving the tinnitus by maintaining a low level of background noise. Several advantages and benefits have been attributed to sound therapy (Table 4). A variety of devices can be used.15
Environmental enrichment devices such as portable machines that generate pleasant sounds (eg, rain, waterfalls, ocean waves), tabletop water fountains, fans, or even televisions or radios can be used to promote relief, provide distraction, and decrease the patient’s awareness of tinnitus.
Hearing aids amplify ambient sounds, reducing the perception of tinnitus.16,17 They also improve communication.
Sound generators, worn in the ear, produce a stable broadband signal (“white noise”). These devices may be used by patients who have normal or near-normal hearing sensitivity and therefore neither benefit from nor require amplification.
Combination instruments are both hearing aids and white-noise generators. These allow patients who have both hearing loss and tinnitus to use a single device.
Music can distract from the tinnitus and help patients relax. Patients may find benefit listening to their preferred music on a personal listening device such as an MP3 or CD player.
Neuromonics Inc. (Bethlehem, PA) makes a sophisticated device for tinnitus treatment. Resembling an MP3 player, it is used with headphones and plays soothing music (baroque or new age) that contains a tinnitus-masking noise. The music is modified to compensate for the patient’s hearing loss, if present. After approximately 2 months of use, the embedded noise is removed to help desensitize the patient to the tinnitus. Results of small trials have been promising.18,19
DENTISTRY: TREATING TINNITUS BY TREATING TMD
Temporomandibular disorder (TMD), involving the temporomandibular joints, the muscles of mastication, and the teeth, is associated with tinnitus.20,21 The prevalence of tinnitus in a Cleveland Clinic study of 109 patients with TMD was 36%.22
There is also an association between cervical muscle disorders and masticatory muscle function. For example, patients who grind their teeth at night must contract the sternocleidomastoid muscles of the neck to stabilize the head during grinding. Correcting cervical posture, changing the sleep position, and controlling conscious parafunctional habits (eg, clenching the teeth, grinding the teeth together) can decrease many of the symptoms of TMD.
The dental examination for tinnitus patients
The dentist looks for a history of TMD symptoms, use of orthotic devices, and head and neck trauma, and performs a clinical examination.
The clinical examination includes mandibular range of motion, auscultation and palpation of the temporomandibular joints, palpation of masticatory and cervical muscles, and cervical range of motion. The intraoral examination includes identifying occlusal attrition patterns, “load testing” of the temporomandibular joints, and identifying premature tooth contacts. Additionally, attempts to restrict jaw opening and lateral movements may modulate the patient’s tinnitus, thus confirming the role of TMD in the patient’s tinnitus.
How tinnitus is treated by managing TMD
Tinnitus can be treated by managing TMD, specifically through the use of dental orthotics (splints, nightguards) to improve abnormal jaw mechanics and tracking.23–25
Tullberg and Ernberg26 treated patients with TMD and tinnitus using a variety of methods, including occlusal splinting, jaw muscle exercises, and relaxation. They reported that 43% of the patients experienced an improvement in their tinnitus after these interventions.
A home exercise program may help patients maintain muscle strength and harmony. Self-help therapies provide patients with a protocol to recognize daytime parafunctional habits and provide suggestions to decrease clenching and other overloading of the masticatory system.
In addition, management of TMD-related tinnitus often involves physical therapy, which can include soft-tissue mobilization, deep heat, ultrasound, low-current electrical stimulation, myofascial trigger-point release techniques, and posture retraining. Occlusal correction procedures (bite correction) can often provide long-term stability to the masticatory system.
NEUROLOGY: LOOKING FOR AN UNDERLYING CONDITION
The comprehensive neurologic evaluation of the tinnitus patient should include a thorough neurologic history, review of systems, examination, and appropriate imaging. The aim is to identify accompanying symptoms or disorders that may help to localize and ultimately diagnose the underlying condition.
Related disorders could manifest with vestibular symptoms (dizziness, imbalance), various pain syndromes including facial pain and headache (tension or migraine),27 or other cranial nerve disorders such as Bell palsy (facial nerve injury)28 or trigeminal neuralgia.
Medical and surgical interventions for tinnitus-associated neurologic conditions
In cases in which there is a treatable underlying neurologic condition, tinnitus-focused interventions should be deferred until treatment has been completed or discontinued.
At that point, other options including various oral medications (eg, antiarrhythmics, anticonvulsants, benzodiazepines, and antidepressants) and anesthetic blocks (eg, intravenous anesthetic-plus-steroid injections)29 may be considered on a case-by-case basis. Results of randomized clinical trials of the aforementioned drugs have not been promising30; however, drugs that affect the emotional status of the patient by reducing anxiety, depression, and sleep disturbance have been shown to be beneficial.31,32
In addition, some experimental surgical treatments (eg, deep brain stimulation, dural grid stimulation)33,34 are being evaluated and show potential for managing tinnitus.
PHYSICAL THERAPY
A preliminary physical therapy evaluation can identify biomechanical problems of the head, neck, and jaw that can contribute to tinnitus.
Subsequent therapy is designed to restore proper cervical and temporomandibular biomechanics and to educate the patient on proper posture, ergonomics, and exercise techniques that together could help minimize these abnormalities and reduce the severity of tinnitus in some patients.11,24–26,35
PSYCHOLOGY: ADDRESSING DEPRESSION, ANXIETY
Tinnitus exacts an emotional toll on its sufferers. Some estimates suggest that 40% to 50% of tinnitus patients experience significant perceived handicap and psychological distress.36 Consequently, many patients respond to the onset of tinnitus with anxiety or depression, or both. Owing to these responses, the chronicity of the condition, and the patient’s perception that tinnitus is uncontrollable, tinnitus can produce notable distress and impairment in quality of life.
When a patient’s responses include both depression and anxiety, the reduction in quality of life and impairment in coping capacities can be significant.37 Sleep problems, poor concentration, social withdrawal, feelings of helplessness, avoidance behaviors, and upset in interpersonal relationships are common signs that quality of life is compromised.
One of the greatest challenges for the primary care physician when treating tinnitus patients is attending to their emotional suffering and disability. Simple screening tools can be useful in quickly assessing a patient’s emotional response to tinnitus and in helping to enter into a conversation with the patient about this topic. These tools include:
The THI-S (Table 3)14
The Patient Health Questionnaire-9 (PHQ-9)38
The Generalized Anxiety Disorder-7 (GAD-7).39
Suicidal ideas need to be addressed
The final question on the PHQ-9 asks about suicidal ideation. This cannot be overlooked when assessing patients with tinnitus. The questionnaire invites the patient to communicate this rather painful topic to the physician in a direct matter.
The physician should be prepared to address suicidal ideas, plans, means, intentions, and safety measures with the patient. This requires that the physician be comfortable conducting these conversations in a direct and forthright manner; it also requires that the physician have reliable referrals to qualified mental health practitioners at the ready to assist the distressed tinnitus patient.
Asking a patient to commit to calling 911 or going to the nearest emergency room if he or she has any impulse toward self-harm is a simple option that many distressed patients may have never considered.
Treatments for depression and anxiety in tinnitus patients
Some patients may already have been seeing a mental health professional before the onset of tinnitus and may elect to discuss treatment with their current provider. However, many need guidance in selecting appropriate treatment. Their options may include:
Psychotropic drugs such as selective serotonin reuptake inhibitors and benzodiazepines, to provide quick relief from debilitating depression and anxiety.
Cognitive behavioral therapy, designed to provide a more active and durable adjustment to tinnitus. It is the most widely validated psychotherapeutic treatment approach to tinnitus.40
Acceptance and commitment therapy, which emphasizes strategies for acceptance, mindfulness, and cognitive defusion (the process of separating thoughts from emotions that have become fused together). There is some preliminary evidence that it also may be effective in reducing the distress of tinnitus sufferers, as well as those with other chronic medical conditions.41Table 5 contains a sample of the approaches used in cognitive behavioral therapy and acceptance and commitment therapy for tinnitus.
References
Møller AR. The role of neural plasticity in tinnitus. Prog Brain Res2007; 166:37–45.
Dobie RA. Overview: suffering from tinnitus. In:Snow JB, ed. Tinnitus: Theory and Management. Hamilton, Ontario: BC Decker; 2004:1–7.
Henry JA, Dennis KC, Schechter MA. General review of tinnitus: prevalence, mechanisms, effects, and management. J Speech Lang Hear Res2005; 48:1204–1235.
Hoffman HJ, Reed GW. Epidemiology of tinnitus. In:Snow JB, editor. Tinnitus: Theory and Management. Hamilton, Ontario: BC Decker; 2004:16–41.
Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in U.S. Soldiers returning from Iraq. N Engl J Med2008; 358:453–63.
Rauschecker JP, Leaver AM, Mühlau M. Tuning out the noise: limbicauditory interactions in tinnitus. Neuron2010; 66:819–826.
Kaltenbach JA, Zhang J, Finlayson P. Tinnitus as a plastic phenomenon and its possible neural underpinnings in the dorsal cochlear nucleus. Hear Res2005; 206:200–226.
Georgiewa P, Klapp BF, Fischer F, et al. An integrative model of developing tinnitus based on recent neurobiological findings. Med Hypotheses2006; 66:592–600.
Cacace AT. Expanding the biological basis of tinnitus: crossmodal origins and the role of neuroplasticity. Hear Res2003; 175:112–132.
Levine RA. Somatic tinnitus. In:Snow JB, editor. Tinnitus: Theory and Management. Hamilton, Ontario: BC Decker; 2004:108–124.
Sanchez TG, Kii MA. Modulating tinnitus with visual, muscular, and tactile stimulation. Semin Hear2008; 29:350–360.
Schleuning AL, Shi BY, Martin WH. Tinnitus. In:Bailey BJ, Johnson JT, Newlands SD, et al, editors. Head and Neck Surgery—Otolarygnology. 4th ed, vol 2. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:2237–2246.
Newman CW, Sandridge SA, Bolek L. Development and psychometric adequacy of the screening version of the Tinnitus Handicap Inventory. Otol Neurotol2008; 29:276–281.
Kochkin S, Tyler R. Tinnitus treatment and the effectiveness of hearing aids: hearing care professional perceptions. Hearing Review2008; 15:14–18.
Sheldrake JB, Jasterboff MM. Role of hearing aids in management of tinnitus. In:Snow JB, editor. Tinnitus: Theory and Management. Hamilton, Ontario: BC Decker; 2004:310–313.
Davis PB, Paki B, Hanley PJ. Neuromonics Tinnitus Treatment: third clinical trial. Ear Hear2007; 28:242–259.
Davis PB, Wilde RA, Steed LG, Hanley PJ. Treatment of tinnitus with a customized acoustic neural stimulus: a controlled clinical study. Ear Nose Throat J2008; 87:330–339.
Lam DK, Lawrence HP, Tenenbaum HC. Aural symptoms in temporomandibular disorder patients attending a craniofacial pain unit. J Orofac Pain2001; 15:146–157.
Steigerwald DP, Verne SV, Young D. A retrospective evaluation of the impact of temporomandibular joint arthroscopy on the symptoms of headache, neck pain, shoulder pain, dizziness, and tinnitus. Cranio1996; 14:46–54.
Kahn K. Multidisciplinary strategies for managing patients with tinnitus. Poster presented at the American Equilibration Society, Chicago, IL, February 24–25, 2010.
Morgan DH. Tinnitus caused by a temporomandibular disorder. In:Reich GE, Vernon JA, editors. Proceedings of the Fifth International Tinnitus Seminar. Portland, Oregon: American Tinnitus Association; 1996:653–654.
Wright EF, Bifano SL. Tinnitus improvement through TMD therapy. J Am Dent Assoc1997; 128:1424–1432.
Latifpour DH, Grenner J, Sjödahl C. The effect of a new treatment based on somatosensory stimulation in a group of patients with somatically related tinnitus. Int Tinnitus J2009; 15:94–99.
Tullberg M, Ernberg M. Long-term effect on tinnitus by treatment of temporomandibular disorders: a two-year follow-up by questionnaire. Acta Odontol Scand2006; 64:89–96.
Volcy M, Sheftell FD, Tepper SJ, Rapoport AM, Bigal ME. Tinnitus in migraine: an allodynic symptom secondary to abnormal cortical functioning?Headache2005; 45:1083–1087.
Yamamoto E, Nishimura H, Hirono Y. Occurrence of sequelae in Bell’s palsy. Acta Otolaryngol Suppl1988; 446:93–96.
Duckert LG, Rees TS. Treatment of tinnitus with intravenous lidocaine: a double-blind randomized trial. Otolaryngol Head Neck Surg1983; 91:550–555.
Dobie RA. Clinical trials and drug therapy for tinnitus. In:Snow JB, editor. Tinnitus: Theory and Management. Hamilton, Ontario: BC Decker; 2004:266–277.
Johnson RM, Brummett R, Schleuning A. Use of alprazolam for relief of tinnitus. A double-blind study. Arch Otolaryngol Head Neck Surg1993; 119:842–845.
Brummett R. Drugs for and against tinnitus. The Hearing Journal1989; 42:34–37.
Cheung SW, Larson PS. Tinnitus modulation by deep brain stimulation in locus of caudate neurons (area LC). Neuroscience2010; 169:1768–1778.
Friedland DR, Gaggl W, Runge-Samuelson C, Ulmer JL, Kopell BH. Feasibility of auditory cortical stimulation for the treatment of tinnitus. Otol Neurotol2007; 28:1005–1012.
Simmons R, Dambra C, Lobarinas E, Stocking C, Salvi R. Head, neck, and eye movements that modulate tinnitus. Semin Hear2008; 29:361–370.
Bauch CD, Lynn SG, Williams DE, Mellon MW, Weaver AL. Tinnitus impact: three different measurement tools. J Am Acad Audiol2003; 14:181–187.
Bartels H, Middel BL, van der Laan BF, Staal MJ, Albers FW. The additive effect of co-occurring anxiety and depression on health status, quality of life and coping strategies in help-seeking tinnitus sufferers. Ear Hear2008; 29:947–956.
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med2001; 16:606–613.
Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med2006; 166:1092–1097.
Andersson G. Psychological aspects of tinnitus and the application of cognitive-behavioral therapy. Clin Psychol Rev2002; 22:977–990.
Hesser H, Westin V, Hayes SC, Andersson G. Clients’ in-session acceptance and cognitive defusion behaviors in acceptance-based treatment of tinnitus distress. Behav Res Ther2009; 47:523–528.
References
Møller AR. The role of neural plasticity in tinnitus. Prog Brain Res2007; 166:37–45.
Dobie RA. Overview: suffering from tinnitus. In:Snow JB, ed. Tinnitus: Theory and Management. Hamilton, Ontario: BC Decker; 2004:1–7.
Henry JA, Dennis KC, Schechter MA. General review of tinnitus: prevalence, mechanisms, effects, and management. J Speech Lang Hear Res2005; 48:1204–1235.
Hoffman HJ, Reed GW. Epidemiology of tinnitus. In:Snow JB, editor. Tinnitus: Theory and Management. Hamilton, Ontario: BC Decker; 2004:16–41.
Hoge CW, McGurk D, Thomas JL, Cox AL, Engel CC, Castro CA. Mild traumatic brain injury in U.S. Soldiers returning from Iraq. N Engl J Med2008; 358:453–63.
Rauschecker JP, Leaver AM, Mühlau M. Tuning out the noise: limbicauditory interactions in tinnitus. Neuron2010; 66:819–826.
Kaltenbach JA, Zhang J, Finlayson P. Tinnitus as a plastic phenomenon and its possible neural underpinnings in the dorsal cochlear nucleus. Hear Res2005; 206:200–226.
Georgiewa P, Klapp BF, Fischer F, et al. An integrative model of developing tinnitus based on recent neurobiological findings. Med Hypotheses2006; 66:592–600.
Cacace AT. Expanding the biological basis of tinnitus: crossmodal origins and the role of neuroplasticity. Hear Res2003; 175:112–132.
Levine RA. Somatic tinnitus. In:Snow JB, editor. Tinnitus: Theory and Management. Hamilton, Ontario: BC Decker; 2004:108–124.
Sanchez TG, Kii MA. Modulating tinnitus with visual, muscular, and tactile stimulation. Semin Hear2008; 29:350–360.
Schleuning AL, Shi BY, Martin WH. Tinnitus. In:Bailey BJ, Johnson JT, Newlands SD, et al, editors. Head and Neck Surgery—Otolarygnology. 4th ed, vol 2. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:2237–2246.
Newman CW, Sandridge SA, Bolek L. Development and psychometric adequacy of the screening version of the Tinnitus Handicap Inventory. Otol Neurotol2008; 29:276–281.
Kochkin S, Tyler R. Tinnitus treatment and the effectiveness of hearing aids: hearing care professional perceptions. Hearing Review2008; 15:14–18.
Sheldrake JB, Jasterboff MM. Role of hearing aids in management of tinnitus. In:Snow JB, editor. Tinnitus: Theory and Management. Hamilton, Ontario: BC Decker; 2004:310–313.
Davis PB, Paki B, Hanley PJ. Neuromonics Tinnitus Treatment: third clinical trial. Ear Hear2007; 28:242–259.
Davis PB, Wilde RA, Steed LG, Hanley PJ. Treatment of tinnitus with a customized acoustic neural stimulus: a controlled clinical study. Ear Nose Throat J2008; 87:330–339.
Lam DK, Lawrence HP, Tenenbaum HC. Aural symptoms in temporomandibular disorder patients attending a craniofacial pain unit. J Orofac Pain2001; 15:146–157.
Steigerwald DP, Verne SV, Young D. A retrospective evaluation of the impact of temporomandibular joint arthroscopy on the symptoms of headache, neck pain, shoulder pain, dizziness, and tinnitus. Cranio1996; 14:46–54.
Kahn K. Multidisciplinary strategies for managing patients with tinnitus. Poster presented at the American Equilibration Society, Chicago, IL, February 24–25, 2010.
Morgan DH. Tinnitus caused by a temporomandibular disorder. In:Reich GE, Vernon JA, editors. Proceedings of the Fifth International Tinnitus Seminar. Portland, Oregon: American Tinnitus Association; 1996:653–654.
Wright EF, Bifano SL. Tinnitus improvement through TMD therapy. J Am Dent Assoc1997; 128:1424–1432.
Latifpour DH, Grenner J, Sjödahl C. The effect of a new treatment based on somatosensory stimulation in a group of patients with somatically related tinnitus. Int Tinnitus J2009; 15:94–99.
Tullberg M, Ernberg M. Long-term effect on tinnitus by treatment of temporomandibular disorders: a two-year follow-up by questionnaire. Acta Odontol Scand2006; 64:89–96.
Volcy M, Sheftell FD, Tepper SJ, Rapoport AM, Bigal ME. Tinnitus in migraine: an allodynic symptom secondary to abnormal cortical functioning?Headache2005; 45:1083–1087.
Yamamoto E, Nishimura H, Hirono Y. Occurrence of sequelae in Bell’s palsy. Acta Otolaryngol Suppl1988; 446:93–96.
Duckert LG, Rees TS. Treatment of tinnitus with intravenous lidocaine: a double-blind randomized trial. Otolaryngol Head Neck Surg1983; 91:550–555.
Dobie RA. Clinical trials and drug therapy for tinnitus. In:Snow JB, editor. Tinnitus: Theory and Management. Hamilton, Ontario: BC Decker; 2004:266–277.
Johnson RM, Brummett R, Schleuning A. Use of alprazolam for relief of tinnitus. A double-blind study. Arch Otolaryngol Head Neck Surg1993; 119:842–845.
Brummett R. Drugs for and against tinnitus. The Hearing Journal1989; 42:34–37.
Cheung SW, Larson PS. Tinnitus modulation by deep brain stimulation in locus of caudate neurons (area LC). Neuroscience2010; 169:1768–1778.
Friedland DR, Gaggl W, Runge-Samuelson C, Ulmer JL, Kopell BH. Feasibility of auditory cortical stimulation for the treatment of tinnitus. Otol Neurotol2007; 28:1005–1012.
Simmons R, Dambra C, Lobarinas E, Stocking C, Salvi R. Head, neck, and eye movements that modulate tinnitus. Semin Hear2008; 29:361–370.
Bauch CD, Lynn SG, Williams DE, Mellon MW, Weaver AL. Tinnitus impact: three different measurement tools. J Am Acad Audiol2003; 14:181–187.
Bartels H, Middel BL, van der Laan BF, Staal MJ, Albers FW. The additive effect of co-occurring anxiety and depression on health status, quality of life and coping strategies in help-seeking tinnitus sufferers. Ear Hear2008; 29:947–956.
Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure. J Gen Intern Med2001; 16:606–613.
Spitzer RL, Kroenke K, Williams JB, Löwe B. A brief measure for assessing generalized anxiety disorder: the GAD-7. Arch Intern Med2006; 166:1092–1097.
Andersson G. Psychological aspects of tinnitus and the application of cognitive-behavioral therapy. Clin Psychol Rev2002; 22:977–990.
Hesser H, Westin V, Hayes SC, Andersson G. Clients’ in-session acceptance and cognitive defusion behaviors in acceptance-based treatment of tinnitus distress. Behav Res Ther2009; 47:523–528.
The first step is to rule out underlying otologic disease.
Nonotologic interventions range from minimal counseling in the office to referrals to specialists in one or more fields, including audiology, dentistry, neurology, physical therapy, psychology, and psychiatry.
A simple algorithm can help determine if patient education is all that is required or if referral is needed.
This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.
This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.
This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.
This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.
This information is provided by your physician and the Cleveland Clinic Journal of Medicine. It is not designed to replace a physician’s medical assessment and judgment.
This page may be reproduced noncommercially to share with patients. Any other reproduction is subject to Cleveland Clinic Journal of Medicine approval. Bulk color reprints are available by calling 216-444-2661.
A 49-year-old man has had ulcerative colitis for more than 30 years. It is well controlled with sulfasalazine (Azulfidine). Now, he has come to see his primary care physician because for the past 3 months he has had mild, intermittent pain in his right upper abdominal quadrant.
His physical examination is normal. Routine laboratory testing shows the following:
Hemoglobin 14.2 g/dL (reference range 13.5–17.5)
White blood cell count 6.7 × 109/L (3.5–10.5)
Platelet count 279 × 109/L (150–450)
Alkaline phosphatase 387 U/L (45–115)
Total bilirubin 0.9 mg/dL (0.1–1.0)
Aspartate aminotransferase (AST) 35 U/L (35–48)
Alanine aminotransferase (ALT) 30 U/L (7–55).
Figure 1. Intraoperative cholangiography demonstrates annular, multifocal stricturing and beading of the extrahepatic biliary system (arrow).His physician is concerned about his elevated alkaline phosphatase level, which can be a sign of cholestatic liver disease (ie, involving blockage of the flow of bile). He sends him for ultrasonography, which reveals mild thickening of the gallbladder wall. The patient is referred to a general surgeon, who decides to remove the gallbladder. The procedure goes well, but when contrast dye is injected into the biliary system during cholangiography, the image is markedly abnormal (Figure 1). The patient is referred to Mayo Clinic for further evaluation.
WHAT IS THE DIAGNOSIS?
1.Based on this information, which of the following is the most likely diagnosis?
Autoimmune hepatitis
Primary sclerosing cholangitis
Primary biliary cirrhosis
Idiopathic adulthood ductopenia
Primary sclerosing cholangitis
The most likely diagnosis is primary sclerosing cholangitis, a chronic cholestatic liver disease characterized by diffuse inflammatory destruction of intrahepatic and extrahepatic bile ducts, resulting in fibrosis, cirrhosis, and liver failure. Its cause is unknown, but it is likely the result of acquired exposures interacting with predisposing host factors. Current diagnostic criteria include:
Characteristic cholangiographic abnormalities of the biliary tree
Compatible clinical and biochemical findings (typically cholestasis with elevated alkaline phosphatase levels for at least 6 months)
Exclusion of causes of secondary sclerosing cholangitis: secondary sclerosing cholangitis is characterized by a similar multifocal biliary stricturing process, but with an identifiable cause such as long-term biliary obstruction, surgical biliary trauma, or recurrent pancreatitis.1
At presentation, the most common liver enzyme abnormality is an elevated alkaline phosphatase level, often three or four times the normal level.2 In contrast, aminotransferase levels are only modestly elevated, less than three times the upper limit of normal.3 At the time of diagnosis, serum bilirubin levels are normal in 60% of patients.4
Two large epidemiologic studies (one from Olmsted County, MN,5 the other from Swansea, Wales, UK6) estimated the age-adjusted incidence of primary sclerosing cholangitis to be 0.9 per 100,000 individuals. The median age of the patients at onset was in the 30s or 40s, and most were men. At 10 years, an estimated 65% were still alive and had not undergone liver transplantation—a significantly lower percentage than in age- and sex-matched populations.
It is estimated that more than 70% of patients with primary sclerosing cholangitis also have inflammatory bowel disease.5 In fact, the most common presentation of primary sclerosing cholangitis is asymptomatic inflammatory bowel disease and persistently elevated alkaline phosphatase—usually first noted on routine biochemical screening, as in our patient.
Imaging of the biliary tree is essential for the diagnosis of primary sclerosing cholangitis. Typical findings on cholangiography include multifocal stricturing and beading, usually involving both the intrahepatic and the extrahepatic biliary systems, as in our patient (Figure 1). Endoscopic retrograde cholangiopancreatography (ERCP) is considered the gold standard imaging test, but recent studies have shown that magnetic resonance cholangiopancreatography (MRCP) is an acceptable noninvasive substitute,7 and it may cost less per diagnosis.8
Liver biopsy alone is generally nondiagnostic because the histologic changes are quite variable in different segments of the same liver. The classic “onion-skin fibrosis” of primary sclerosing cholangitis is seen in fewer than 10% of biopsy specimens.9
Autoimmune hepatitis
Autoimmune hepatitis is chronic and is characterized by circulating autoantibodies and high serum globulin concentrations.10 Its presentation is heterogeneous, varying from no symptoms to nonspecific symptoms of malaise, fatigue, abdominal pain, itching, and arthralgia. Generally, elevations in aminotransferases are much more prominent than abnormalities in bilirubin and alkaline phosphatase levels10—unlike the pattern in our patient.
Primary biliary cirrhosis
Primary biliary cirrhosis is diagnosed if the patient has at least two of these three clinical criteria:
Biochemical evidence of cholestasis, with elevation of alkaline phosphatase for at least 6 months
Antimitochondrial antibody
Histologic evidence of nonsuppurative cholangitis and destruction of small or medium-sized bile ducts.11
In patients who lack antimitochondrial antibody, liver biopsy is necessary to establish the diagnosis. Given that primary biliary cirrhosis involves only small and medium-sized bile ducts, cholangiography is usually normal unless the patient has advanced cirrhosis.
Idiopathic adulthood ductopenia
Idiopathic adulthood ductopenia is a rare condition of unknown cause that involves the progressive destruction of segments of the small bile ducts inside the liver (“small-duct” biliary disease).12 Laboratory findings reveal a cholestatic pattern of liver injury, but biopsy samples show no features diagnostic or suggestive of another biliary disease; cholangiography is typically normal.12,13
ASSOCIATION WITH INFLAMMATORY BOWEL DISEASE
2. Which statement best characterizes inflammatory bowel disease associated with primary sclerosing cholangitis?
Crohn disease of the small bowel is the most common form
Liver disease often precedes the bowel disease
Treating the underlying bowel disease improves the long-term prognosis for the liver condition
Patients with primary sclerosing cholangitis and chronic ulcerative colitis are at higher risk of colonic dysplasia than patients with chronic ulcerative colitis alone
From 70% to 80% of patients with primary sclerosing cholangitis also have inflammatory bowel disease, usually chronic ulcerative colitis.14,15 Conversely, 2.4% to 4% of patients with ulcerative colitis and 1.4% to 3.4% of patients with Crohn disease have primary sclerosing cholangitis.1
Typically, the diagnosis of inflammatory bowel disease is made 8 to 10 years before the diagnosis of liver disease, although cases have also been reported to occur years after the diagnosis of cholangitis.15,16
No association between the severity of bowel disease and liver disease has been reported, and treating the inflammatory bowel disease does not alter the natural history of primary sclerosing cholangitis. Particularly, proctocolectomy, the most aggressive treatment for chronic ulcerative colitis, appears to have no effect on the course of the cholangitis.17
In patients with both primary sclerosing cholangitis and chronic ulcerative colitis, the risk of colonic dysplasia is higher than in patients with chronic ulcerative colitis alone.18 Recent studies have predicted that the risk of colorectal carcinoma in patients with primary sclerosing cholangitis and inflammatory bowel disease is as high as 25% after 10 years.19,20 Therefore, annual colonoscopy with surveillance biopsy is recommended in patients with both primary sclerosing cholangitis and chronic ulcerative colitis, since screening and early detection improve survival rates.15
TREATMENT AND PROGNOSIS
After being diagnosed with primary sclerosing cholangitis, the patient inquires about ongoing medical therapy and long-term prognosis.
3.Which is the only life-prolonging therapy for primary sclerosing cholangitis?
Methotrexate (Trexall)
Ursodeoxycholic acid (UDCA) (Actigall) at a standard dosage (13–15 mg/kg/day)
UDCA at a high dosage (20–30 mg/kg/day)
Liver transplantation
Drug therapy has not been shown to improve the prognosis of primary sclerosing cholangitis.
In randomized placebo-controlled trials, penicillamine (Depen), colchicine (Colcrys), methotrexate, and UDCA (13–15 mg/kg per day) failed to show efficacy.21–23
In pilot studies, high-dose UDCA (20 to 30 mg/kg/day) initially appeared to bring an improvement in survival probability, with trends toward histologic improvement,24,25 but larger randomized placebo-controlled trials found no improvement in symptoms, quality of life, survival rates, or risk of cholangiocarcinoma with high-dose UDCA.26,27 In fact, in 5 years of follow-up, patients on high-dose UDCA had a risk of death or transplantation two times higher than with placebo.27 One study indicated UDCA may decrease the incidence of colonic dysplasia in patients with primary sclerosing cholangitis and chronic ulcerative colitis.28 However, more prospective studies are required to better define the routine use of UDCA as a prophylactic agent.
Liver transplantation remains the most effective treatment for primary sclerosing cholangitis, and it improves the rate of survival.29 Nevertheless, about 20% of patients who undergo transplantation have a recurrence of cholangitis, and it may recur earlier after living-donor liver transplantation, particularly when the graft is from a biologically related donor.30 Proposed risk factors for recurrence include inflammatory bowel disease, prolonged ischemia time, the number of cellular rejection events, prior biliary surgery, cytomegalovirus infection, and lymphocytotoxic cross-match.31
4.In addition to cirrhosis and cholangitis, which of the following is a potential long-term complication of primary sclerosing cholangitis?
Colon cancer
Cholangiocarcinoma
Osteoporosis
Fat-soluble vitamin deficiency
All of the above
All are potential long-term complications.
Colon cancer. Concomitant chronic ulcerative colitis puts the patient at a higher risk of colonic dysplasia compared with patients with chronic ulcerative colitis alone.18 According to recent studies of patients with primary sclerosing cholangitis and inflammatory bowel disease, 19,20 the risk of colorectal carcinoma after 10 years of disease is as high as 25%.
Cholangiocarcinoma. Primary sclerosing cholangitis is considered a risk factor for cholangiocarcinoma, with an estimated 10-year cumulative incidence of 7% to 9%.1,20 In a retrospective study of 30 patients,32 the median survival was 5 months from the time of diagnosis of cholangiocarcinoma; at the time of diagnosis approximately 19 patients (63%) had metastatic disease.
At present, early detection of cholangiocarcinoma is hampered by the low sensitivity and specificity of standard diagnostic approaches. Carbohydrate antigen 19-9 has been used as a marker, but it has questionable accuracy, since elevations of this antigen can also be a result of pancreatic malignancy and bacterial cholangitis. However, cholangiocarcinoma should be suspected when patients present with progressive jaundice, weight loss, abdominal discomfort, and a sudden rise in carbohydrate antigen 19-9.
Conventional ultrasonography and computed tomography (CT) have poor sensitivity for detecting this malignancy. ERCP with biliary brushings should be considered when evaluating for biliary malignancy. New diagnostic methods such as digitized image analysis and fluorescence in situ hybridization on biliary brushings offer promise to evaluate bile duct lesions for cellular aneuploidy and chromosomal aberrations, which may improve the detection of cholangiocarcinoma.33 A recent large-scale study of nearly 500 patients showed that fluorescence in situ hybridization had a higher sensitivity (42.9%) than routine cytology (20.1%) with identical specificity (99.6%) for malignancy.34
Metabolic bone disease, usually osteoporosis rather than osteomalacia, is relatively common and is an important complication of primary sclerosing cholangitis.35 Patients with osteoporosis should be treated with vitamin D and calcium supplementation. Bisphosphonates have been used with varying results in primary biliary cirrhosis36 and can be considered in patients with advanced osteoporosis.
Fat-soluble vitamin deficiency is relatively common in primary sclerosing cholangitis, particularly as it progresses to advanced liver disease. Up to 40% of patients have vitamin A deficiency, 14% have vitamin D deficiency, and 2% have vitamin E deficiency.37 Patients can undergo simple oral replacement therapy.
A stone is removed, fever develops
Three years after the diagnosis of primary sclerosing cholangitis, the patient develops mild hyperbilirubinemia and undergoes ERCP at his local hospital. A stone is found obstructing the common bile duct and is successfully extracted.
Twenty-four hours after this procedure, he develops severe right-upper-quadrant pain and fever. He is seen at his local emergency department and blood cultures are drawn. He is started on antibiotics and is transferred to Mayo Clinic for further management.
5.In addition to continuing a broad-spectrum antibiotic, which would be the next best step for this patient?
ERCP
MRCP
Abdominal ultrasonography
Abdominal CT
The patient’s clinical presentation is consistent with acute bacterial cholangitis. The classic Charcot triad of fever, right-upper-quadrant pain, and jaundice occurs in only 50% to 75% of patients with acute cholangitis.38 In addition to receiving a broad-spectrum antibiotic, patients with bacterial cholangitis require emergency endoscopic evaluation—ERCP—to find and remove stones from the bile ducts and, if necessary, to dilate the biliary strictures to allow adequate drainage.
In our experience, more than 10% of patients with primary sclerosing cholangitis who undergo ERCP develop complications requiring hospitalization.39 The procedure generally takes longer to perform and the incidence of cholangitis is higher, despite routine antibiotic prophylaxis, in patients with primary sclerosing cholangitis than in those without it. However, the overall risk of pancreatitis, perforation, and bleeding was similar in patients with or without sclerosing cholangitis.39
MRCP is a promising noninvasive substitute for ERCP in establishing the diagnosis of primary sclerosing cholangitis.7,8 Unfortunately, as with other noninvasive imaging studies such as abdominal ultrasonography and CT, MRCP does not allow for therapeutic biliary decompression.
The patient undergoes ERCP with stenting
The patient’s acute cholangitis is thought to be a complication of his recent ERCP procedure. He undergoes emergency ERCP with balloon dilation and placement of a temporary left hepatic stent. His fever improves and he is discharged 48 hours later. He completes a 14-day course of antibiotics for Enterococcus faecalis bacteremia. Six weeks later, he undergoes ERCP yet again to remove the stent and tolerates the procedure well without complications.
TAKE-HOME POINTS
Primary sclerosing cholangitis is a progressive cholestatic liver disease of unknown etiology that primarily affects men during the fourth decade of life.
This condition is strongly associated with inflammatory bowel disease, particularly with ulcerative colitis.
Cholangiocarcinoma and colon cancer are dreaded complications.
Liver transplantation is the only life-extending therapy for primary sclerosing cholangitis; however, the condition can recur in the allograft.
References
Chapman R, Fevery J, Kalloo A, et al; American Association for the Study of Liver Diseases. Diagnosis and management of primary sclerosing cholangitis. Hepatology2010; 51:660–678.
Silveira MG, Lindor KD. Clinical features and management of primary sclerosing cholangitis. World J Gastroenterol2008; 14:3338–3349.
Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med1995; 332:924–933.
Bambha K, Kim WR, Talwalkar J, et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology2003; 125:1364–1369.
Kingham JG, Kochar N, Gravenor MB. Incidence, clinical patterns, and outcomes of primary sclerosing cholangitis in South Wales, United Kingdom. Gastroenterology2004; 126:1929–1930.
Berstad AE, Aabakken L, Smith HJ, Aasen S, Boberg KM, Schrumpf E. Diagnostic accuracy of magnetic resonance and endoscopic retrograde cholangiography in primary sclerosing cholangitis. Clin Gastroenterol Hepatol2006; 4:514–520.
Talwalkar JA, Angulo P, Johnson CD, Petersen BT, Lindor KD. Cost-minimization analysis of MRC versus ERCP for the diagnosis of primary sclerosing cholangitis. Hepatology2004; 40:39–45.
Ludwig J, Barham SS, LaRusso NF, Elveback LR, Wiesner RH, McCall JT. Morphologic features of chronic hepatitis associated with primary sclerosing cholangitis and chronic ulcerative colitis. Hepatology1981; 1:632–640.
Krawitt EL. Autoimmune hepatitis. N Engl J Med2006; 354:54–66.
Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ; American Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology2009; 50:291–308.
Ludwig J, Wiesner RH, LaRusso NF. Idiopathic adulthood ductopenia. A cause of chronic cholestatic liver disease and biliary cirrhosis. J Hepatol1988; 7:193–199.
Ludwig J. Idiopathic adulthood ductopenia: an update. Mayo Clin Proc1998; 73:285–291.
Fausa O, Schrumpf E, Elgjo K. Relationship of inflammatory bowel disease and primary sclerosing cholangitis. Semin Liver Dis1991; 11:31–39.
Loftus EV, Aguilar HI, Sandborn WJ, et al. Risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis following orthotopic liver transplantation. Hepatology1998; 27:685–690.
Loftus EV, Sandborn WJ, Tremaine WJ, et al. Risk of colorectal neoplasia in patients with primary sclerosing cholangitis. Gastroenterology1996; 110:432–440.
Cangemi JR, Wiesner RH, Beaver SJ, et al. Effect of proctocolectomy for chronic ulcerative colitis on the natural history of primary sclerosing cholangitis. Gastroenterology1989; 96:790–794.
Broomé U, Löfberg R, Veress B, Eriksson LS. Primary sclerosing cholangitis and ulcerative colitis: evidence for increased neoplastic potential. Hepatology1995; 22:1404–1408.
Kornfeld D, Ekbom A, Ihre T. Is there an excess risk for colorectal cancer in patients with ulcerative colitis and concomitant primary sclerosing cholangitis? A population based study. Gut1997; 41:522–525.
Claessen MM, Vleggaar FP, Tytgat KM, Siersema PD, van Buuren HR. High lifetime risk of cancer in primary sclerosing cholangitis. J Hepatol2009; 50:158–164.
Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med1997; 336:691–695.
Olsson R, Broomé U, Danielsson A, et al. Colchicine treatment of primary sclerosing cholangitis. Gastroenterology1995; 108:1199–1203.
LaRusso NF, Wiesner RH, Ludwig J, MacCarty RL, Beaver SJ, Zinsmeister AR. Prospective trial of penicillamine in primary sclerosing cholangitis. Gastroenterology1988; 95:1036–1042.
Mitchell SA, Bansi DS, Hunt N, Von Bergmann K, Fleming KA, Chapman RW. A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology2001; 121:900–907.
Cullen SN, Rust C, Fleming K, Edwards C, Beuers U, Chapman RW. High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis is safe and effective. J Hepatol2008; 48:792–800.
Olsson R, Boberg KM, de Muckadell OS, et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology2005; 129:1464–1472.
Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology2009; 50:808–814.
Tung BY, Emond MJ, Haggitt RC, et al. Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med2001; 134:89–95.
Wiesner RH, Porayko MK, Hay JE, et al. Liver transplantation for primary sclerosing cholangitis: impact of risk factors on outcome. Liver Transpl Surg1996; 2(suppl 1):99–108..
Tamura S, Sugawara Y, Kaneko J, Matsui Y, Togashi J, Makuuchi M. Recurrence of primary sclerosing cholangitis after living donor liver transplantation. Liver Int2007; 27:86–94.
Gautam M, Cheruvattath R, Balan V. Recurrence of autoimmune liver disease after liver transplantation: a systematic review. Liver Transpl2006; 12:1813–1824.
Fritcher EG, Kipp BR, Halling KC, et al. A multivariable model using advanced cytologic methods for the evaluation of indeterminate pancreatobiliary strictures. Gastroenterology2009; 136:2180–2186.
Hay JE, Lindor KD, Wiesner RH, Dickson ER, Krom RA, LaRusso NF. The metabolic bone disease of primary sclerosing cholangitis. Hepatology1991; 14:257–261.
Guañabens N, Parés A, Ros I, et al. Alendronate is more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis. Am J Gastroenterol2003; 98:2268–2274.
Douglas L. Nguyen, MD Resident Physician, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN
Konstantinos N. Lazaridis, MD Associate Professor of Medicine, Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
Address: Konstantinos N. Lazaridis, MD, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905; e-mail [email protected]
Douglas L. Nguyen, MD Resident Physician, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN
Konstantinos N. Lazaridis, MD Associate Professor of Medicine, Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
Address: Konstantinos N. Lazaridis, MD, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905; e-mail [email protected]
Author and Disclosure Information
Douglas L. Nguyen, MD Resident Physician, Department of Internal Medicine, Mayo Clinic College of Medicine, Rochester, MN
Konstantinos N. Lazaridis, MD Associate Professor of Medicine, Center for Basic Research in Digestive Diseases, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN
Address: Konstantinos N. Lazaridis, MD, Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905; e-mail [email protected]
A 49-year-old man has had ulcerative colitis for more than 30 years. It is well controlled with sulfasalazine (Azulfidine). Now, he has come to see his primary care physician because for the past 3 months he has had mild, intermittent pain in his right upper abdominal quadrant.
His physical examination is normal. Routine laboratory testing shows the following:
Hemoglobin 14.2 g/dL (reference range 13.5–17.5)
White blood cell count 6.7 × 109/L (3.5–10.5)
Platelet count 279 × 109/L (150–450)
Alkaline phosphatase 387 U/L (45–115)
Total bilirubin 0.9 mg/dL (0.1–1.0)
Aspartate aminotransferase (AST) 35 U/L (35–48)
Alanine aminotransferase (ALT) 30 U/L (7–55).
Figure 1. Intraoperative cholangiography demonstrates annular, multifocal stricturing and beading of the extrahepatic biliary system (arrow).His physician is concerned about his elevated alkaline phosphatase level, which can be a sign of cholestatic liver disease (ie, involving blockage of the flow of bile). He sends him for ultrasonography, which reveals mild thickening of the gallbladder wall. The patient is referred to a general surgeon, who decides to remove the gallbladder. The procedure goes well, but when contrast dye is injected into the biliary system during cholangiography, the image is markedly abnormal (Figure 1). The patient is referred to Mayo Clinic for further evaluation.
WHAT IS THE DIAGNOSIS?
1.Based on this information, which of the following is the most likely diagnosis?
Autoimmune hepatitis
Primary sclerosing cholangitis
Primary biliary cirrhosis
Idiopathic adulthood ductopenia
Primary sclerosing cholangitis
The most likely diagnosis is primary sclerosing cholangitis, a chronic cholestatic liver disease characterized by diffuse inflammatory destruction of intrahepatic and extrahepatic bile ducts, resulting in fibrosis, cirrhosis, and liver failure. Its cause is unknown, but it is likely the result of acquired exposures interacting with predisposing host factors. Current diagnostic criteria include:
Characteristic cholangiographic abnormalities of the biliary tree
Compatible clinical and biochemical findings (typically cholestasis with elevated alkaline phosphatase levels for at least 6 months)
Exclusion of causes of secondary sclerosing cholangitis: secondary sclerosing cholangitis is characterized by a similar multifocal biliary stricturing process, but with an identifiable cause such as long-term biliary obstruction, surgical biliary trauma, or recurrent pancreatitis.1
At presentation, the most common liver enzyme abnormality is an elevated alkaline phosphatase level, often three or four times the normal level.2 In contrast, aminotransferase levels are only modestly elevated, less than three times the upper limit of normal.3 At the time of diagnosis, serum bilirubin levels are normal in 60% of patients.4
Two large epidemiologic studies (one from Olmsted County, MN,5 the other from Swansea, Wales, UK6) estimated the age-adjusted incidence of primary sclerosing cholangitis to be 0.9 per 100,000 individuals. The median age of the patients at onset was in the 30s or 40s, and most were men. At 10 years, an estimated 65% were still alive and had not undergone liver transplantation—a significantly lower percentage than in age- and sex-matched populations.
It is estimated that more than 70% of patients with primary sclerosing cholangitis also have inflammatory bowel disease.5 In fact, the most common presentation of primary sclerosing cholangitis is asymptomatic inflammatory bowel disease and persistently elevated alkaline phosphatase—usually first noted on routine biochemical screening, as in our patient.
Imaging of the biliary tree is essential for the diagnosis of primary sclerosing cholangitis. Typical findings on cholangiography include multifocal stricturing and beading, usually involving both the intrahepatic and the extrahepatic biliary systems, as in our patient (Figure 1). Endoscopic retrograde cholangiopancreatography (ERCP) is considered the gold standard imaging test, but recent studies have shown that magnetic resonance cholangiopancreatography (MRCP) is an acceptable noninvasive substitute,7 and it may cost less per diagnosis.8
Liver biopsy alone is generally nondiagnostic because the histologic changes are quite variable in different segments of the same liver. The classic “onion-skin fibrosis” of primary sclerosing cholangitis is seen in fewer than 10% of biopsy specimens.9
Autoimmune hepatitis
Autoimmune hepatitis is chronic and is characterized by circulating autoantibodies and high serum globulin concentrations.10 Its presentation is heterogeneous, varying from no symptoms to nonspecific symptoms of malaise, fatigue, abdominal pain, itching, and arthralgia. Generally, elevations in aminotransferases are much more prominent than abnormalities in bilirubin and alkaline phosphatase levels10—unlike the pattern in our patient.
Primary biliary cirrhosis
Primary biliary cirrhosis is diagnosed if the patient has at least two of these three clinical criteria:
Biochemical evidence of cholestasis, with elevation of alkaline phosphatase for at least 6 months
Antimitochondrial antibody
Histologic evidence of nonsuppurative cholangitis and destruction of small or medium-sized bile ducts.11
In patients who lack antimitochondrial antibody, liver biopsy is necessary to establish the diagnosis. Given that primary biliary cirrhosis involves only small and medium-sized bile ducts, cholangiography is usually normal unless the patient has advanced cirrhosis.
Idiopathic adulthood ductopenia
Idiopathic adulthood ductopenia is a rare condition of unknown cause that involves the progressive destruction of segments of the small bile ducts inside the liver (“small-duct” biliary disease).12 Laboratory findings reveal a cholestatic pattern of liver injury, but biopsy samples show no features diagnostic or suggestive of another biliary disease; cholangiography is typically normal.12,13
ASSOCIATION WITH INFLAMMATORY BOWEL DISEASE
2. Which statement best characterizes inflammatory bowel disease associated with primary sclerosing cholangitis?
Crohn disease of the small bowel is the most common form
Liver disease often precedes the bowel disease
Treating the underlying bowel disease improves the long-term prognosis for the liver condition
Patients with primary sclerosing cholangitis and chronic ulcerative colitis are at higher risk of colonic dysplasia than patients with chronic ulcerative colitis alone
From 70% to 80% of patients with primary sclerosing cholangitis also have inflammatory bowel disease, usually chronic ulcerative colitis.14,15 Conversely, 2.4% to 4% of patients with ulcerative colitis and 1.4% to 3.4% of patients with Crohn disease have primary sclerosing cholangitis.1
Typically, the diagnosis of inflammatory bowel disease is made 8 to 10 years before the diagnosis of liver disease, although cases have also been reported to occur years after the diagnosis of cholangitis.15,16
No association between the severity of bowel disease and liver disease has been reported, and treating the inflammatory bowel disease does not alter the natural history of primary sclerosing cholangitis. Particularly, proctocolectomy, the most aggressive treatment for chronic ulcerative colitis, appears to have no effect on the course of the cholangitis.17
In patients with both primary sclerosing cholangitis and chronic ulcerative colitis, the risk of colonic dysplasia is higher than in patients with chronic ulcerative colitis alone.18 Recent studies have predicted that the risk of colorectal carcinoma in patients with primary sclerosing cholangitis and inflammatory bowel disease is as high as 25% after 10 years.19,20 Therefore, annual colonoscopy with surveillance biopsy is recommended in patients with both primary sclerosing cholangitis and chronic ulcerative colitis, since screening and early detection improve survival rates.15
TREATMENT AND PROGNOSIS
After being diagnosed with primary sclerosing cholangitis, the patient inquires about ongoing medical therapy and long-term prognosis.
3.Which is the only life-prolonging therapy for primary sclerosing cholangitis?
Methotrexate (Trexall)
Ursodeoxycholic acid (UDCA) (Actigall) at a standard dosage (13–15 mg/kg/day)
UDCA at a high dosage (20–30 mg/kg/day)
Liver transplantation
Drug therapy has not been shown to improve the prognosis of primary sclerosing cholangitis.
In randomized placebo-controlled trials, penicillamine (Depen), colchicine (Colcrys), methotrexate, and UDCA (13–15 mg/kg per day) failed to show efficacy.21–23
In pilot studies, high-dose UDCA (20 to 30 mg/kg/day) initially appeared to bring an improvement in survival probability, with trends toward histologic improvement,24,25 but larger randomized placebo-controlled trials found no improvement in symptoms, quality of life, survival rates, or risk of cholangiocarcinoma with high-dose UDCA.26,27 In fact, in 5 years of follow-up, patients on high-dose UDCA had a risk of death or transplantation two times higher than with placebo.27 One study indicated UDCA may decrease the incidence of colonic dysplasia in patients with primary sclerosing cholangitis and chronic ulcerative colitis.28 However, more prospective studies are required to better define the routine use of UDCA as a prophylactic agent.
Liver transplantation remains the most effective treatment for primary sclerosing cholangitis, and it improves the rate of survival.29 Nevertheless, about 20% of patients who undergo transplantation have a recurrence of cholangitis, and it may recur earlier after living-donor liver transplantation, particularly when the graft is from a biologically related donor.30 Proposed risk factors for recurrence include inflammatory bowel disease, prolonged ischemia time, the number of cellular rejection events, prior biliary surgery, cytomegalovirus infection, and lymphocytotoxic cross-match.31
4.In addition to cirrhosis and cholangitis, which of the following is a potential long-term complication of primary sclerosing cholangitis?
Colon cancer
Cholangiocarcinoma
Osteoporosis
Fat-soluble vitamin deficiency
All of the above
All are potential long-term complications.
Colon cancer. Concomitant chronic ulcerative colitis puts the patient at a higher risk of colonic dysplasia compared with patients with chronic ulcerative colitis alone.18 According to recent studies of patients with primary sclerosing cholangitis and inflammatory bowel disease, 19,20 the risk of colorectal carcinoma after 10 years of disease is as high as 25%.
Cholangiocarcinoma. Primary sclerosing cholangitis is considered a risk factor for cholangiocarcinoma, with an estimated 10-year cumulative incidence of 7% to 9%.1,20 In a retrospective study of 30 patients,32 the median survival was 5 months from the time of diagnosis of cholangiocarcinoma; at the time of diagnosis approximately 19 patients (63%) had metastatic disease.
At present, early detection of cholangiocarcinoma is hampered by the low sensitivity and specificity of standard diagnostic approaches. Carbohydrate antigen 19-9 has been used as a marker, but it has questionable accuracy, since elevations of this antigen can also be a result of pancreatic malignancy and bacterial cholangitis. However, cholangiocarcinoma should be suspected when patients present with progressive jaundice, weight loss, abdominal discomfort, and a sudden rise in carbohydrate antigen 19-9.
Conventional ultrasonography and computed tomography (CT) have poor sensitivity for detecting this malignancy. ERCP with biliary brushings should be considered when evaluating for biliary malignancy. New diagnostic methods such as digitized image analysis and fluorescence in situ hybridization on biliary brushings offer promise to evaluate bile duct lesions for cellular aneuploidy and chromosomal aberrations, which may improve the detection of cholangiocarcinoma.33 A recent large-scale study of nearly 500 patients showed that fluorescence in situ hybridization had a higher sensitivity (42.9%) than routine cytology (20.1%) with identical specificity (99.6%) for malignancy.34
Metabolic bone disease, usually osteoporosis rather than osteomalacia, is relatively common and is an important complication of primary sclerosing cholangitis.35 Patients with osteoporosis should be treated with vitamin D and calcium supplementation. Bisphosphonates have been used with varying results in primary biliary cirrhosis36 and can be considered in patients with advanced osteoporosis.
Fat-soluble vitamin deficiency is relatively common in primary sclerosing cholangitis, particularly as it progresses to advanced liver disease. Up to 40% of patients have vitamin A deficiency, 14% have vitamin D deficiency, and 2% have vitamin E deficiency.37 Patients can undergo simple oral replacement therapy.
A stone is removed, fever develops
Three years after the diagnosis of primary sclerosing cholangitis, the patient develops mild hyperbilirubinemia and undergoes ERCP at his local hospital. A stone is found obstructing the common bile duct and is successfully extracted.
Twenty-four hours after this procedure, he develops severe right-upper-quadrant pain and fever. He is seen at his local emergency department and blood cultures are drawn. He is started on antibiotics and is transferred to Mayo Clinic for further management.
5.In addition to continuing a broad-spectrum antibiotic, which would be the next best step for this patient?
ERCP
MRCP
Abdominal ultrasonography
Abdominal CT
The patient’s clinical presentation is consistent with acute bacterial cholangitis. The classic Charcot triad of fever, right-upper-quadrant pain, and jaundice occurs in only 50% to 75% of patients with acute cholangitis.38 In addition to receiving a broad-spectrum antibiotic, patients with bacterial cholangitis require emergency endoscopic evaluation—ERCP—to find and remove stones from the bile ducts and, if necessary, to dilate the biliary strictures to allow adequate drainage.
In our experience, more than 10% of patients with primary sclerosing cholangitis who undergo ERCP develop complications requiring hospitalization.39 The procedure generally takes longer to perform and the incidence of cholangitis is higher, despite routine antibiotic prophylaxis, in patients with primary sclerosing cholangitis than in those without it. However, the overall risk of pancreatitis, perforation, and bleeding was similar in patients with or without sclerosing cholangitis.39
MRCP is a promising noninvasive substitute for ERCP in establishing the diagnosis of primary sclerosing cholangitis.7,8 Unfortunately, as with other noninvasive imaging studies such as abdominal ultrasonography and CT, MRCP does not allow for therapeutic biliary decompression.
The patient undergoes ERCP with stenting
The patient’s acute cholangitis is thought to be a complication of his recent ERCP procedure. He undergoes emergency ERCP with balloon dilation and placement of a temporary left hepatic stent. His fever improves and he is discharged 48 hours later. He completes a 14-day course of antibiotics for Enterococcus faecalis bacteremia. Six weeks later, he undergoes ERCP yet again to remove the stent and tolerates the procedure well without complications.
TAKE-HOME POINTS
Primary sclerosing cholangitis is a progressive cholestatic liver disease of unknown etiology that primarily affects men during the fourth decade of life.
This condition is strongly associated with inflammatory bowel disease, particularly with ulcerative colitis.
Cholangiocarcinoma and colon cancer are dreaded complications.
Liver transplantation is the only life-extending therapy for primary sclerosing cholangitis; however, the condition can recur in the allograft.
A 49-year-old man has had ulcerative colitis for more than 30 years. It is well controlled with sulfasalazine (Azulfidine). Now, he has come to see his primary care physician because for the past 3 months he has had mild, intermittent pain in his right upper abdominal quadrant.
His physical examination is normal. Routine laboratory testing shows the following:
Hemoglobin 14.2 g/dL (reference range 13.5–17.5)
White blood cell count 6.7 × 109/L (3.5–10.5)
Platelet count 279 × 109/L (150–450)
Alkaline phosphatase 387 U/L (45–115)
Total bilirubin 0.9 mg/dL (0.1–1.0)
Aspartate aminotransferase (AST) 35 U/L (35–48)
Alanine aminotransferase (ALT) 30 U/L (7–55).
Figure 1. Intraoperative cholangiography demonstrates annular, multifocal stricturing and beading of the extrahepatic biliary system (arrow).His physician is concerned about his elevated alkaline phosphatase level, which can be a sign of cholestatic liver disease (ie, involving blockage of the flow of bile). He sends him for ultrasonography, which reveals mild thickening of the gallbladder wall. The patient is referred to a general surgeon, who decides to remove the gallbladder. The procedure goes well, but when contrast dye is injected into the biliary system during cholangiography, the image is markedly abnormal (Figure 1). The patient is referred to Mayo Clinic for further evaluation.
WHAT IS THE DIAGNOSIS?
1.Based on this information, which of the following is the most likely diagnosis?
Autoimmune hepatitis
Primary sclerosing cholangitis
Primary biliary cirrhosis
Idiopathic adulthood ductopenia
Primary sclerosing cholangitis
The most likely diagnosis is primary sclerosing cholangitis, a chronic cholestatic liver disease characterized by diffuse inflammatory destruction of intrahepatic and extrahepatic bile ducts, resulting in fibrosis, cirrhosis, and liver failure. Its cause is unknown, but it is likely the result of acquired exposures interacting with predisposing host factors. Current diagnostic criteria include:
Characteristic cholangiographic abnormalities of the biliary tree
Compatible clinical and biochemical findings (typically cholestasis with elevated alkaline phosphatase levels for at least 6 months)
Exclusion of causes of secondary sclerosing cholangitis: secondary sclerosing cholangitis is characterized by a similar multifocal biliary stricturing process, but with an identifiable cause such as long-term biliary obstruction, surgical biliary trauma, or recurrent pancreatitis.1
At presentation, the most common liver enzyme abnormality is an elevated alkaline phosphatase level, often three or four times the normal level.2 In contrast, aminotransferase levels are only modestly elevated, less than three times the upper limit of normal.3 At the time of diagnosis, serum bilirubin levels are normal in 60% of patients.4
Two large epidemiologic studies (one from Olmsted County, MN,5 the other from Swansea, Wales, UK6) estimated the age-adjusted incidence of primary sclerosing cholangitis to be 0.9 per 100,000 individuals. The median age of the patients at onset was in the 30s or 40s, and most were men. At 10 years, an estimated 65% were still alive and had not undergone liver transplantation—a significantly lower percentage than in age- and sex-matched populations.
It is estimated that more than 70% of patients with primary sclerosing cholangitis also have inflammatory bowel disease.5 In fact, the most common presentation of primary sclerosing cholangitis is asymptomatic inflammatory bowel disease and persistently elevated alkaline phosphatase—usually first noted on routine biochemical screening, as in our patient.
Imaging of the biliary tree is essential for the diagnosis of primary sclerosing cholangitis. Typical findings on cholangiography include multifocal stricturing and beading, usually involving both the intrahepatic and the extrahepatic biliary systems, as in our patient (Figure 1). Endoscopic retrograde cholangiopancreatography (ERCP) is considered the gold standard imaging test, but recent studies have shown that magnetic resonance cholangiopancreatography (MRCP) is an acceptable noninvasive substitute,7 and it may cost less per diagnosis.8
Liver biopsy alone is generally nondiagnostic because the histologic changes are quite variable in different segments of the same liver. The classic “onion-skin fibrosis” of primary sclerosing cholangitis is seen in fewer than 10% of biopsy specimens.9
Autoimmune hepatitis
Autoimmune hepatitis is chronic and is characterized by circulating autoantibodies and high serum globulin concentrations.10 Its presentation is heterogeneous, varying from no symptoms to nonspecific symptoms of malaise, fatigue, abdominal pain, itching, and arthralgia. Generally, elevations in aminotransferases are much more prominent than abnormalities in bilirubin and alkaline phosphatase levels10—unlike the pattern in our patient.
Primary biliary cirrhosis
Primary biliary cirrhosis is diagnosed if the patient has at least two of these three clinical criteria:
Biochemical evidence of cholestasis, with elevation of alkaline phosphatase for at least 6 months
Antimitochondrial antibody
Histologic evidence of nonsuppurative cholangitis and destruction of small or medium-sized bile ducts.11
In patients who lack antimitochondrial antibody, liver biopsy is necessary to establish the diagnosis. Given that primary biliary cirrhosis involves only small and medium-sized bile ducts, cholangiography is usually normal unless the patient has advanced cirrhosis.
Idiopathic adulthood ductopenia
Idiopathic adulthood ductopenia is a rare condition of unknown cause that involves the progressive destruction of segments of the small bile ducts inside the liver (“small-duct” biliary disease).12 Laboratory findings reveal a cholestatic pattern of liver injury, but biopsy samples show no features diagnostic or suggestive of another biliary disease; cholangiography is typically normal.12,13
ASSOCIATION WITH INFLAMMATORY BOWEL DISEASE
2. Which statement best characterizes inflammatory bowel disease associated with primary sclerosing cholangitis?
Crohn disease of the small bowel is the most common form
Liver disease often precedes the bowel disease
Treating the underlying bowel disease improves the long-term prognosis for the liver condition
Patients with primary sclerosing cholangitis and chronic ulcerative colitis are at higher risk of colonic dysplasia than patients with chronic ulcerative colitis alone
From 70% to 80% of patients with primary sclerosing cholangitis also have inflammatory bowel disease, usually chronic ulcerative colitis.14,15 Conversely, 2.4% to 4% of patients with ulcerative colitis and 1.4% to 3.4% of patients with Crohn disease have primary sclerosing cholangitis.1
Typically, the diagnosis of inflammatory bowel disease is made 8 to 10 years before the diagnosis of liver disease, although cases have also been reported to occur years after the diagnosis of cholangitis.15,16
No association between the severity of bowel disease and liver disease has been reported, and treating the inflammatory bowel disease does not alter the natural history of primary sclerosing cholangitis. Particularly, proctocolectomy, the most aggressive treatment for chronic ulcerative colitis, appears to have no effect on the course of the cholangitis.17
In patients with both primary sclerosing cholangitis and chronic ulcerative colitis, the risk of colonic dysplasia is higher than in patients with chronic ulcerative colitis alone.18 Recent studies have predicted that the risk of colorectal carcinoma in patients with primary sclerosing cholangitis and inflammatory bowel disease is as high as 25% after 10 years.19,20 Therefore, annual colonoscopy with surveillance biopsy is recommended in patients with both primary sclerosing cholangitis and chronic ulcerative colitis, since screening and early detection improve survival rates.15
TREATMENT AND PROGNOSIS
After being diagnosed with primary sclerosing cholangitis, the patient inquires about ongoing medical therapy and long-term prognosis.
3.Which is the only life-prolonging therapy for primary sclerosing cholangitis?
Methotrexate (Trexall)
Ursodeoxycholic acid (UDCA) (Actigall) at a standard dosage (13–15 mg/kg/day)
UDCA at a high dosage (20–30 mg/kg/day)
Liver transplantation
Drug therapy has not been shown to improve the prognosis of primary sclerosing cholangitis.
In randomized placebo-controlled trials, penicillamine (Depen), colchicine (Colcrys), methotrexate, and UDCA (13–15 mg/kg per day) failed to show efficacy.21–23
In pilot studies, high-dose UDCA (20 to 30 mg/kg/day) initially appeared to bring an improvement in survival probability, with trends toward histologic improvement,24,25 but larger randomized placebo-controlled trials found no improvement in symptoms, quality of life, survival rates, or risk of cholangiocarcinoma with high-dose UDCA.26,27 In fact, in 5 years of follow-up, patients on high-dose UDCA had a risk of death or transplantation two times higher than with placebo.27 One study indicated UDCA may decrease the incidence of colonic dysplasia in patients with primary sclerosing cholangitis and chronic ulcerative colitis.28 However, more prospective studies are required to better define the routine use of UDCA as a prophylactic agent.
Liver transplantation remains the most effective treatment for primary sclerosing cholangitis, and it improves the rate of survival.29 Nevertheless, about 20% of patients who undergo transplantation have a recurrence of cholangitis, and it may recur earlier after living-donor liver transplantation, particularly when the graft is from a biologically related donor.30 Proposed risk factors for recurrence include inflammatory bowel disease, prolonged ischemia time, the number of cellular rejection events, prior biliary surgery, cytomegalovirus infection, and lymphocytotoxic cross-match.31
4.In addition to cirrhosis and cholangitis, which of the following is a potential long-term complication of primary sclerosing cholangitis?
Colon cancer
Cholangiocarcinoma
Osteoporosis
Fat-soluble vitamin deficiency
All of the above
All are potential long-term complications.
Colon cancer. Concomitant chronic ulcerative colitis puts the patient at a higher risk of colonic dysplasia compared with patients with chronic ulcerative colitis alone.18 According to recent studies of patients with primary sclerosing cholangitis and inflammatory bowel disease, 19,20 the risk of colorectal carcinoma after 10 years of disease is as high as 25%.
Cholangiocarcinoma. Primary sclerosing cholangitis is considered a risk factor for cholangiocarcinoma, with an estimated 10-year cumulative incidence of 7% to 9%.1,20 In a retrospective study of 30 patients,32 the median survival was 5 months from the time of diagnosis of cholangiocarcinoma; at the time of diagnosis approximately 19 patients (63%) had metastatic disease.
At present, early detection of cholangiocarcinoma is hampered by the low sensitivity and specificity of standard diagnostic approaches. Carbohydrate antigen 19-9 has been used as a marker, but it has questionable accuracy, since elevations of this antigen can also be a result of pancreatic malignancy and bacterial cholangitis. However, cholangiocarcinoma should be suspected when patients present with progressive jaundice, weight loss, abdominal discomfort, and a sudden rise in carbohydrate antigen 19-9.
Conventional ultrasonography and computed tomography (CT) have poor sensitivity for detecting this malignancy. ERCP with biliary brushings should be considered when evaluating for biliary malignancy. New diagnostic methods such as digitized image analysis and fluorescence in situ hybridization on biliary brushings offer promise to evaluate bile duct lesions for cellular aneuploidy and chromosomal aberrations, which may improve the detection of cholangiocarcinoma.33 A recent large-scale study of nearly 500 patients showed that fluorescence in situ hybridization had a higher sensitivity (42.9%) than routine cytology (20.1%) with identical specificity (99.6%) for malignancy.34
Metabolic bone disease, usually osteoporosis rather than osteomalacia, is relatively common and is an important complication of primary sclerosing cholangitis.35 Patients with osteoporosis should be treated with vitamin D and calcium supplementation. Bisphosphonates have been used with varying results in primary biliary cirrhosis36 and can be considered in patients with advanced osteoporosis.
Fat-soluble vitamin deficiency is relatively common in primary sclerosing cholangitis, particularly as it progresses to advanced liver disease. Up to 40% of patients have vitamin A deficiency, 14% have vitamin D deficiency, and 2% have vitamin E deficiency.37 Patients can undergo simple oral replacement therapy.
A stone is removed, fever develops
Three years after the diagnosis of primary sclerosing cholangitis, the patient develops mild hyperbilirubinemia and undergoes ERCP at his local hospital. A stone is found obstructing the common bile duct and is successfully extracted.
Twenty-four hours after this procedure, he develops severe right-upper-quadrant pain and fever. He is seen at his local emergency department and blood cultures are drawn. He is started on antibiotics and is transferred to Mayo Clinic for further management.
5.In addition to continuing a broad-spectrum antibiotic, which would be the next best step for this patient?
ERCP
MRCP
Abdominal ultrasonography
Abdominal CT
The patient’s clinical presentation is consistent with acute bacterial cholangitis. The classic Charcot triad of fever, right-upper-quadrant pain, and jaundice occurs in only 50% to 75% of patients with acute cholangitis.38 In addition to receiving a broad-spectrum antibiotic, patients with bacterial cholangitis require emergency endoscopic evaluation—ERCP—to find and remove stones from the bile ducts and, if necessary, to dilate the biliary strictures to allow adequate drainage.
In our experience, more than 10% of patients with primary sclerosing cholangitis who undergo ERCP develop complications requiring hospitalization.39 The procedure generally takes longer to perform and the incidence of cholangitis is higher, despite routine antibiotic prophylaxis, in patients with primary sclerosing cholangitis than in those without it. However, the overall risk of pancreatitis, perforation, and bleeding was similar in patients with or without sclerosing cholangitis.39
MRCP is a promising noninvasive substitute for ERCP in establishing the diagnosis of primary sclerosing cholangitis.7,8 Unfortunately, as with other noninvasive imaging studies such as abdominal ultrasonography and CT, MRCP does not allow for therapeutic biliary decompression.
The patient undergoes ERCP with stenting
The patient’s acute cholangitis is thought to be a complication of his recent ERCP procedure. He undergoes emergency ERCP with balloon dilation and placement of a temporary left hepatic stent. His fever improves and he is discharged 48 hours later. He completes a 14-day course of antibiotics for Enterococcus faecalis bacteremia. Six weeks later, he undergoes ERCP yet again to remove the stent and tolerates the procedure well without complications.
TAKE-HOME POINTS
Primary sclerosing cholangitis is a progressive cholestatic liver disease of unknown etiology that primarily affects men during the fourth decade of life.
This condition is strongly associated with inflammatory bowel disease, particularly with ulcerative colitis.
Cholangiocarcinoma and colon cancer are dreaded complications.
Liver transplantation is the only life-extending therapy for primary sclerosing cholangitis; however, the condition can recur in the allograft.
References
Chapman R, Fevery J, Kalloo A, et al; American Association for the Study of Liver Diseases. Diagnosis and management of primary sclerosing cholangitis. Hepatology2010; 51:660–678.
Silveira MG, Lindor KD. Clinical features and management of primary sclerosing cholangitis. World J Gastroenterol2008; 14:3338–3349.
Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med1995; 332:924–933.
Bambha K, Kim WR, Talwalkar J, et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology2003; 125:1364–1369.
Kingham JG, Kochar N, Gravenor MB. Incidence, clinical patterns, and outcomes of primary sclerosing cholangitis in South Wales, United Kingdom. Gastroenterology2004; 126:1929–1930.
Berstad AE, Aabakken L, Smith HJ, Aasen S, Boberg KM, Schrumpf E. Diagnostic accuracy of magnetic resonance and endoscopic retrograde cholangiography in primary sclerosing cholangitis. Clin Gastroenterol Hepatol2006; 4:514–520.
Talwalkar JA, Angulo P, Johnson CD, Petersen BT, Lindor KD. Cost-minimization analysis of MRC versus ERCP for the diagnosis of primary sclerosing cholangitis. Hepatology2004; 40:39–45.
Ludwig J, Barham SS, LaRusso NF, Elveback LR, Wiesner RH, McCall JT. Morphologic features of chronic hepatitis associated with primary sclerosing cholangitis and chronic ulcerative colitis. Hepatology1981; 1:632–640.
Krawitt EL. Autoimmune hepatitis. N Engl J Med2006; 354:54–66.
Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ; American Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology2009; 50:291–308.
Ludwig J, Wiesner RH, LaRusso NF. Idiopathic adulthood ductopenia. A cause of chronic cholestatic liver disease and biliary cirrhosis. J Hepatol1988; 7:193–199.
Ludwig J. Idiopathic adulthood ductopenia: an update. Mayo Clin Proc1998; 73:285–291.
Fausa O, Schrumpf E, Elgjo K. Relationship of inflammatory bowel disease and primary sclerosing cholangitis. Semin Liver Dis1991; 11:31–39.
Loftus EV, Aguilar HI, Sandborn WJ, et al. Risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis following orthotopic liver transplantation. Hepatology1998; 27:685–690.
Loftus EV, Sandborn WJ, Tremaine WJ, et al. Risk of colorectal neoplasia in patients with primary sclerosing cholangitis. Gastroenterology1996; 110:432–440.
Cangemi JR, Wiesner RH, Beaver SJ, et al. Effect of proctocolectomy for chronic ulcerative colitis on the natural history of primary sclerosing cholangitis. Gastroenterology1989; 96:790–794.
Broomé U, Löfberg R, Veress B, Eriksson LS. Primary sclerosing cholangitis and ulcerative colitis: evidence for increased neoplastic potential. Hepatology1995; 22:1404–1408.
Kornfeld D, Ekbom A, Ihre T. Is there an excess risk for colorectal cancer in patients with ulcerative colitis and concomitant primary sclerosing cholangitis? A population based study. Gut1997; 41:522–525.
Claessen MM, Vleggaar FP, Tytgat KM, Siersema PD, van Buuren HR. High lifetime risk of cancer in primary sclerosing cholangitis. J Hepatol2009; 50:158–164.
Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med1997; 336:691–695.
Olsson R, Broomé U, Danielsson A, et al. Colchicine treatment of primary sclerosing cholangitis. Gastroenterology1995; 108:1199–1203.
LaRusso NF, Wiesner RH, Ludwig J, MacCarty RL, Beaver SJ, Zinsmeister AR. Prospective trial of penicillamine in primary sclerosing cholangitis. Gastroenterology1988; 95:1036–1042.
Mitchell SA, Bansi DS, Hunt N, Von Bergmann K, Fleming KA, Chapman RW. A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology2001; 121:900–907.
Cullen SN, Rust C, Fleming K, Edwards C, Beuers U, Chapman RW. High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis is safe and effective. J Hepatol2008; 48:792–800.
Olsson R, Boberg KM, de Muckadell OS, et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology2005; 129:1464–1472.
Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology2009; 50:808–814.
Tung BY, Emond MJ, Haggitt RC, et al. Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med2001; 134:89–95.
Wiesner RH, Porayko MK, Hay JE, et al. Liver transplantation for primary sclerosing cholangitis: impact of risk factors on outcome. Liver Transpl Surg1996; 2(suppl 1):99–108..
Tamura S, Sugawara Y, Kaneko J, Matsui Y, Togashi J, Makuuchi M. Recurrence of primary sclerosing cholangitis after living donor liver transplantation. Liver Int2007; 27:86–94.
Gautam M, Cheruvattath R, Balan V. Recurrence of autoimmune liver disease after liver transplantation: a systematic review. Liver Transpl2006; 12:1813–1824.
Fritcher EG, Kipp BR, Halling KC, et al. A multivariable model using advanced cytologic methods for the evaluation of indeterminate pancreatobiliary strictures. Gastroenterology2009; 136:2180–2186.
Hay JE, Lindor KD, Wiesner RH, Dickson ER, Krom RA, LaRusso NF. The metabolic bone disease of primary sclerosing cholangitis. Hepatology1991; 14:257–261.
Guañabens N, Parés A, Ros I, et al. Alendronate is more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis. Am J Gastroenterol2003; 98:2268–2274.
Saik RP, Greenburg AG, Farris JM, Peskin GW. Spectrum of cholangitis. Am J Surg1975; 130:143–150.
Bangarulingam SY, Gossard AA, Petersen BT, Ott BJ, Lindor KD. Complications of endoscopic retrograde cholangiopancreatography in primary sclerosing cholangitis. Am J Gastroenterol2009; 104:855–860.
References
Chapman R, Fevery J, Kalloo A, et al; American Association for the Study of Liver Diseases. Diagnosis and management of primary sclerosing cholangitis. Hepatology2010; 51:660–678.
Silveira MG, Lindor KD. Clinical features and management of primary sclerosing cholangitis. World J Gastroenterol2008; 14:3338–3349.
Lee YM, Kaplan MM. Primary sclerosing cholangitis. N Engl J Med1995; 332:924–933.
Bambha K, Kim WR, Talwalkar J, et al. Incidence, clinical spectrum, and outcomes of primary sclerosing cholangitis in a United States community. Gastroenterology2003; 125:1364–1369.
Kingham JG, Kochar N, Gravenor MB. Incidence, clinical patterns, and outcomes of primary sclerosing cholangitis in South Wales, United Kingdom. Gastroenterology2004; 126:1929–1930.
Berstad AE, Aabakken L, Smith HJ, Aasen S, Boberg KM, Schrumpf E. Diagnostic accuracy of magnetic resonance and endoscopic retrograde cholangiography in primary sclerosing cholangitis. Clin Gastroenterol Hepatol2006; 4:514–520.
Talwalkar JA, Angulo P, Johnson CD, Petersen BT, Lindor KD. Cost-minimization analysis of MRC versus ERCP for the diagnosis of primary sclerosing cholangitis. Hepatology2004; 40:39–45.
Ludwig J, Barham SS, LaRusso NF, Elveback LR, Wiesner RH, McCall JT. Morphologic features of chronic hepatitis associated with primary sclerosing cholangitis and chronic ulcerative colitis. Hepatology1981; 1:632–640.
Krawitt EL. Autoimmune hepatitis. N Engl J Med2006; 354:54–66.
Lindor KD, Gershwin ME, Poupon R, Kaplan M, Bergasa NV, Heathcote EJ; American Association for Study of Liver Diseases. Primary biliary cirrhosis. Hepatology2009; 50:291–308.
Ludwig J, Wiesner RH, LaRusso NF. Idiopathic adulthood ductopenia. A cause of chronic cholestatic liver disease and biliary cirrhosis. J Hepatol1988; 7:193–199.
Ludwig J. Idiopathic adulthood ductopenia: an update. Mayo Clin Proc1998; 73:285–291.
Fausa O, Schrumpf E, Elgjo K. Relationship of inflammatory bowel disease and primary sclerosing cholangitis. Semin Liver Dis1991; 11:31–39.
Loftus EV, Aguilar HI, Sandborn WJ, et al. Risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis following orthotopic liver transplantation. Hepatology1998; 27:685–690.
Loftus EV, Sandborn WJ, Tremaine WJ, et al. Risk of colorectal neoplasia in patients with primary sclerosing cholangitis. Gastroenterology1996; 110:432–440.
Cangemi JR, Wiesner RH, Beaver SJ, et al. Effect of proctocolectomy for chronic ulcerative colitis on the natural history of primary sclerosing cholangitis. Gastroenterology1989; 96:790–794.
Broomé U, Löfberg R, Veress B, Eriksson LS. Primary sclerosing cholangitis and ulcerative colitis: evidence for increased neoplastic potential. Hepatology1995; 22:1404–1408.
Kornfeld D, Ekbom A, Ihre T. Is there an excess risk for colorectal cancer in patients with ulcerative colitis and concomitant primary sclerosing cholangitis? A population based study. Gut1997; 41:522–525.
Claessen MM, Vleggaar FP, Tytgat KM, Siersema PD, van Buuren HR. High lifetime risk of cancer in primary sclerosing cholangitis. J Hepatol2009; 50:158–164.
Lindor KD. Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis-Ursodeoxycholic Acid Study Group. N Engl J Med1997; 336:691–695.
Olsson R, Broomé U, Danielsson A, et al. Colchicine treatment of primary sclerosing cholangitis. Gastroenterology1995; 108:1199–1203.
LaRusso NF, Wiesner RH, Ludwig J, MacCarty RL, Beaver SJ, Zinsmeister AR. Prospective trial of penicillamine in primary sclerosing cholangitis. Gastroenterology1988; 95:1036–1042.
Mitchell SA, Bansi DS, Hunt N, Von Bergmann K, Fleming KA, Chapman RW. A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis. Gastroenterology2001; 121:900–907.
Cullen SN, Rust C, Fleming K, Edwards C, Beuers U, Chapman RW. High dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis is safe and effective. J Hepatol2008; 48:792–800.
Olsson R, Boberg KM, de Muckadell OS, et al. High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study. Gastroenterology2005; 129:1464–1472.
Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the treatment of primary sclerosing cholangitis. Hepatology2009; 50:808–814.
Tung BY, Emond MJ, Haggitt RC, et al. Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med2001; 134:89–95.
Wiesner RH, Porayko MK, Hay JE, et al. Liver transplantation for primary sclerosing cholangitis: impact of risk factors on outcome. Liver Transpl Surg1996; 2(suppl 1):99–108..
Tamura S, Sugawara Y, Kaneko J, Matsui Y, Togashi J, Makuuchi M. Recurrence of primary sclerosing cholangitis after living donor liver transplantation. Liver Int2007; 27:86–94.
Gautam M, Cheruvattath R, Balan V. Recurrence of autoimmune liver disease after liver transplantation: a systematic review. Liver Transpl2006; 12:1813–1824.
Fritcher EG, Kipp BR, Halling KC, et al. A multivariable model using advanced cytologic methods for the evaluation of indeterminate pancreatobiliary strictures. Gastroenterology2009; 136:2180–2186.
Hay JE, Lindor KD, Wiesner RH, Dickson ER, Krom RA, LaRusso NF. The metabolic bone disease of primary sclerosing cholangitis. Hepatology1991; 14:257–261.
Guañabens N, Parés A, Ros I, et al. Alendronate is more effective than etidronate for increasing bone mass in osteopenic patients with primary biliary cirrhosis. Am J Gastroenterol2003; 98:2268–2274.
A 12-year-old boy presents with painless swelling and ulceration on and around his nose that has progressed gradually over the last 6 months. The lesion has increased in size despite treatment with topical neomycin and oral erythromycin. He has no systemic symptoms.
Figure 1. Ulcerated plaque with destruction of the right nasal wing.On examination (Figure 1), we note an indurated, nontender plaque with scarring at places on his right cheek, nose, and the vermilion border of the lip. In addition, there are two purulent ulcerations on the nose partly destroying the right nasal wing. The upper lip is also infiltrated, studded with a solitary ulceration. There is no regional lymphadenopathy. An examination of systems is normal.
Cutaneous tuberculosis occurs in many forms, and lupus vulgaris is one of the most common.1 Lupus vulgaris usually arises as a result of hematogenous spread from an endogenous source. It may also arise from exogenous inoculation or as a complication of vaccination with bacille Calmette-Guérin.2
Several morphologic variants have been described.1,2 One form is characterized by plaques, often studded with psoriasiform scales. Large plaques may show irregular areas of scarring with islands of active lupus tissue and a thickened and hyperkeratotic margin. Ulcerative and mutilating variants of lupus vulgaris are characterized by scarring, ulceration, crusts over areas of necrosis, and destruction of the deep tissues and cartilage, resulting in deformities. The vegetative form produces marked infiltration, ulceration, and necrosis, with minimal scarring. Mucous membranes and cartilages are often destroyed. Tumor-like hypertrophic lesions and multiple papular and nodular lesions may also be seen. Nasal lesions may start as nodules, which may bleed and then ulcerate, sometimes resulting in cartilage destruction.
CLINICAL FEATURES AND LABORATORY WORKUP CLINCHED THE DIAGNOSIS
A number of factors helped to confirm the diagnosis in this patient:
A strongly positive Mantoux test (22-mm induration at 48 hours)
Acid-fast bacilli on Ziehl-Neelsen staining of the smear taken from the purulent ulceration
Isolation of Mycobacterium tuberculosis from the purulent exudates via culture in Lowenstein-Jensen medium
Figure 2. Epithelioid cell granuloma and giant cells (hematoxylin and eosin, × 100).A suggestive histopathologic picture (Figure 2)
The features on presentation
A significant clinical improvement within 2 months of starting antituberculosis therapy.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis includes all the conditions in the question above. However, the absence of respiratory and renal involvement helps rule out Wegener granulomatosis; the absence of impaired sensation and nerve thickening helps rule out Hansen disease; and the absence of a nasal septal defect helps rule out Wegener granulomatosis, midline lethal granuloma, and Hansen disease.
On the other hand, the lupoid form of cutaneous leishmaniasis usually presents as an erythematous, infiltrated plaque that often closely resembles lupus vulgaris, but these lesions are usually less destructive than lupus vulgaris. However, the laboratory workup including the microbiological and histopathologic examination clearly excluded the other potential diagnoses in this patient.
TREATMENT
Lupus vulgaris is treated with standard antituberculosis therapy.3 The first phase of a fourdrug regimen is given for 2 months—isoniazid, rifampin (Rifadin), pyrazinamide, and ethambutol (Myambutol). The second phase consists of isoniazid and rifampin for 4 months.3
Early recognition and confirmation of the diagnosis followed by treatment are of immense importance for preventing permanent disfigurement.
References
Freitag DS, Chin R. Facial granulomas with nasal destruction. Chest1988; 93:422–423.
Sudip Kumar Ghosh, MD, DNB Assistant Professor, Department of Dermatology, Venereology, and Leprosy, R. G. Kar Medical College, Kolkata, India
Debarbrata Bandyopadhyay, MD Professor, Department of Dermatology, Venereology, and Leprosy, R. G. Kar Medical College, Kolkata, India
Loknath Ghoshal, MD Resident Medical Officer-cum-Clinical Tutor, Department of Dermatology, Venereology, and Leprosy, R. G. Kar Medical College, Kolkata, India
Address: Sudip Kumar Ghosh, MD, DNB, Department of Dermatology, Venereology, and Leprosy, R. G. Kar Medical College, 1, Khudiram Bose Sarani, 700004 Kolkata, India; e-mail [email protected]
Sudip Kumar Ghosh, MD, DNB Assistant Professor, Department of Dermatology, Venereology, and Leprosy, R. G. Kar Medical College, Kolkata, India
Debarbrata Bandyopadhyay, MD Professor, Department of Dermatology, Venereology, and Leprosy, R. G. Kar Medical College, Kolkata, India
Loknath Ghoshal, MD Resident Medical Officer-cum-Clinical Tutor, Department of Dermatology, Venereology, and Leprosy, R. G. Kar Medical College, Kolkata, India
Address: Sudip Kumar Ghosh, MD, DNB, Department of Dermatology, Venereology, and Leprosy, R. G. Kar Medical College, 1, Khudiram Bose Sarani, 700004 Kolkata, India; e-mail [email protected]
Author and Disclosure Information
Sudip Kumar Ghosh, MD, DNB Assistant Professor, Department of Dermatology, Venereology, and Leprosy, R. G. Kar Medical College, Kolkata, India
Debarbrata Bandyopadhyay, MD Professor, Department of Dermatology, Venereology, and Leprosy, R. G. Kar Medical College, Kolkata, India
Loknath Ghoshal, MD Resident Medical Officer-cum-Clinical Tutor, Department of Dermatology, Venereology, and Leprosy, R. G. Kar Medical College, Kolkata, India
Address: Sudip Kumar Ghosh, MD, DNB, Department of Dermatology, Venereology, and Leprosy, R. G. Kar Medical College, 1, Khudiram Bose Sarani, 700004 Kolkata, India; e-mail [email protected]
A 12-year-old boy presents with painless swelling and ulceration on and around his nose that has progressed gradually over the last 6 months. The lesion has increased in size despite treatment with topical neomycin and oral erythromycin. He has no systemic symptoms.
Figure 1. Ulcerated plaque with destruction of the right nasal wing.On examination (Figure 1), we note an indurated, nontender plaque with scarring at places on his right cheek, nose, and the vermilion border of the lip. In addition, there are two purulent ulcerations on the nose partly destroying the right nasal wing. The upper lip is also infiltrated, studded with a solitary ulceration. There is no regional lymphadenopathy. An examination of systems is normal.
Cutaneous tuberculosis occurs in many forms, and lupus vulgaris is one of the most common.1 Lupus vulgaris usually arises as a result of hematogenous spread from an endogenous source. It may also arise from exogenous inoculation or as a complication of vaccination with bacille Calmette-Guérin.2
Several morphologic variants have been described.1,2 One form is characterized by plaques, often studded with psoriasiform scales. Large plaques may show irregular areas of scarring with islands of active lupus tissue and a thickened and hyperkeratotic margin. Ulcerative and mutilating variants of lupus vulgaris are characterized by scarring, ulceration, crusts over areas of necrosis, and destruction of the deep tissues and cartilage, resulting in deformities. The vegetative form produces marked infiltration, ulceration, and necrosis, with minimal scarring. Mucous membranes and cartilages are often destroyed. Tumor-like hypertrophic lesions and multiple papular and nodular lesions may also be seen. Nasal lesions may start as nodules, which may bleed and then ulcerate, sometimes resulting in cartilage destruction.
CLINICAL FEATURES AND LABORATORY WORKUP CLINCHED THE DIAGNOSIS
A number of factors helped to confirm the diagnosis in this patient:
A strongly positive Mantoux test (22-mm induration at 48 hours)
Acid-fast bacilli on Ziehl-Neelsen staining of the smear taken from the purulent ulceration
Isolation of Mycobacterium tuberculosis from the purulent exudates via culture in Lowenstein-Jensen medium
Figure 2. Epithelioid cell granuloma and giant cells (hematoxylin and eosin, × 100).A suggestive histopathologic picture (Figure 2)
The features on presentation
A significant clinical improvement within 2 months of starting antituberculosis therapy.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis includes all the conditions in the question above. However, the absence of respiratory and renal involvement helps rule out Wegener granulomatosis; the absence of impaired sensation and nerve thickening helps rule out Hansen disease; and the absence of a nasal septal defect helps rule out Wegener granulomatosis, midline lethal granuloma, and Hansen disease.
On the other hand, the lupoid form of cutaneous leishmaniasis usually presents as an erythematous, infiltrated plaque that often closely resembles lupus vulgaris, but these lesions are usually less destructive than lupus vulgaris. However, the laboratory workup including the microbiological and histopathologic examination clearly excluded the other potential diagnoses in this patient.
TREATMENT
Lupus vulgaris is treated with standard antituberculosis therapy.3 The first phase of a fourdrug regimen is given for 2 months—isoniazid, rifampin (Rifadin), pyrazinamide, and ethambutol (Myambutol). The second phase consists of isoniazid and rifampin for 4 months.3
Early recognition and confirmation of the diagnosis followed by treatment are of immense importance for preventing permanent disfigurement.
A 12-year-old boy presents with painless swelling and ulceration on and around his nose that has progressed gradually over the last 6 months. The lesion has increased in size despite treatment with topical neomycin and oral erythromycin. He has no systemic symptoms.
Figure 1. Ulcerated plaque with destruction of the right nasal wing.On examination (Figure 1), we note an indurated, nontender plaque with scarring at places on his right cheek, nose, and the vermilion border of the lip. In addition, there are two purulent ulcerations on the nose partly destroying the right nasal wing. The upper lip is also infiltrated, studded with a solitary ulceration. There is no regional lymphadenopathy. An examination of systems is normal.
Cutaneous tuberculosis occurs in many forms, and lupus vulgaris is one of the most common.1 Lupus vulgaris usually arises as a result of hematogenous spread from an endogenous source. It may also arise from exogenous inoculation or as a complication of vaccination with bacille Calmette-Guérin.2
Several morphologic variants have been described.1,2 One form is characterized by plaques, often studded with psoriasiform scales. Large plaques may show irregular areas of scarring with islands of active lupus tissue and a thickened and hyperkeratotic margin. Ulcerative and mutilating variants of lupus vulgaris are characterized by scarring, ulceration, crusts over areas of necrosis, and destruction of the deep tissues and cartilage, resulting in deformities. The vegetative form produces marked infiltration, ulceration, and necrosis, with minimal scarring. Mucous membranes and cartilages are often destroyed. Tumor-like hypertrophic lesions and multiple papular and nodular lesions may also be seen. Nasal lesions may start as nodules, which may bleed and then ulcerate, sometimes resulting in cartilage destruction.
CLINICAL FEATURES AND LABORATORY WORKUP CLINCHED THE DIAGNOSIS
A number of factors helped to confirm the diagnosis in this patient:
A strongly positive Mantoux test (22-mm induration at 48 hours)
Acid-fast bacilli on Ziehl-Neelsen staining of the smear taken from the purulent ulceration
Isolation of Mycobacterium tuberculosis from the purulent exudates via culture in Lowenstein-Jensen medium
Figure 2. Epithelioid cell granuloma and giant cells (hematoxylin and eosin, × 100).A suggestive histopathologic picture (Figure 2)
The features on presentation
A significant clinical improvement within 2 months of starting antituberculosis therapy.
DIFFERENTIAL DIAGNOSIS
The differential diagnosis includes all the conditions in the question above. However, the absence of respiratory and renal involvement helps rule out Wegener granulomatosis; the absence of impaired sensation and nerve thickening helps rule out Hansen disease; and the absence of a nasal septal defect helps rule out Wegener granulomatosis, midline lethal granuloma, and Hansen disease.
On the other hand, the lupoid form of cutaneous leishmaniasis usually presents as an erythematous, infiltrated plaque that often closely resembles lupus vulgaris, but these lesions are usually less destructive than lupus vulgaris. However, the laboratory workup including the microbiological and histopathologic examination clearly excluded the other potential diagnoses in this patient.
TREATMENT
Lupus vulgaris is treated with standard antituberculosis therapy.3 The first phase of a fourdrug regimen is given for 2 months—isoniazid, rifampin (Rifadin), pyrazinamide, and ethambutol (Myambutol). The second phase consists of isoniazid and rifampin for 4 months.3
Early recognition and confirmation of the diagnosis followed by treatment are of immense importance for preventing permanent disfigurement.
References
Freitag DS, Chin R. Facial granulomas with nasal destruction. Chest1988; 93:422–423.
An otherwise healthy 46-year-old man presents with fever, chills, and rigors that began 1 day ago. He reports shortness of breath, nausea, neck pain, sore throat, and right-sided jaw pain, but no chest pain, headache, or photophobia.
His vital signs are within normal limits, except for a temperature of 38.5°C (101.3°F). His jugular venous pressure and heart sounds are normal, and no focal deficit or nuchal rigidity is elicited. Laboratory tests (hemography, biochemistry panel, and cardiac biomarkers) are normal. An enzyme immunoassay for influenza A and B is negative, as is a rapid antigen detection test for streptococcal infection.
Figure 1. The electrocardiogram at admission shows ST-segment elevation in leads V1 and V2 (arrows) at a body temperature of 38.5°C.Chest radiography and computed tomography of the head are normal. Standard 12-lead electrocardiography (ECG) shows 3-mm ST-segment elevation in leads V1 and V2 (Figure 1).
Figure 2. After cardiac catheterization, the electrocardiogram shows the type 1 Brugada pattern at a body temperature of 39.3°C.He receives sublingual nitroglycerin, aspirin, clopidogrel (Plavix) 600 mg, and morphine. Emergency cardiac catheterization shows no obstructive atherosclerotic coronary disease. ECG after catheterization shows “coved” ST-segment elevations in the right precordial leads V1 and V2 (Figure 2). At this point, his temperature is 39.3°C (102°F).
Q: What is the most likely diagnosis?
Acute myocardial infarction
Coronary vasospasm
Brugada syndrome
Acute pericarditis
Acute meningitis
A: ST elevation commonly represents acute myocardial infarction, but it is associated with other conditions, including Prinzmetal angina, hyperkalemia, hypercalcemia, early repolarization, Brugada syndrome, and acute pericarditis.1 These conditions should be considered before an invasive intervention. The ECG findings (ST elevation in the right precordial leads) in this patient were consistent with those of Brugada syndrome.
WHAT IS BRUGADA SYNDROME?
Brugada syndrome is an arrhythmogenic disease characterized by ST-segment elevation in the right precordial leads, right bundle branch block, and a high incidence of sudden cardiac death in younger people.2 It accounts for 4% of all sudden deaths.3
Three different types of changes on ECG have been associated with Brugada syndrome. Type 1 is a coved ST-segment elevation of at least 2 mm, followed by a negative T wave, with little or no isoelectric separation, and present in more than one right precordial lead (from V1 to V3). Type 2 and type 3 patterns on ECG show the same 2-mm or greater J-point elevation, but a positive T wave gives the “saddleback” appearance to the ST-T portion.
Brugada syndrome is confirmed when a type 1 pattern is observed in conjunction with one of the following:
Documented ventricular fibrillation
Polymorphic ventricular tachycardia
A family history of sudden cardiac death at 45 years of age or younger
Type 1 pattern on ECG in family members
Ventricular tachycardia that can be induced with programmed electrical stimulation
Syncope
Nocturnal agonal respiration.3
This patient had type 1 changes on ECG but none of the above findings.
Brugada syndrome is inherited as an autosomal dominant trait, and mutations in gene SCN5A account for 18% to 30% of cases.3 These mutations impair the function of the sodium channel current, leading to an unopposed outward shift of net transmembrane current at the end of phase 1 of the right ventricular epicardial action potential. Interestingly, changes on ECG that are associated with Brugada syndrome are often dynamic or concealed and are unmasked by sodium channel blockers, fever, vagotonic agents, adrenergic agonists or antagonists, and various electrolyte abnormalities.3
At temperatures above the physiologic range, the inward sodium current is reduced, either because of failure of expression of sodium channels or because of premature closing of the sodium channels in genetically susceptible individuals.4 Therefore, fever can unmask Brugada syndrome, as it did in our patient.
For patients with symptomatic Brugada syndrome, the only current treatment is implantation of a cardioverter-defibrillator.5 Patients without symptoms may benefit from an electrophysiologic study for risk stratification, and an implantable cardioverter-defibrillator is recommended for those in whom ventricular fibrillation can be induced.3,5
CASE CONTINUED
The patient remained febrile after catheterization and received vancomycin (Vancocin) and ceftriaxone (Rocephin) empirically for presumed meningitis. Multiple peripheral blood cultures grew gram-positive cocci in pairs and chains, which were identified as Streptococcus pneumoniae. His fever abated soon after the antibiotic therapy was started.
Lumbar puncture was not done. Transesophageal echocardiography revealed no vegetations, with preserved ejection fraction. The patient has no family history of sudden death and no personal history of syncope or presyncope.
On hospital day 3, although his fever was gone, ECG still showed a Brugada pattern. He was discharged home on a 3-week regimen of intravenous penicillin, with plans for appropriate follow-up, and he was counseled that his family should be screened. An electrophysiologic study was not done, and he had no symptoms 1 year later.
As seen in this patient, Brugada syndrome is important to consider in the differential diagnosis in young patients who present with fever and ST elevations.
References
Wang K, Asinger RW, Marriott HJ. ST-segment elevation in conditions other than acute myocardial infarction. N Engl J Med2003; 349:2128–2135.
Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol1992; 20:1391–1396.
Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation2005; 111:659–670.
Dumaine R, Towbin JA, Brugada P, et al. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res1999; 85:803–809.
Antzelevitch C, Nof E. Brugada syndrome: recent advances and controversies. Curr Cardiol Rep2008; 10:376–383.
An otherwise healthy 46-year-old man presents with fever, chills, and rigors that began 1 day ago. He reports shortness of breath, nausea, neck pain, sore throat, and right-sided jaw pain, but no chest pain, headache, or photophobia.
His vital signs are within normal limits, except for a temperature of 38.5°C (101.3°F). His jugular venous pressure and heart sounds are normal, and no focal deficit or nuchal rigidity is elicited. Laboratory tests (hemography, biochemistry panel, and cardiac biomarkers) are normal. An enzyme immunoassay for influenza A and B is negative, as is a rapid antigen detection test for streptococcal infection.
Figure 1. The electrocardiogram at admission shows ST-segment elevation in leads V1 and V2 (arrows) at a body temperature of 38.5°C.Chest radiography and computed tomography of the head are normal. Standard 12-lead electrocardiography (ECG) shows 3-mm ST-segment elevation in leads V1 and V2 (Figure 1).
Figure 2. After cardiac catheterization, the electrocardiogram shows the type 1 Brugada pattern at a body temperature of 39.3°C.He receives sublingual nitroglycerin, aspirin, clopidogrel (Plavix) 600 mg, and morphine. Emergency cardiac catheterization shows no obstructive atherosclerotic coronary disease. ECG after catheterization shows “coved” ST-segment elevations in the right precordial leads V1 and V2 (Figure 2). At this point, his temperature is 39.3°C (102°F).
Q: What is the most likely diagnosis?
Acute myocardial infarction
Coronary vasospasm
Brugada syndrome
Acute pericarditis
Acute meningitis
A: ST elevation commonly represents acute myocardial infarction, but it is associated with other conditions, including Prinzmetal angina, hyperkalemia, hypercalcemia, early repolarization, Brugada syndrome, and acute pericarditis.1 These conditions should be considered before an invasive intervention. The ECG findings (ST elevation in the right precordial leads) in this patient were consistent with those of Brugada syndrome.
WHAT IS BRUGADA SYNDROME?
Brugada syndrome is an arrhythmogenic disease characterized by ST-segment elevation in the right precordial leads, right bundle branch block, and a high incidence of sudden cardiac death in younger people.2 It accounts for 4% of all sudden deaths.3
Three different types of changes on ECG have been associated with Brugada syndrome. Type 1 is a coved ST-segment elevation of at least 2 mm, followed by a negative T wave, with little or no isoelectric separation, and present in more than one right precordial lead (from V1 to V3). Type 2 and type 3 patterns on ECG show the same 2-mm or greater J-point elevation, but a positive T wave gives the “saddleback” appearance to the ST-T portion.
Brugada syndrome is confirmed when a type 1 pattern is observed in conjunction with one of the following:
Documented ventricular fibrillation
Polymorphic ventricular tachycardia
A family history of sudden cardiac death at 45 years of age or younger
Type 1 pattern on ECG in family members
Ventricular tachycardia that can be induced with programmed electrical stimulation
Syncope
Nocturnal agonal respiration.3
This patient had type 1 changes on ECG but none of the above findings.
Brugada syndrome is inherited as an autosomal dominant trait, and mutations in gene SCN5A account for 18% to 30% of cases.3 These mutations impair the function of the sodium channel current, leading to an unopposed outward shift of net transmembrane current at the end of phase 1 of the right ventricular epicardial action potential. Interestingly, changes on ECG that are associated with Brugada syndrome are often dynamic or concealed and are unmasked by sodium channel blockers, fever, vagotonic agents, adrenergic agonists or antagonists, and various electrolyte abnormalities.3
At temperatures above the physiologic range, the inward sodium current is reduced, either because of failure of expression of sodium channels or because of premature closing of the sodium channels in genetically susceptible individuals.4 Therefore, fever can unmask Brugada syndrome, as it did in our patient.
For patients with symptomatic Brugada syndrome, the only current treatment is implantation of a cardioverter-defibrillator.5 Patients without symptoms may benefit from an electrophysiologic study for risk stratification, and an implantable cardioverter-defibrillator is recommended for those in whom ventricular fibrillation can be induced.3,5
CASE CONTINUED
The patient remained febrile after catheterization and received vancomycin (Vancocin) and ceftriaxone (Rocephin) empirically for presumed meningitis. Multiple peripheral blood cultures grew gram-positive cocci in pairs and chains, which were identified as Streptococcus pneumoniae. His fever abated soon after the antibiotic therapy was started.
Lumbar puncture was not done. Transesophageal echocardiography revealed no vegetations, with preserved ejection fraction. The patient has no family history of sudden death and no personal history of syncope or presyncope.
On hospital day 3, although his fever was gone, ECG still showed a Brugada pattern. He was discharged home on a 3-week regimen of intravenous penicillin, with plans for appropriate follow-up, and he was counseled that his family should be screened. An electrophysiologic study was not done, and he had no symptoms 1 year later.
As seen in this patient, Brugada syndrome is important to consider in the differential diagnosis in young patients who present with fever and ST elevations.
An otherwise healthy 46-year-old man presents with fever, chills, and rigors that began 1 day ago. He reports shortness of breath, nausea, neck pain, sore throat, and right-sided jaw pain, but no chest pain, headache, or photophobia.
His vital signs are within normal limits, except for a temperature of 38.5°C (101.3°F). His jugular venous pressure and heart sounds are normal, and no focal deficit or nuchal rigidity is elicited. Laboratory tests (hemography, biochemistry panel, and cardiac biomarkers) are normal. An enzyme immunoassay for influenza A and B is negative, as is a rapid antigen detection test for streptococcal infection.
Figure 1. The electrocardiogram at admission shows ST-segment elevation in leads V1 and V2 (arrows) at a body temperature of 38.5°C.Chest radiography and computed tomography of the head are normal. Standard 12-lead electrocardiography (ECG) shows 3-mm ST-segment elevation in leads V1 and V2 (Figure 1).
Figure 2. After cardiac catheterization, the electrocardiogram shows the type 1 Brugada pattern at a body temperature of 39.3°C.He receives sublingual nitroglycerin, aspirin, clopidogrel (Plavix) 600 mg, and morphine. Emergency cardiac catheterization shows no obstructive atherosclerotic coronary disease. ECG after catheterization shows “coved” ST-segment elevations in the right precordial leads V1 and V2 (Figure 2). At this point, his temperature is 39.3°C (102°F).
Q: What is the most likely diagnosis?
Acute myocardial infarction
Coronary vasospasm
Brugada syndrome
Acute pericarditis
Acute meningitis
A: ST elevation commonly represents acute myocardial infarction, but it is associated with other conditions, including Prinzmetal angina, hyperkalemia, hypercalcemia, early repolarization, Brugada syndrome, and acute pericarditis.1 These conditions should be considered before an invasive intervention. The ECG findings (ST elevation in the right precordial leads) in this patient were consistent with those of Brugada syndrome.
WHAT IS BRUGADA SYNDROME?
Brugada syndrome is an arrhythmogenic disease characterized by ST-segment elevation in the right precordial leads, right bundle branch block, and a high incidence of sudden cardiac death in younger people.2 It accounts for 4% of all sudden deaths.3
Three different types of changes on ECG have been associated with Brugada syndrome. Type 1 is a coved ST-segment elevation of at least 2 mm, followed by a negative T wave, with little or no isoelectric separation, and present in more than one right precordial lead (from V1 to V3). Type 2 and type 3 patterns on ECG show the same 2-mm or greater J-point elevation, but a positive T wave gives the “saddleback” appearance to the ST-T portion.
Brugada syndrome is confirmed when a type 1 pattern is observed in conjunction with one of the following:
Documented ventricular fibrillation
Polymorphic ventricular tachycardia
A family history of sudden cardiac death at 45 years of age or younger
Type 1 pattern on ECG in family members
Ventricular tachycardia that can be induced with programmed electrical stimulation
Syncope
Nocturnal agonal respiration.3
This patient had type 1 changes on ECG but none of the above findings.
Brugada syndrome is inherited as an autosomal dominant trait, and mutations in gene SCN5A account for 18% to 30% of cases.3 These mutations impair the function of the sodium channel current, leading to an unopposed outward shift of net transmembrane current at the end of phase 1 of the right ventricular epicardial action potential. Interestingly, changes on ECG that are associated with Brugada syndrome are often dynamic or concealed and are unmasked by sodium channel blockers, fever, vagotonic agents, adrenergic agonists or antagonists, and various electrolyte abnormalities.3
At temperatures above the physiologic range, the inward sodium current is reduced, either because of failure of expression of sodium channels or because of premature closing of the sodium channels in genetically susceptible individuals.4 Therefore, fever can unmask Brugada syndrome, as it did in our patient.
For patients with symptomatic Brugada syndrome, the only current treatment is implantation of a cardioverter-defibrillator.5 Patients without symptoms may benefit from an electrophysiologic study for risk stratification, and an implantable cardioverter-defibrillator is recommended for those in whom ventricular fibrillation can be induced.3,5
CASE CONTINUED
The patient remained febrile after catheterization and received vancomycin (Vancocin) and ceftriaxone (Rocephin) empirically for presumed meningitis. Multiple peripheral blood cultures grew gram-positive cocci in pairs and chains, which were identified as Streptococcus pneumoniae. His fever abated soon after the antibiotic therapy was started.
Lumbar puncture was not done. Transesophageal echocardiography revealed no vegetations, with preserved ejection fraction. The patient has no family history of sudden death and no personal history of syncope or presyncope.
On hospital day 3, although his fever was gone, ECG still showed a Brugada pattern. He was discharged home on a 3-week regimen of intravenous penicillin, with plans for appropriate follow-up, and he was counseled that his family should be screened. An electrophysiologic study was not done, and he had no symptoms 1 year later.
As seen in this patient, Brugada syndrome is important to consider in the differential diagnosis in young patients who present with fever and ST elevations.
References
Wang K, Asinger RW, Marriott HJ. ST-segment elevation in conditions other than acute myocardial infarction. N Engl J Med2003; 349:2128–2135.
Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol1992; 20:1391–1396.
Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation2005; 111:659–670.
Dumaine R, Towbin JA, Brugada P, et al. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res1999; 85:803–809.
Antzelevitch C, Nof E. Brugada syndrome: recent advances and controversies. Curr Cardiol Rep2008; 10:376–383.
References
Wang K, Asinger RW, Marriott HJ. ST-segment elevation in conditions other than acute myocardial infarction. N Engl J Med2003; 349:2128–2135.
Brugada P, Brugada J. Right bundle branch block, persistent ST segment elevation and sudden cardiac death: a distinct clinical and electrocardiographic syndrome. A multicenter report. J Am Coll Cardiol1992; 20:1391–1396.
Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation2005; 111:659–670.
Dumaine R, Towbin JA, Brugada P, et al. Ionic mechanisms responsible for the electrocardiographic phenotype of the Brugada syndrome are temperature dependent. Circ Res1999; 85:803–809.
Antzelevitch C, Nof E. Brugada syndrome: recent advances and controversies. Curr Cardiol Rep2008; 10:376–383.
The discussion of angiotensin-converting enzyme (ACE) inhibitor therapy and visceral angioedema by Korniyenko et al in this issue of the Journal prompted me to consider the diagnostic epiphany.
This group had a patient with unexplained abdominal pain who ultimately underwent laparotomy, which did not reveal the diagnosis. I can reconstruct the thought processes that led to the decision for surgery, but far more intriguing is what provoked the “aha” moment when the true diagnosis—ACE inhibitor-associated angioedema—finally occurred to someone.
This is a rare complication of a common therapy, perhaps read about but not reasonable to expect all physicians to recall. If that is true, why can’t we incorporate technology into our care system to intelligently supplement the individual physician’s memory? What would have been the result if a “smart” electronic record had flagged the combination of ACE inhibitor therapy and recurrent abdominal pain and provided a citation on visceral angioedema?
We have all experienced a diagnostic epiphany, the sudden recognition of an arcane or unexpected diagnosis—as on the TV show House, but without the sneer or commercials. Some epiphanies result from suddenly seeing theretofore disconnected dots as a recognizable pattern. Some result from sudden recall of “I saw something like this once.” The superb diagnosticians seem to have these experiences more than the rest of us. Their powers of clinical reasoning are not always transparent. Some are based on the gestalt born of perception and experience, others are the result of incredibly compulsive structured analysis. Both require experience, contextual knowledge, and accurate historical information. These components will need to be incorporated into any diagnostic assistive software. But is this possible?
Those who have read my previous commentaries know that I value highly the clinical skills of history-taking and examination. I believe that these fundamental processes should be used to direct laboratory and imaging studies. I also optimistically expect that electronic medical records will evolve to become far more useful than most currently are, ultimately acting as true auxiliary brains, able to remind us of facts that we can’t recall (eg, that visceral angioedema is associated with ACE inhibitors). But there will never be a substitute for the artful and compulsive interview that establishes whether our patient is actually taking his or her medication, and whether there is a relationship between when a medication is ingested and when symptoms appear. The quality of the data entered into our electronic medical record (or other auxiliary brains), to then be associated with various informational databases, will always depend on the skill of the listening and examining clinician.
The discussion of angiotensin-converting enzyme (ACE) inhibitor therapy and visceral angioedema by Korniyenko et al in this issue of the Journal prompted me to consider the diagnostic epiphany.
This group had a patient with unexplained abdominal pain who ultimately underwent laparotomy, which did not reveal the diagnosis. I can reconstruct the thought processes that led to the decision for surgery, but far more intriguing is what provoked the “aha” moment when the true diagnosis—ACE inhibitor-associated angioedema—finally occurred to someone.
This is a rare complication of a common therapy, perhaps read about but not reasonable to expect all physicians to recall. If that is true, why can’t we incorporate technology into our care system to intelligently supplement the individual physician’s memory? What would have been the result if a “smart” electronic record had flagged the combination of ACE inhibitor therapy and recurrent abdominal pain and provided a citation on visceral angioedema?
We have all experienced a diagnostic epiphany, the sudden recognition of an arcane or unexpected diagnosis—as on the TV show House, but without the sneer or commercials. Some epiphanies result from suddenly seeing theretofore disconnected dots as a recognizable pattern. Some result from sudden recall of “I saw something like this once.” The superb diagnosticians seem to have these experiences more than the rest of us. Their powers of clinical reasoning are not always transparent. Some are based on the gestalt born of perception and experience, others are the result of incredibly compulsive structured analysis. Both require experience, contextual knowledge, and accurate historical information. These components will need to be incorporated into any diagnostic assistive software. But is this possible?
Those who have read my previous commentaries know that I value highly the clinical skills of history-taking and examination. I believe that these fundamental processes should be used to direct laboratory and imaging studies. I also optimistically expect that electronic medical records will evolve to become far more useful than most currently are, ultimately acting as true auxiliary brains, able to remind us of facts that we can’t recall (eg, that visceral angioedema is associated with ACE inhibitors). But there will never be a substitute for the artful and compulsive interview that establishes whether our patient is actually taking his or her medication, and whether there is a relationship between when a medication is ingested and when symptoms appear. The quality of the data entered into our electronic medical record (or other auxiliary brains), to then be associated with various informational databases, will always depend on the skill of the listening and examining clinician.
The discussion of angiotensin-converting enzyme (ACE) inhibitor therapy and visceral angioedema by Korniyenko et al in this issue of the Journal prompted me to consider the diagnostic epiphany.
This group had a patient with unexplained abdominal pain who ultimately underwent laparotomy, which did not reveal the diagnosis. I can reconstruct the thought processes that led to the decision for surgery, but far more intriguing is what provoked the “aha” moment when the true diagnosis—ACE inhibitor-associated angioedema—finally occurred to someone.
This is a rare complication of a common therapy, perhaps read about but not reasonable to expect all physicians to recall. If that is true, why can’t we incorporate technology into our care system to intelligently supplement the individual physician’s memory? What would have been the result if a “smart” electronic record had flagged the combination of ACE inhibitor therapy and recurrent abdominal pain and provided a citation on visceral angioedema?
We have all experienced a diagnostic epiphany, the sudden recognition of an arcane or unexpected diagnosis—as on the TV show House, but without the sneer or commercials. Some epiphanies result from suddenly seeing theretofore disconnected dots as a recognizable pattern. Some result from sudden recall of “I saw something like this once.” The superb diagnosticians seem to have these experiences more than the rest of us. Their powers of clinical reasoning are not always transparent. Some are based on the gestalt born of perception and experience, others are the result of incredibly compulsive structured analysis. Both require experience, contextual knowledge, and accurate historical information. These components will need to be incorporated into any diagnostic assistive software. But is this possible?
Those who have read my previous commentaries know that I value highly the clinical skills of history-taking and examination. I believe that these fundamental processes should be used to direct laboratory and imaging studies. I also optimistically expect that electronic medical records will evolve to become far more useful than most currently are, ultimately acting as true auxiliary brains, able to remind us of facts that we can’t recall (eg, that visceral angioedema is associated with ACE inhibitors). But there will never be a substitute for the artful and compulsive interview that establishes whether our patient is actually taking his or her medication, and whether there is a relationship between when a medication is ingested and when symptoms appear. The quality of the data entered into our electronic medical record (or other auxiliary brains), to then be associated with various informational databases, will always depend on the skill of the listening and examining clinician.
