An otherwise healthy 54-year-old woman presented with a 3-month history of an asymptomatic lesion on the face, at the site of a previous mosquito bite. Physical examination revealed a firm, pink nodule 10 mm in diameter (Figure 1). Telangiectasias were visible, more clearly by dermoscopy, but other features of a basal cell carcinoma were absent. No other skin problem was noted, and no lymphadenopathy was detected.

Histologic study of a biopsy specimen noted a dense dermal inflammatory infiltrate consisting of B lymphocytes (CD20+) with a smaller number of T lymphocytes (CD3+) arranged in several germinal centers, with an admixture of plasma cells and eosinophils (Figure 2). No clonal population was identified by gene-rearrangement studies. Borrelia burgdorferi infection was ruled out.

Q: Which is the most likely diagnosis?

• Basal cell carcinoma
• Squamous cell carcinoma
• Lymphocytoma cutis
• Amelanotic melanoma
• Pyogenic granuloma

A: The correct answer is lymphocytoma cutis. The differential diagnosis of a pink papule on the face of a middle-aged person includes nonmelanoma skin cancer, lymphoma, lymphocytoma cutis, metastatic disease, certain infections, Jessner lymphocytic infiltrate, connective tissue disease, and some adnexal tumors. Histologic study is a useful diagnostic aid in this context.

Basal cell carcinoma is the most common cutaneous malignant neoplasm, and although these tumors rarely metastasize, they are capable of gross tissue destruction, particularly those lesions arising on the face. Clinically, this tumor presents as a shiny, pearly nodule with telangiectasias on the surface, as in our patient, but skin biopsy shows large basaloid lobules of varying shape and size forming a relatively circumscribed mass with a “palisade” around the rim of the lobule.

Squamous cell carcinoma manifests as shallow ulcers, often with a keratinous crust and elevated, indurate borders, but also as plaques or nodules. The clinical diagnosis should be confirmed with skin biopsy, which reveals atypical keratinocytes extending from the epidermis to the dermis with dyskeratosis, intercellular bridges, variable central keratinization, and horn pearl formation, depending on the differentiation of the tumor.

Amelanotic melanoma is nonpigmented and appears as a pink nodule mimicking basal cell carcinoma or squamous cell carcinoma. Histologic study is necessary for the diagnosis, and shows an atypical proliferation of melanocytic cells in the epidermis and dermis.

Pyogenic granuloma is a very common benign vascular lesion considered to be a hyperplastic process or a vascular neoplasm. The lesion typically presents as a red or bluish papule or polyp that bleeds easily, and a reddish homogeneous area surrounded by a white “collarette” is found in most cases. Histologic features of an early lesion resemble granulation tissue and include lobules of capillaries and venules that often radiate from larger, more central vessels.

LYMPHOCYTOMA CUTIS: KEY FEATURES

Lymphocytoma cutis (pseudolymphoma) is a benign reactive polyclonal and inflammatory disorder that most frequently includes B lymphocytes, with a smaller population of T lymphocytes. It infiltrates the skin and resembles rudimentary germinal follicles, as in the present case. The lesion usually presents as an asymptomatic red-brown or violet papule or nodule, 3 mm to 5 cm in diameter, most often on the face, chest, or upper extremities.¹ The lesion may be solitary, as in our patient, but lesions may also be grouped or numerous and widespread. It is three times more common in women than in men. It may resolve spontaneously, but it may also recur.

In Europe, lymphocytoma cutis occurs most often in B burgdorferi infection after a tick bite. Lymphocytoma cutis occurs in 1.3% of cases of B burgdorferi infection,² although other infectious, physical, or chemical agents may produce the same reaction pattern. Tattooing (particularly red areas), acupuncture, vaccination, arthropod reactions, hyposensitization antigen reaction, and ingestion of drug have been implicated in this form of lymphoid hyperplasia.^3,4

DIAGNOSTIC CHALLENGES

Lymphocytoma cutis can be challenging to diagnose, and although it can be suspected clinically, incisional biopsy is usually necessary in order to differentiate it from cutaneous B lymphoma.⁵

The infiltrate is predominantly nodular (> 90%) and located in the upper and mid dermis (“top heavy”) in lymphocytoma cutis, whereas it can be nodular or diffuse in cutaneous B lymphoma, with sharply demarcated borders that are convex rather than concave. Lymphoid follicles with germinal centers are sometimes present, and the interfollicular cellular population is polymorphic in lymphocytoma cutis (lymphocytes, plasma cells, histiocytes, eosinophils). In lymphocytoma cutis, cells express the phenotype of mature B lymphocytes (CD20, CD79a) and show regular and sharply demarcated networks of CD21+ follicular dendritic cells, whereas in cutaneous B lymphoma these networks are irregular. Light chains are usually polyclonal, although monoclonal populations of B cell in cases of cutaneous lymphocytoma cutis have been described. Extracutaneous involvement is possible in cutaneous B lymphoma but is usually absent in lymphocytoma cutis.

Lymphocytoma cutis typically involutes over a period of months, even with no treatment, as it did in our patient. Otherwise, there are different therapeutic options, including intralesional and topical corticosteroids, surgery, and cryosurgery.⁶ Photodynamic therapy with delta-aminolevulinic acid is an effective and safe modality for the treatment of lymphocytoma cutis and may be cosmetically beneficial.⁷

An otherwise healthy 54-year-old woman presented with a 3-month history of an asymptomatic lesion on the face, at the site of a previous mosquito bite. Physical examination revealed a firm, pink nodule 10 mm in diameter (Figure 1). Telangiectasias were visible, more clearly by dermoscopy, but other features of a basal cell carcinoma were absent. No other skin problem was noted, and no lymphadenopathy was detected.

Histologic study of a biopsy specimen noted a dense dermal inflammatory infiltrate consisting of B lymphocytes (CD20+) with a smaller number of T lymphocytes (CD3+) arranged in several germinal centers, with an admixture of plasma cells and eosinophils (Figure 2). No clonal population was identified by gene-rearrangement studies. Borrelia burgdorferi infection was ruled out.

Q: Which is the most likely diagnosis?

• Basal cell carcinoma
• Squamous cell carcinoma
• Lymphocytoma cutis
• Amelanotic melanoma
• Pyogenic granuloma

A: The correct answer is lymphocytoma cutis. The differential diagnosis of a pink papule on the face of a middle-aged person includes nonmelanoma skin cancer, lymphoma, lymphocytoma cutis, metastatic disease, certain infections, Jessner lymphocytic infiltrate, connective tissue disease, and some adnexal tumors. Histologic study is a useful diagnostic aid in this context.

Basal cell carcinoma is the most common cutaneous malignant neoplasm, and although these tumors rarely metastasize, they are capable of gross tissue destruction, particularly those lesions arising on the face. Clinically, this tumor presents as a shiny, pearly nodule with telangiectasias on the surface, as in our patient, but skin biopsy shows large basaloid lobules of varying shape and size forming a relatively circumscribed mass with a “palisade” around the rim of the lobule.

Squamous cell carcinoma manifests as shallow ulcers, often with a keratinous crust and elevated, indurate borders, but also as plaques or nodules. The clinical diagnosis should be confirmed with skin biopsy, which reveals atypical keratinocytes extending from the epidermis to the dermis with dyskeratosis, intercellular bridges, variable central keratinization, and horn pearl formation, depending on the differentiation of the tumor.

Amelanotic melanoma is nonpigmented and appears as a pink nodule mimicking basal cell carcinoma or squamous cell carcinoma. Histologic study is necessary for the diagnosis, and shows an atypical proliferation of melanocytic cells in the epidermis and dermis.

Pyogenic granuloma is a very common benign vascular lesion considered to be a hyperplastic process or a vascular neoplasm. The lesion typically presents as a red or bluish papule or polyp that bleeds easily, and a reddish homogeneous area surrounded by a white “collarette” is found in most cases. Histologic features of an early lesion resemble granulation tissue and include lobules of capillaries and venules that often radiate from larger, more central vessels.

LYMPHOCYTOMA CUTIS: KEY FEATURES

Lymphocytoma cutis (pseudolymphoma) is a benign reactive polyclonal and inflammatory disorder that most frequently includes B lymphocytes, with a smaller population of T lymphocytes. It infiltrates the skin and resembles rudimentary germinal follicles, as in the present case. The lesion usually presents as an asymptomatic red-brown or violet papule or nodule, 3 mm to 5 cm in diameter, most often on the face, chest, or upper extremities.¹ The lesion may be solitary, as in our patient, but lesions may also be grouped or numerous and widespread. It is three times more common in women than in men. It may resolve spontaneously, but it may also recur.

In Europe, lymphocytoma cutis occurs most often in B burgdorferi infection after a tick bite. Lymphocytoma cutis occurs in 1.3% of cases of B burgdorferi infection,² although other infectious, physical, or chemical agents may produce the same reaction pattern. Tattooing (particularly red areas), acupuncture, vaccination, arthropod reactions, hyposensitization antigen reaction, and ingestion of drug have been implicated in this form of lymphoid hyperplasia.^3,4

DIAGNOSTIC CHALLENGES

Lymphocytoma cutis can be challenging to diagnose, and although it can be suspected clinically, incisional biopsy is usually necessary in order to differentiate it from cutaneous B lymphoma.⁵

The infiltrate is predominantly nodular (> 90%) and located in the upper and mid dermis (“top heavy”) in lymphocytoma cutis, whereas it can be nodular or diffuse in cutaneous B lymphoma, with sharply demarcated borders that are convex rather than concave. Lymphoid follicles with germinal centers are sometimes present, and the interfollicular cellular population is polymorphic in lymphocytoma cutis (lymphocytes, plasma cells, histiocytes, eosinophils). In lymphocytoma cutis, cells express the phenotype of mature B lymphocytes (CD20, CD79a) and show regular and sharply demarcated networks of CD21+ follicular dendritic cells, whereas in cutaneous B lymphoma these networks are irregular. Light chains are usually polyclonal, although monoclonal populations of B cell in cases of cutaneous lymphocytoma cutis have been described. Extracutaneous involvement is possible in cutaneous B lymphoma but is usually absent in lymphocytoma cutis.

Lymphocytoma cutis typically involutes over a period of months, even with no treatment, as it did in our patient. Otherwise, there are different therapeutic options, including intralesional and topical corticosteroids, surgery, and cryosurgery.⁶ Photodynamic therapy with delta-aminolevulinic acid is an effective and safe modality for the treatment of lymphocytoma cutis and may be cosmetically beneficial.⁷

An otherwise healthy 54-year-old woman presented with a 3-month history of an asymptomatic lesion on the face, at the site of a previous mosquito bite. Physical examination revealed a firm, pink nodule 10 mm in diameter (Figure 1). Telangiectasias were visible, more clearly by dermoscopy, but other features of a basal cell carcinoma were absent. No other skin problem was noted, and no lymphadenopathy was detected.

Histologic study of a biopsy specimen noted a dense dermal inflammatory infiltrate consisting of B lymphocytes (CD20+) with a smaller number of T lymphocytes (CD3+) arranged in several germinal centers, with an admixture of plasma cells and eosinophils (Figure 2). No clonal population was identified by gene-rearrangement studies. Borrelia burgdorferi infection was ruled out.

Q: Which is the most likely diagnosis?

• Basal cell carcinoma
• Squamous cell carcinoma
• Lymphocytoma cutis
• Amelanotic melanoma
• Pyogenic granuloma

A: The correct answer is lymphocytoma cutis. The differential diagnosis of a pink papule on the face of a middle-aged person includes nonmelanoma skin cancer, lymphoma, lymphocytoma cutis, metastatic disease, certain infections, Jessner lymphocytic infiltrate, connective tissue disease, and some adnexal tumors. Histologic study is a useful diagnostic aid in this context.

Basal cell carcinoma is the most common cutaneous malignant neoplasm, and although these tumors rarely metastasize, they are capable of gross tissue destruction, particularly those lesions arising on the face. Clinically, this tumor presents as a shiny, pearly nodule with telangiectasias on the surface, as in our patient, but skin biopsy shows large basaloid lobules of varying shape and size forming a relatively circumscribed mass with a “palisade” around the rim of the lobule.

Squamous cell carcinoma manifests as shallow ulcers, often with a keratinous crust and elevated, indurate borders, but also as plaques or nodules. The clinical diagnosis should be confirmed with skin biopsy, which reveals atypical keratinocytes extending from the epidermis to the dermis with dyskeratosis, intercellular bridges, variable central keratinization, and horn pearl formation, depending on the differentiation of the tumor.

Amelanotic melanoma is nonpigmented and appears as a pink nodule mimicking basal cell carcinoma or squamous cell carcinoma. Histologic study is necessary for the diagnosis, and shows an atypical proliferation of melanocytic cells in the epidermis and dermis.

Pyogenic granuloma is a very common benign vascular lesion considered to be a hyperplastic process or a vascular neoplasm. The lesion typically presents as a red or bluish papule or polyp that bleeds easily, and a reddish homogeneous area surrounded by a white “collarette” is found in most cases. Histologic features of an early lesion resemble granulation tissue and include lobules of capillaries and venules that often radiate from larger, more central vessels.

LYMPHOCYTOMA CUTIS: KEY FEATURES

Lymphocytoma cutis (pseudolymphoma) is a benign reactive polyclonal and inflammatory disorder that most frequently includes B lymphocytes, with a smaller population of T lymphocytes. It infiltrates the skin and resembles rudimentary germinal follicles, as in the present case. The lesion usually presents as an asymptomatic red-brown or violet papule or nodule, 3 mm to 5 cm in diameter, most often on the face, chest, or upper extremities.¹ The lesion may be solitary, as in our patient, but lesions may also be grouped or numerous and widespread. It is three times more common in women than in men. It may resolve spontaneously, but it may also recur.

In Europe, lymphocytoma cutis occurs most often in B burgdorferi infection after a tick bite. Lymphocytoma cutis occurs in 1.3% of cases of B burgdorferi infection,² although other infectious, physical, or chemical agents may produce the same reaction pattern. Tattooing (particularly red areas), acupuncture, vaccination, arthropod reactions, hyposensitization antigen reaction, and ingestion of drug have been implicated in this form of lymphoid hyperplasia.^3,4

DIAGNOSTIC CHALLENGES

Lymphocytoma cutis can be challenging to diagnose, and although it can be suspected clinically, incisional biopsy is usually necessary in order to differentiate it from cutaneous B lymphoma.⁵

The infiltrate is predominantly nodular (> 90%) and located in the upper and mid dermis (“top heavy”) in lymphocytoma cutis, whereas it can be nodular or diffuse in cutaneous B lymphoma, with sharply demarcated borders that are convex rather than concave. Lymphoid follicles with germinal centers are sometimes present, and the interfollicular cellular population is polymorphic in lymphocytoma cutis (lymphocytes, plasma cells, histiocytes, eosinophils). In lymphocytoma cutis, cells express the phenotype of mature B lymphocytes (CD20, CD79a) and show regular and sharply demarcated networks of CD21+ follicular dendritic cells, whereas in cutaneous B lymphoma these networks are irregular. Light chains are usually polyclonal, although monoclonal populations of B cell in cases of cutaneous lymphocytoma cutis have been described. Extracutaneous involvement is possible in cutaneous B lymphoma but is usually absent in lymphocytoma cutis.

Lymphocytoma cutis typically involutes over a period of months, even with no treatment, as it did in our patient. Otherwise, there are different therapeutic options, including intralesional and topical corticosteroids, surgery, and cryosurgery.⁶ Photodynamic therapy with delta-aminolevulinic acid is an effective and safe modality for the treatment of lymphocytoma cutis and may be cosmetically beneficial.⁷

For most patients with gastroesophageal reflux disease (GERD), a proton pump inhibitor (PPI) is the first choice for treatment.¹ But some patients have symptoms that persist despite PPI therapy, some desire surgery despite successful PPI therapy, and some have persistent extraesophageal symptoms or other complications of reflux. For these patients, surgery is an option.²

In this article, we review the management of GERD and clarify the indications for antireflux surgery based on evidence of safety and efficacy.

GERD DEFINED: SYMPTOMS OR COMPLICATIONS

Defining the role of antireflux surgery is difficult, given the variety of presentations and the absence of a gold standard for diagnosing GERD. Most adults experience several episodes of physiologic reflux daily without symptoms.³ But a broad array of symptoms have been attributed to GERD, including chest pain, cough, and sore throat, and some conditions caused by acid reflux (eg, Barrett esophagus) can be asymptomatic.^4,5

Given these challenges, in 2006 the Montreal Consensus Group defined GERD as “a condition which develops when the reflux of stomach contents causes troublesome symptoms or complications.” ⁴ Critical to the Montreal definition is the distinction between “troublesome symptoms” and “complications” or bodily injury (Table 1).

HEARTBURN ISN’T ALWAYS GERD

Typical GERD presents with the classic symptoms of pyrosis (heartburn) or acid regurgitation, or both.

Although these symptoms are often thought to be specific for GERD, other causes of esophageal injury— eg, eosinophilic esophagitis, infection (Candida, cytomegalovirus, herpes simplex virus), pill-induced esophagitis, or radiation therapy—can produce similar symptoms. Other causes, including coronary artery disease, biliary colic, foregut malignancy, or peptic ulcer disease, should also be considered in patients with supposedly typical GERD. Life-threatening mimics of GERD, such as unstable angina, should be excluded if they are likely, before proceeding with evaluating for possible GERD. Therefore, the initial history and examination should focus on appropriate diagnosis, with careful delineation of symptom quality.

Alarm features for advanced pathology^6–8 include involuntary weight loss, dysphagia, vomiting, evidence of gastrointestinal blood loss, anemia, chest pain, and an epigastric mass.⁷ Admittedly, these features are only mediocre for detecting or excluding gastric or esophageal cancer, with a sensitivity of 67% and a specificity 66%.⁹ Nevertheless, they should prompt an endoscopic examination. In patients who have alarm features but have not yet been treated for GERD, upper endoscopy can identify an abnormality in about 60% of patients.^10–12

PPIs HAVE REPLACED ANTACIDS AND HISTAMINE-2 RECEPTOR ANTAGONISTS

When the symptoms suggest GERD and no alarm features are present, an initial trial of the following lifestyle changes is reasonable:

• Avoiding acidic or refluxogenic foods (coffee, alcohol, chocolate, peppermint, fatty foods, citrus foods)
• Avoiding certain medications (anticholinergics, estrogens, calcium-channel blockers, nitroglycerine, benzodiazepines)
• Losing weight
• Quitting smoking
• Raising the head of the bed
• Staying upright for 2 to 3 hours after meals.

For someone with mild symptoms, these changes pose minimal risk. Unfortunately, they are unlikely to provide adequate symptom control for most patients.^13–17

Before PPIs were invented, drug therapy for GERD symptoms that did not resolve with lifestyle changes consisted of antacids and, later, histamine-2 receptor antagonists. When maximal therapy failed to control symptoms, fundoplication surgery was considered an appropriate next step.

PPIs substantially changed the management of GERD, suppressing acid secretion much better than histamine-2 receptor antagonists. Taken 30 minutes before breakfast, a single daily dose of a PPI normalizes esophageal acid exposure in 67% of patients.¹⁸ Adding a second dose 30 minutes before dinner raises the number to more than 90%.¹⁹

PPIs have consistently outperformed histamine-2 blockers in the healing of esophagitis and in improving heartburn symptoms and are now the first-line medical therapy for uncomplicated GERD.^6,8,20–25

WHEN PPIs WORK, SURGERY OFFERS NO ADVANTAGE

Patients may not want to take a PPI for the rest of their life, for a number of reasons: cost, the need to take one or more pills daily, and potential adverse effects.²⁶ In these cases, the physician can counsel the patient on the relative merits of long-term medical therapy vs surgery (Table 2).^2,26

The LOTUS trial (Long-Term Usage of Esomeprazole vs Surgery for Treatment of Chronic GERD) compared long-term drug therapy with surgery to maintain remission of symptoms in GERD.²⁷ In this trial, 554 patients whose symptoms initially responded to the PPI esomeprazole (Nexium) were randomized to continue to receive esomeprazole (n = 266) or to undergo laparoscopic antireflux surgery (288 were randomly assigned, and 248 had the operation). Dose adjustment of the esomeprazole was allowed (20–40 mg/day). A total of 372 patients completed 5 years of follow-up (192 esomeprazole, 180 surgery).

Symptoms stayed in remission in 92% of the esomeprazole group and 85% of the surgery group (P = .048). However, the difference was no longer statistically significant after modeling the effects of study dropout. The rate of severe adverse events was similar in both groups: 24.1% with esomeprazole and 28.6% with surgery.

These findings indicate that if symptoms fully abate with medical therapy, surgery offers no advantage. In addition, patients who desire surgery in the hope of avoiding lifelong drug therapy should be made aware that drug therapy and reoperation are often necessary after surgery.²⁸ In most cases, antireflux surgery is unnecessary for patients whose GERD fully responds to PPI therapy.

 

IF PPIs FAIL, FURTHER TESTING NEEDED

But many patients who take PPIs still have symptoms, even though these drugs suppress acid secretion and heal esophagitis. In fact, symptoms completely resolve in only about one-half of patients with erosive disease and one-third of those without erosive disease.²¹

Reasons for an incomplete symptomatic response to PPIs are various. Acid reflux can persist, but this accounts for only 10% of cases.²⁹ About one-third of patients have persistent reflux that is weakly acidic, with a pH higher than 4.29. However, most patients with persistent typical GERD symptoms do not have significant, persistent reflux, or their symptoms are not related to reflux events. In these cases, an alternative cause of the refractory symptoms should be sought.

Further diagnostic testing is indicated when symptoms persist despite PPI therapy. Upper endoscopy will reveal an abnormality such as persistent erosive esophagitis, eosinophilic esophagitis, esophageal stricture, Barrett esophagus, or esophageal cancer in roughly 10% of patients in whom empiric therapy fails.¹⁰

Although patients with persistent symptoms have not been enrolled in many randomized controlled trials, a multivariate analysis showed that failure of medical therapy heralds a poor response to surgery.³⁰ Data such as these have led most experts to discourage fundoplication for such patients now, unlike in the pre-PPI era.

pH and intraluminal impedance testing

However, this recommendation against surgery is not a hard-and-fast rule.

When symptoms of GERD do not respond to twice-daily PPI therapy and the results of upper endoscopy are negative, then an esophageal pH study combined with multichannel intraluminal impedance (MII-pH) testing may help identify patients who will respond to an intensification of medical therapy or to surgery, particularly if symptoms correlate with documented reflux events^31–33 (Figure 1). Most experts believe that esophageal MII-pH testing should be performed while the patient is taking a PPI to best identify patients whose refractory symptoms are most likely to be related to ongoing reflux.

In patients with esophageal regurgitation, most will not achieve adequate relief of symptoms with PPI therapy alone.³⁴ The therapeutic gain of PPI therapy vs placebo averaged just 17% in seven randomized, controlled trials, more than 20% less than the response rate for heartburn.³⁴ This is likely because of structural abnormalities such as reduced lower esophageal sphincter pressure, hiatal hernia, or delayed gastric emptying. Antireflux surgery can correct these structural abnormalities or prevent them from causing so much trouble; however, the presence of true regurgitation should first be confirmed by MII testing. If regurgitation is confirmed, antireflux surgery is warranted, particularly in patients with nocturnal symptoms who may be at high risk of aspiration. With careful patient selection, regurgitation symptoms improve in about 90% after surgery.²

In patients with heartburn, if esophageal acid exposure continues to be abnormal on MII-pH testing, then an escalation of therapy may improve symptoms, particularly if symptoms occur during reflux or if they partially responded to PPI therapy. Options in this scenario include alteration or intensification of acid-suppressive therapy, treatment with baclofen (Lioresal), and antireflux surgery.^18,35,36 In randomized controlled trials of patients whose symptoms partially responded to PPIs, antireflux surgery has performed similarly to PPIs in terms of improving typical GERD symptoms, particularly regurgitation.^27,37–41 Although this scenario is a reasonable indication for antireflux surgery, recommendations should be made with appropriate restraint since it is not easily reversible, some patients experience complications, and up to one-third will have no therapeutic benefit.³⁰

Nonacid reflux. In some cases, MII-pH testing during PPI therapy will reveal reflux of weakly acidic (pH > 4) or alkaline stomach contents, often called “nonacid reflux.”²⁹ Nonacid reflux is often present in patients with esophagitis that persists despite PPI therapy, indicating that even weakly acidic stomach contents can injure the mucosa.⁴² Since intensifying the acid-suppressive therapy is unlikely to improve these symptoms, antireflux surgery may have a role.

In one study,⁴³ nonacid reflux was well controlled by laparoscopic Nissen fundoplication, although 15 (48%) of 31 patients had persistent symptoms of GERD after surgery. No patient had a strong symptom correlation with postoperative reflux events, suggesting an alternative cause of the persistent symptoms. Therefore, antireflux surgery for nonacid reflux should be limited exclusively to patients with strong symptom correlation, and even then it should be considered with restraint, given the limited evidence for benefit and the potential for harm.

If testing is negative. In studies investigating the diagnostic yield of MII-pH testing, more than 50% of patients who had refractory symptoms had a negative MII-pH test.²⁹ In such situations, when the symptoms are strongly correlated with reflux events, the patient is said to have “esophageal hypersensitivity.” A few small studies have suggested that such patients may benefit from surgery, but these data have not been replicated in randomized controlled trials.³²

When the testing is negative and there is no correlation between the patient’s symptoms and reflux events, the patient is unlikely to benefit from antireflux surgery. Care of these patients is beyond the scope of this review.

SURGERY RARELY IMPROVES COUGH, ASTHMA, OR LARYNGITIS

GERD has been implicated as a cause of chronic cough, asthma, and laryngitis, although each of these has many potential causes.^44–46 Despite these associations, the evidence for therapeutic benefit from antireflux therapy is weak.

PPI therapy shows no benefit over placebo for chronic cough of uncertain etiology, but some benefit if GERD is objectively demonstrated.⁴⁷ Laryngitis resolved in just 15% of patients on esomeprazole vs 16% of patients on placebo after excluding patients with moderate to severe heartburn.⁴⁸

In a large randomized controlled trial in patients with asthma, there was no overall improvement in peak flow for the PPI group vs the placebo group, although significant improvement occurred in patients with heartburn and nocturnal respiratory symptoms.⁴⁶

Potent antisecretory therapy seems to improve extraesophageal symptoms when typical GERD symptoms are also present, but it otherwise has shown little evidence of benefit.

The evidence for a benefit from antireflux surgery in patients with extraesophageal GERD syndromes is even more limited. Although one systematic review⁴⁹ found that cough and other laryngeal symptoms improved in 60% to 100% of patients with objective evidence of GERD who underwent fundoplication, virtually all of the studies were uncontrolled case series.⁴⁹

The lone randomized controlled trial in the systematic review compared Nissen fundoplication with ranitidine (Zantac) or antacids only for patients with asthma and GERD, and found no significant difference in peak expiratory flow among the three groups after 2 years. However, asthma symptom scores improved in 75% of the surgical group, 9% of the medical group, and 4% of the control group.⁵⁰

In a study that was not included in the prior systematic review, patients with laryngopharyngeal reflux unresponsive to aggressive acid suppression who subsequently underwent fundoplication fared no better than those who did not.⁵¹

Thus, based on the available data, antireflux surgery is only rarely indicated for extraesophageal symptoms, especially in patients who have no typical GERD symptoms or in patients whose symptoms are refractory to medical therapy.

 

SURGERY FOR EROSIVE ESOPHAGITIS OR BARRETT ESOPHAGUS IF PPI FAILS

Lifelong antireflux therapy is indicated for patients with severe erosive esophagitis or Barrett esophagus. Erosive esophagitis recurs in more than 80% within 12 months of discontinuing antisecretory therapy.⁵² Both Barrett esophagus and esophageal adenocarcinoma are strongly associated with GERD, and nearly 10% of patients with chronic reflux have Barrett esophagus.^53,54 It is suspected that suppressing reflux reduces the rate of progression of Barrett esophagus to esophageal adenocarcinoma, but this remains to be proven.

Perhaps the strongest indication for surgery in the PPI era is for patients who have persistent symptoms and severe erosive esophagitis (Los Angeles grade C or D) despite high-dose PPI therapy. If other causes of persistent esophagitis have been ruled out, fundoplication can induce healing and improve symptoms.^55,56 In these cases, surgery is done to induce remission of the disease when maximal medical therapy has been truly unsuccessful.

Randomized controlled trials suggest that medical and surgical therapies are equally effective for preventing the recurrence of erosive esophagitis or the progression of Barrett esophagus. In a study of 225 patients, at 7 years of follow-up, esophagitis had recurred in 10.4% of patients on omeprazole vs 11.8% of those who had undergone antireflux surgery.⁴⁰ Similarly, open Nissen fundoplication was no different from drug therapy (histamine-2 receptor antagonist or PPI) for progression of Barrett esophagus over a median of 5 years.⁵⁷ A meta-analysis with nearly 5,000 person-years each in the medical and surgical groups also found no significant difference in rates of cancer progression.⁵⁸

Notably, symptoms such as dysphagia, flatulence, and the inability to burp occurred significantly more often in the surgical groups in these studies.

In view of these data, antireflux surgery has no significant advantage over medical therapy for maintaining healing of erosive esophagitis or preventing progression of Barrett esophagus. Thus, it should be reserved for patients who do not desire lifelong drug therapy, provided they understand that there is no therapeutic advantage for their esophagitis or for Barrett esophagus.

SPECIFIC INDICATIONS FOR ANTIREFLUX SURGERY

Now that we have PPIs, several situations remain in which surgery for GERD is either indicated or worth considering.

Antireflux surgery is clearly indicated for:

• Patients with erosive esophagitis that does not heal with maximal drug therapy
• Patients with volume regurgitation, particularly if it occurs at night or if there is evidence of aspiration
• Patients who require lifelong treatment for reflux but who have had a serious adverse event related to PPI therapy, such as refractory Clostridium difficile infection.

Antireflux surgery is also worth considering in patients who for personal reasons wish to avoid long-term or lifelong drug therapy.

Patients should be informed, however, that antireflux surgery has not been shown to be better than medical therapy for maintaining remission of symptoms, for preventing progression of Barrett esophagus, or for maintaining healing of erosive esophagitis. Medical therapy is still the first option for these patients.

Surgery may also be considered in patients with persistent symptoms who have a partial response to medical therapy, who show persistent acidic or weakly acidic reflux on MII-pH testing, and whose symptoms have been correlated with reflux events. Although surgery is not sure to improve their symptoms, benefit is more likely in this patient population compared with those without these characteristics.

Extraesophageal GERD

In patients suspected of having extraesophageal GERD, surgery should be considered if typical GERD symptoms are present and improve with PPI therapy, if the extraesophageal syndrome partially responds to PPI therapy, and if MII-pH testing demonstrates a correlation between symptoms and reflux. Surgery may have a stronger indication in this setting if the patient has nocturnal reflux or extraesophageal symptoms.

When is surgery not an option?

In general, surgery should not be considered in patients who do not have a partial response to PPI therapy or who do not have a strong symptom-reflux correlation on MII-pH testing. In all cases of failed medical therapy without persistent severe erosive disease, the threshold for opting for surgery should be high, given the uncertain response of these patients to surgery.

Peristaltic dysfunction is a relative but not an absolute contraindication to surgery.⁵⁹

RISKS, BENEFITS OF SURGERY FOR GERD

The patient’s preference for surgery over drug therapy should always be balanced against the risks of surgery, including both short-term and long-term adverse events, to allow the patient to make an adequately informed decision (Table 2).^2,26

Adverse events associated with PPI therapy are rare and in many cases the association is debatable.²⁶ Nonetheless, long-term PPI therapy has been most strongly associated with an increased risk of C difficile infection and other enteric infections, although the absolute risk of these events remains low.

Complication rates after antireflux surgery depend on the surgeon’s experience and technique. Death is exceedingly rare. In most high-volume centers, the need to convert from laparoscopic to open fundoplication occurs in fewer than 2.4% of patients.²

Potential perioperative complications include perforation (4%), wound infection (3%), and pneumothorax (2%).²

Antireflux surgery is also associated with a significant risk of dysphagia, bloating, an inability to burp, and excessive flatulence, all of which can markedly impair the quality of life.

A major consideration is that fundoplication is generally irreversible. Reoperation rates have been reported to range from 0% to 15%.² Furthermore, up to 50% of patients still need medical therapy after surgery.^60,61 Of note, only about 25% of patients on medical therapy after surgery will actually have an abnormal pH study.⁶¹

MORE STUDY NEEDED

Future studies directly comparing medical and surgical therapy for carefully selected patients with extraesophageal manifestations of GERD and refractory symptoms should help further delineate outcome in this difficult group of patients.

Under development are new drugs that may inhibit transient relaxation of the lower esophageal sphincter, as well as minimally invasive procedures, which may alter the indications for surgery in coming years.³⁶
 

---

Acknowledgment: The research for this article was supported in part by a grant from the National Institutes of Health (T32 DK07634).

For most patients with gastroesophageal reflux disease (GERD), a proton pump inhibitor (PPI) is the first choice for treatment.¹ But some patients have symptoms that persist despite PPI therapy, some desire surgery despite successful PPI therapy, and some have persistent extraesophageal symptoms or other complications of reflux. For these patients, surgery is an option.²

In this article, we review the management of GERD and clarify the indications for antireflux surgery based on evidence of safety and efficacy.

GERD DEFINED: SYMPTOMS OR COMPLICATIONS

Defining the role of antireflux surgery is difficult, given the variety of presentations and the absence of a gold standard for diagnosing GERD. Most adults experience several episodes of physiologic reflux daily without symptoms.³ But a broad array of symptoms have been attributed to GERD, including chest pain, cough, and sore throat, and some conditions caused by acid reflux (eg, Barrett esophagus) can be asymptomatic.^4,5

Given these challenges, in 2006 the Montreal Consensus Group defined GERD as “a condition which develops when the reflux of stomach contents causes troublesome symptoms or complications.” ⁴ Critical to the Montreal definition is the distinction between “troublesome symptoms” and “complications” or bodily injury (Table 1).

HEARTBURN ISN’T ALWAYS GERD

Typical GERD presents with the classic symptoms of pyrosis (heartburn) or acid regurgitation, or both.

Although these symptoms are often thought to be specific for GERD, other causes of esophageal injury— eg, eosinophilic esophagitis, infection (Candida, cytomegalovirus, herpes simplex virus), pill-induced esophagitis, or radiation therapy—can produce similar symptoms. Other causes, including coronary artery disease, biliary colic, foregut malignancy, or peptic ulcer disease, should also be considered in patients with supposedly typical GERD. Life-threatening mimics of GERD, such as unstable angina, should be excluded if they are likely, before proceeding with evaluating for possible GERD. Therefore, the initial history and examination should focus on appropriate diagnosis, with careful delineation of symptom quality.

Alarm features for advanced pathology^6–8 include involuntary weight loss, dysphagia, vomiting, evidence of gastrointestinal blood loss, anemia, chest pain, and an epigastric mass.⁷ Admittedly, these features are only mediocre for detecting or excluding gastric or esophageal cancer, with a sensitivity of 67% and a specificity 66%.⁹ Nevertheless, they should prompt an endoscopic examination. In patients who have alarm features but have not yet been treated for GERD, upper endoscopy can identify an abnormality in about 60% of patients.^10–12

PPIs HAVE REPLACED ANTACIDS AND HISTAMINE-2 RECEPTOR ANTAGONISTS

When the symptoms suggest GERD and no alarm features are present, an initial trial of the following lifestyle changes is reasonable:

• Avoiding acidic or refluxogenic foods (coffee, alcohol, chocolate, peppermint, fatty foods, citrus foods)
• Avoiding certain medications (anticholinergics, estrogens, calcium-channel blockers, nitroglycerine, benzodiazepines)
• Losing weight
• Quitting smoking
• Raising the head of the bed
• Staying upright for 2 to 3 hours after meals.

For someone with mild symptoms, these changes pose minimal risk. Unfortunately, they are unlikely to provide adequate symptom control for most patients.^13–17

Before PPIs were invented, drug therapy for GERD symptoms that did not resolve with lifestyle changes consisted of antacids and, later, histamine-2 receptor antagonists. When maximal therapy failed to control symptoms, fundoplication surgery was considered an appropriate next step.

PPIs substantially changed the management of GERD, suppressing acid secretion much better than histamine-2 receptor antagonists. Taken 30 minutes before breakfast, a single daily dose of a PPI normalizes esophageal acid exposure in 67% of patients.¹⁸ Adding a second dose 30 minutes before dinner raises the number to more than 90%.¹⁹

PPIs have consistently outperformed histamine-2 blockers in the healing of esophagitis and in improving heartburn symptoms and are now the first-line medical therapy for uncomplicated GERD.^6,8,20–25

WHEN PPIs WORK, SURGERY OFFERS NO ADVANTAGE

Patients may not want to take a PPI for the rest of their life, for a number of reasons: cost, the need to take one or more pills daily, and potential adverse effects.²⁶ In these cases, the physician can counsel the patient on the relative merits of long-term medical therapy vs surgery (Table 2).^2,26

The LOTUS trial (Long-Term Usage of Esomeprazole vs Surgery for Treatment of Chronic GERD) compared long-term drug therapy with surgery to maintain remission of symptoms in GERD.²⁷ In this trial, 554 patients whose symptoms initially responded to the PPI esomeprazole (Nexium) were randomized to continue to receive esomeprazole (n = 266) or to undergo laparoscopic antireflux surgery (288 were randomly assigned, and 248 had the operation). Dose adjustment of the esomeprazole was allowed (20–40 mg/day). A total of 372 patients completed 5 years of follow-up (192 esomeprazole, 180 surgery).

Symptoms stayed in remission in 92% of the esomeprazole group and 85% of the surgery group (P = .048). However, the difference was no longer statistically significant after modeling the effects of study dropout. The rate of severe adverse events was similar in both groups: 24.1% with esomeprazole and 28.6% with surgery.

These findings indicate that if symptoms fully abate with medical therapy, surgery offers no advantage. In addition, patients who desire surgery in the hope of avoiding lifelong drug therapy should be made aware that drug therapy and reoperation are often necessary after surgery.²⁸ In most cases, antireflux surgery is unnecessary for patients whose GERD fully responds to PPI therapy.

 

IF PPIs FAIL, FURTHER TESTING NEEDED

But many patients who take PPIs still have symptoms, even though these drugs suppress acid secretion and heal esophagitis. In fact, symptoms completely resolve in only about one-half of patients with erosive disease and one-third of those without erosive disease.²¹

Reasons for an incomplete symptomatic response to PPIs are various. Acid reflux can persist, but this accounts for only 10% of cases.²⁹ About one-third of patients have persistent reflux that is weakly acidic, with a pH higher than 4.29. However, most patients with persistent typical GERD symptoms do not have significant, persistent reflux, or their symptoms are not related to reflux events. In these cases, an alternative cause of the refractory symptoms should be sought.

Further diagnostic testing is indicated when symptoms persist despite PPI therapy. Upper endoscopy will reveal an abnormality such as persistent erosive esophagitis, eosinophilic esophagitis, esophageal stricture, Barrett esophagus, or esophageal cancer in roughly 10% of patients in whom empiric therapy fails.¹⁰

Although patients with persistent symptoms have not been enrolled in many randomized controlled trials, a multivariate analysis showed that failure of medical therapy heralds a poor response to surgery.³⁰ Data such as these have led most experts to discourage fundoplication for such patients now, unlike in the pre-PPI era.

pH and intraluminal impedance testing

However, this recommendation against surgery is not a hard-and-fast rule.

When symptoms of GERD do not respond to twice-daily PPI therapy and the results of upper endoscopy are negative, then an esophageal pH study combined with multichannel intraluminal impedance (MII-pH) testing may help identify patients who will respond to an intensification of medical therapy or to surgery, particularly if symptoms correlate with documented reflux events^31–33 (Figure 1). Most experts believe that esophageal MII-pH testing should be performed while the patient is taking a PPI to best identify patients whose refractory symptoms are most likely to be related to ongoing reflux.

In patients with esophageal regurgitation, most will not achieve adequate relief of symptoms with PPI therapy alone.³⁴ The therapeutic gain of PPI therapy vs placebo averaged just 17% in seven randomized, controlled trials, more than 20% less than the response rate for heartburn.³⁴ This is likely because of structural abnormalities such as reduced lower esophageal sphincter pressure, hiatal hernia, or delayed gastric emptying. Antireflux surgery can correct these structural abnormalities or prevent them from causing so much trouble; however, the presence of true regurgitation should first be confirmed by MII testing. If regurgitation is confirmed, antireflux surgery is warranted, particularly in patients with nocturnal symptoms who may be at high risk of aspiration. With careful patient selection, regurgitation symptoms improve in about 90% after surgery.²

In patients with heartburn, if esophageal acid exposure continues to be abnormal on MII-pH testing, then an escalation of therapy may improve symptoms, particularly if symptoms occur during reflux or if they partially responded to PPI therapy. Options in this scenario include alteration or intensification of acid-suppressive therapy, treatment with baclofen (Lioresal), and antireflux surgery.^18,35,36 In randomized controlled trials of patients whose symptoms partially responded to PPIs, antireflux surgery has performed similarly to PPIs in terms of improving typical GERD symptoms, particularly regurgitation.^27,37–41 Although this scenario is a reasonable indication for antireflux surgery, recommendations should be made with appropriate restraint since it is not easily reversible, some patients experience complications, and up to one-third will have no therapeutic benefit.³⁰

Nonacid reflux. In some cases, MII-pH testing during PPI therapy will reveal reflux of weakly acidic (pH > 4) or alkaline stomach contents, often called “nonacid reflux.”²⁹ Nonacid reflux is often present in patients with esophagitis that persists despite PPI therapy, indicating that even weakly acidic stomach contents can injure the mucosa.⁴² Since intensifying the acid-suppressive therapy is unlikely to improve these symptoms, antireflux surgery may have a role.

In one study,⁴³ nonacid reflux was well controlled by laparoscopic Nissen fundoplication, although 15 (48%) of 31 patients had persistent symptoms of GERD after surgery. No patient had a strong symptom correlation with postoperative reflux events, suggesting an alternative cause of the persistent symptoms. Therefore, antireflux surgery for nonacid reflux should be limited exclusively to patients with strong symptom correlation, and even then it should be considered with restraint, given the limited evidence for benefit and the potential for harm.

If testing is negative. In studies investigating the diagnostic yield of MII-pH testing, more than 50% of patients who had refractory symptoms had a negative MII-pH test.²⁹ In such situations, when the symptoms are strongly correlated with reflux events, the patient is said to have “esophageal hypersensitivity.” A few small studies have suggested that such patients may benefit from surgery, but these data have not been replicated in randomized controlled trials.³²

When the testing is negative and there is no correlation between the patient’s symptoms and reflux events, the patient is unlikely to benefit from antireflux surgery. Care of these patients is beyond the scope of this review.

SURGERY RARELY IMPROVES COUGH, ASTHMA, OR LARYNGITIS

GERD has been implicated as a cause of chronic cough, asthma, and laryngitis, although each of these has many potential causes.^44–46 Despite these associations, the evidence for therapeutic benefit from antireflux therapy is weak.

PPI therapy shows no benefit over placebo for chronic cough of uncertain etiology, but some benefit if GERD is objectively demonstrated.⁴⁷ Laryngitis resolved in just 15% of patients on esomeprazole vs 16% of patients on placebo after excluding patients with moderate to severe heartburn.⁴⁸

In a large randomized controlled trial in patients with asthma, there was no overall improvement in peak flow for the PPI group vs the placebo group, although significant improvement occurred in patients with heartburn and nocturnal respiratory symptoms.⁴⁶

Potent antisecretory therapy seems to improve extraesophageal symptoms when typical GERD symptoms are also present, but it otherwise has shown little evidence of benefit.

The evidence for a benefit from antireflux surgery in patients with extraesophageal GERD syndromes is even more limited. Although one systematic review⁴⁹ found that cough and other laryngeal symptoms improved in 60% to 100% of patients with objective evidence of GERD who underwent fundoplication, virtually all of the studies were uncontrolled case series.⁴⁹

The lone randomized controlled trial in the systematic review compared Nissen fundoplication with ranitidine (Zantac) or antacids only for patients with asthma and GERD, and found no significant difference in peak expiratory flow among the three groups after 2 years. However, asthma symptom scores improved in 75% of the surgical group, 9% of the medical group, and 4% of the control group.⁵⁰

In a study that was not included in the prior systematic review, patients with laryngopharyngeal reflux unresponsive to aggressive acid suppression who subsequently underwent fundoplication fared no better than those who did not.⁵¹

Thus, based on the available data, antireflux surgery is only rarely indicated for extraesophageal symptoms, especially in patients who have no typical GERD symptoms or in patients whose symptoms are refractory to medical therapy.

 

SURGERY FOR EROSIVE ESOPHAGITIS OR BARRETT ESOPHAGUS IF PPI FAILS

Lifelong antireflux therapy is indicated for patients with severe erosive esophagitis or Barrett esophagus. Erosive esophagitis recurs in more than 80% within 12 months of discontinuing antisecretory therapy.⁵² Both Barrett esophagus and esophageal adenocarcinoma are strongly associated with GERD, and nearly 10% of patients with chronic reflux have Barrett esophagus.^53,54 It is suspected that suppressing reflux reduces the rate of progression of Barrett esophagus to esophageal adenocarcinoma, but this remains to be proven.

Perhaps the strongest indication for surgery in the PPI era is for patients who have persistent symptoms and severe erosive esophagitis (Los Angeles grade C or D) despite high-dose PPI therapy. If other causes of persistent esophagitis have been ruled out, fundoplication can induce healing and improve symptoms.^55,56 In these cases, surgery is done to induce remission of the disease when maximal medical therapy has been truly unsuccessful.

Randomized controlled trials suggest that medical and surgical therapies are equally effective for preventing the recurrence of erosive esophagitis or the progression of Barrett esophagus. In a study of 225 patients, at 7 years of follow-up, esophagitis had recurred in 10.4% of patients on omeprazole vs 11.8% of those who had undergone antireflux surgery.⁴⁰ Similarly, open Nissen fundoplication was no different from drug therapy (histamine-2 receptor antagonist or PPI) for progression of Barrett esophagus over a median of 5 years.⁵⁷ A meta-analysis with nearly 5,000 person-years each in the medical and surgical groups also found no significant difference in rates of cancer progression.⁵⁸

Notably, symptoms such as dysphagia, flatulence, and the inability to burp occurred significantly more often in the surgical groups in these studies.

In view of these data, antireflux surgery has no significant advantage over medical therapy for maintaining healing of erosive esophagitis or preventing progression of Barrett esophagus. Thus, it should be reserved for patients who do not desire lifelong drug therapy, provided they understand that there is no therapeutic advantage for their esophagitis or for Barrett esophagus.

SPECIFIC INDICATIONS FOR ANTIREFLUX SURGERY

Now that we have PPIs, several situations remain in which surgery for GERD is either indicated or worth considering.

Antireflux surgery is clearly indicated for:

• Patients with erosive esophagitis that does not heal with maximal drug therapy
• Patients with volume regurgitation, particularly if it occurs at night or if there is evidence of aspiration
• Patients who require lifelong treatment for reflux but who have had a serious adverse event related to PPI therapy, such as refractory Clostridium difficile infection.

Antireflux surgery is also worth considering in patients who for personal reasons wish to avoid long-term or lifelong drug therapy.

Patients should be informed, however, that antireflux surgery has not been shown to be better than medical therapy for maintaining remission of symptoms, for preventing progression of Barrett esophagus, or for maintaining healing of erosive esophagitis. Medical therapy is still the first option for these patients.

Surgery may also be considered in patients with persistent symptoms who have a partial response to medical therapy, who show persistent acidic or weakly acidic reflux on MII-pH testing, and whose symptoms have been correlated with reflux events. Although surgery is not sure to improve their symptoms, benefit is more likely in this patient population compared with those without these characteristics.

Extraesophageal GERD

In patients suspected of having extraesophageal GERD, surgery should be considered if typical GERD symptoms are present and improve with PPI therapy, if the extraesophageal syndrome partially responds to PPI therapy, and if MII-pH testing demonstrates a correlation between symptoms and reflux. Surgery may have a stronger indication in this setting if the patient has nocturnal reflux or extraesophageal symptoms.

When is surgery not an option?

In general, surgery should not be considered in patients who do not have a partial response to PPI therapy or who do not have a strong symptom-reflux correlation on MII-pH testing. In all cases of failed medical therapy without persistent severe erosive disease, the threshold for opting for surgery should be high, given the uncertain response of these patients to surgery.

Peristaltic dysfunction is a relative but not an absolute contraindication to surgery.⁵⁹

RISKS, BENEFITS OF SURGERY FOR GERD

The patient’s preference for surgery over drug therapy should always be balanced against the risks of surgery, including both short-term and long-term adverse events, to allow the patient to make an adequately informed decision (Table 2).^2,26

Adverse events associated with PPI therapy are rare and in many cases the association is debatable.²⁶ Nonetheless, long-term PPI therapy has been most strongly associated with an increased risk of C difficile infection and other enteric infections, although the absolute risk of these events remains low.

Complication rates after antireflux surgery depend on the surgeon’s experience and technique. Death is exceedingly rare. In most high-volume centers, the need to convert from laparoscopic to open fundoplication occurs in fewer than 2.4% of patients.²

Potential perioperative complications include perforation (4%), wound infection (3%), and pneumothorax (2%).²

Antireflux surgery is also associated with a significant risk of dysphagia, bloating, an inability to burp, and excessive flatulence, all of which can markedly impair the quality of life.

A major consideration is that fundoplication is generally irreversible. Reoperation rates have been reported to range from 0% to 15%.² Furthermore, up to 50% of patients still need medical therapy after surgery.^60,61 Of note, only about 25% of patients on medical therapy after surgery will actually have an abnormal pH study.⁶¹

MORE STUDY NEEDED

Future studies directly comparing medical and surgical therapy for carefully selected patients with extraesophageal manifestations of GERD and refractory symptoms should help further delineate outcome in this difficult group of patients.

Under development are new drugs that may inhibit transient relaxation of the lower esophageal sphincter, as well as minimally invasive procedures, which may alter the indications for surgery in coming years.³⁶
 

---

Acknowledgment: The research for this article was supported in part by a grant from the National Institutes of Health (T32 DK07634).

For most patients with gastroesophageal reflux disease (GERD), a proton pump inhibitor (PPI) is the first choice for treatment.¹ But some patients have symptoms that persist despite PPI therapy, some desire surgery despite successful PPI therapy, and some have persistent extraesophageal symptoms or other complications of reflux. For these patients, surgery is an option.²

In this article, we review the management of GERD and clarify the indications for antireflux surgery based on evidence of safety and efficacy.

GERD DEFINED: SYMPTOMS OR COMPLICATIONS

Defining the role of antireflux surgery is difficult, given the variety of presentations and the absence of a gold standard for diagnosing GERD. Most adults experience several episodes of physiologic reflux daily without symptoms.³ But a broad array of symptoms have been attributed to GERD, including chest pain, cough, and sore throat, and some conditions caused by acid reflux (eg, Barrett esophagus) can be asymptomatic.^4,5

Given these challenges, in 2006 the Montreal Consensus Group defined GERD as “a condition which develops when the reflux of stomach contents causes troublesome symptoms or complications.” ⁴ Critical to the Montreal definition is the distinction between “troublesome symptoms” and “complications” or bodily injury (Table 1).

HEARTBURN ISN’T ALWAYS GERD

Typical GERD presents with the classic symptoms of pyrosis (heartburn) or acid regurgitation, or both.

Although these symptoms are often thought to be specific for GERD, other causes of esophageal injury— eg, eosinophilic esophagitis, infection (Candida, cytomegalovirus, herpes simplex virus), pill-induced esophagitis, or radiation therapy—can produce similar symptoms. Other causes, including coronary artery disease, biliary colic, foregut malignancy, or peptic ulcer disease, should also be considered in patients with supposedly typical GERD. Life-threatening mimics of GERD, such as unstable angina, should be excluded if they are likely, before proceeding with evaluating for possible GERD. Therefore, the initial history and examination should focus on appropriate diagnosis, with careful delineation of symptom quality.

Alarm features for advanced pathology^6–8 include involuntary weight loss, dysphagia, vomiting, evidence of gastrointestinal blood loss, anemia, chest pain, and an epigastric mass.⁷ Admittedly, these features are only mediocre for detecting or excluding gastric or esophageal cancer, with a sensitivity of 67% and a specificity 66%.⁹ Nevertheless, they should prompt an endoscopic examination. In patients who have alarm features but have not yet been treated for GERD, upper endoscopy can identify an abnormality in about 60% of patients.^10–12

PPIs HAVE REPLACED ANTACIDS AND HISTAMINE-2 RECEPTOR ANTAGONISTS

When the symptoms suggest GERD and no alarm features are present, an initial trial of the following lifestyle changes is reasonable:

• Avoiding acidic or refluxogenic foods (coffee, alcohol, chocolate, peppermint, fatty foods, citrus foods)
• Avoiding certain medications (anticholinergics, estrogens, calcium-channel blockers, nitroglycerine, benzodiazepines)
• Losing weight
• Quitting smoking
• Raising the head of the bed
• Staying upright for 2 to 3 hours after meals.

For someone with mild symptoms, these changes pose minimal risk. Unfortunately, they are unlikely to provide adequate symptom control for most patients.^13–17

Before PPIs were invented, drug therapy for GERD symptoms that did not resolve with lifestyle changes consisted of antacids and, later, histamine-2 receptor antagonists. When maximal therapy failed to control symptoms, fundoplication surgery was considered an appropriate next step.

PPIs substantially changed the management of GERD, suppressing acid secretion much better than histamine-2 receptor antagonists. Taken 30 minutes before breakfast, a single daily dose of a PPI normalizes esophageal acid exposure in 67% of patients.¹⁸ Adding a second dose 30 minutes before dinner raises the number to more than 90%.¹⁹

PPIs have consistently outperformed histamine-2 blockers in the healing of esophagitis and in improving heartburn symptoms and are now the first-line medical therapy for uncomplicated GERD.^6,8,20–25

WHEN PPIs WORK, SURGERY OFFERS NO ADVANTAGE

Patients may not want to take a PPI for the rest of their life, for a number of reasons: cost, the need to take one or more pills daily, and potential adverse effects.²⁶ In these cases, the physician can counsel the patient on the relative merits of long-term medical therapy vs surgery (Table 2).^2,26

The LOTUS trial (Long-Term Usage of Esomeprazole vs Surgery for Treatment of Chronic GERD) compared long-term drug therapy with surgery to maintain remission of symptoms in GERD.²⁷ In this trial, 554 patients whose symptoms initially responded to the PPI esomeprazole (Nexium) were randomized to continue to receive esomeprazole (n = 266) or to undergo laparoscopic antireflux surgery (288 were randomly assigned, and 248 had the operation). Dose adjustment of the esomeprazole was allowed (20–40 mg/day). A total of 372 patients completed 5 years of follow-up (192 esomeprazole, 180 surgery).

Symptoms stayed in remission in 92% of the esomeprazole group and 85% of the surgery group (P = .048). However, the difference was no longer statistically significant after modeling the effects of study dropout. The rate of severe adverse events was similar in both groups: 24.1% with esomeprazole and 28.6% with surgery.

These findings indicate that if symptoms fully abate with medical therapy, surgery offers no advantage. In addition, patients who desire surgery in the hope of avoiding lifelong drug therapy should be made aware that drug therapy and reoperation are often necessary after surgery.²⁸ In most cases, antireflux surgery is unnecessary for patients whose GERD fully responds to PPI therapy.

 

IF PPIs FAIL, FURTHER TESTING NEEDED

But many patients who take PPIs still have symptoms, even though these drugs suppress acid secretion and heal esophagitis. In fact, symptoms completely resolve in only about one-half of patients with erosive disease and one-third of those without erosive disease.²¹

Reasons for an incomplete symptomatic response to PPIs are various. Acid reflux can persist, but this accounts for only 10% of cases.²⁹ About one-third of patients have persistent reflux that is weakly acidic, with a pH higher than 4.29. However, most patients with persistent typical GERD symptoms do not have significant, persistent reflux, or their symptoms are not related to reflux events. In these cases, an alternative cause of the refractory symptoms should be sought.

Further diagnostic testing is indicated when symptoms persist despite PPI therapy. Upper endoscopy will reveal an abnormality such as persistent erosive esophagitis, eosinophilic esophagitis, esophageal stricture, Barrett esophagus, or esophageal cancer in roughly 10% of patients in whom empiric therapy fails.¹⁰

Although patients with persistent symptoms have not been enrolled in many randomized controlled trials, a multivariate analysis showed that failure of medical therapy heralds a poor response to surgery.³⁰ Data such as these have led most experts to discourage fundoplication for such patients now, unlike in the pre-PPI era.

pH and intraluminal impedance testing

However, this recommendation against surgery is not a hard-and-fast rule.

When symptoms of GERD do not respond to twice-daily PPI therapy and the results of upper endoscopy are negative, then an esophageal pH study combined with multichannel intraluminal impedance (MII-pH) testing may help identify patients who will respond to an intensification of medical therapy or to surgery, particularly if symptoms correlate with documented reflux events^31–33 (Figure 1). Most experts believe that esophageal MII-pH testing should be performed while the patient is taking a PPI to best identify patients whose refractory symptoms are most likely to be related to ongoing reflux.

In patients with esophageal regurgitation, most will not achieve adequate relief of symptoms with PPI therapy alone.³⁴ The therapeutic gain of PPI therapy vs placebo averaged just 17% in seven randomized, controlled trials, more than 20% less than the response rate for heartburn.³⁴ This is likely because of structural abnormalities such as reduced lower esophageal sphincter pressure, hiatal hernia, or delayed gastric emptying. Antireflux surgery can correct these structural abnormalities or prevent them from causing so much trouble; however, the presence of true regurgitation should first be confirmed by MII testing. If regurgitation is confirmed, antireflux surgery is warranted, particularly in patients with nocturnal symptoms who may be at high risk of aspiration. With careful patient selection, regurgitation symptoms improve in about 90% after surgery.²

In patients with heartburn, if esophageal acid exposure continues to be abnormal on MII-pH testing, then an escalation of therapy may improve symptoms, particularly if symptoms occur during reflux or if they partially responded to PPI therapy. Options in this scenario include alteration or intensification of acid-suppressive therapy, treatment with baclofen (Lioresal), and antireflux surgery.^18,35,36 In randomized controlled trials of patients whose symptoms partially responded to PPIs, antireflux surgery has performed similarly to PPIs in terms of improving typical GERD symptoms, particularly regurgitation.^27,37–41 Although this scenario is a reasonable indication for antireflux surgery, recommendations should be made with appropriate restraint since it is not easily reversible, some patients experience complications, and up to one-third will have no therapeutic benefit.³⁰

Nonacid reflux. In some cases, MII-pH testing during PPI therapy will reveal reflux of weakly acidic (pH > 4) or alkaline stomach contents, often called “nonacid reflux.”²⁹ Nonacid reflux is often present in patients with esophagitis that persists despite PPI therapy, indicating that even weakly acidic stomach contents can injure the mucosa.⁴² Since intensifying the acid-suppressive therapy is unlikely to improve these symptoms, antireflux surgery may have a role.

In one study,⁴³ nonacid reflux was well controlled by laparoscopic Nissen fundoplication, although 15 (48%) of 31 patients had persistent symptoms of GERD after surgery. No patient had a strong symptom correlation with postoperative reflux events, suggesting an alternative cause of the persistent symptoms. Therefore, antireflux surgery for nonacid reflux should be limited exclusively to patients with strong symptom correlation, and even then it should be considered with restraint, given the limited evidence for benefit and the potential for harm.

If testing is negative. In studies investigating the diagnostic yield of MII-pH testing, more than 50% of patients who had refractory symptoms had a negative MII-pH test.²⁹ In such situations, when the symptoms are strongly correlated with reflux events, the patient is said to have “esophageal hypersensitivity.” A few small studies have suggested that such patients may benefit from surgery, but these data have not been replicated in randomized controlled trials.³²

When the testing is negative and there is no correlation between the patient’s symptoms and reflux events, the patient is unlikely to benefit from antireflux surgery. Care of these patients is beyond the scope of this review.

SURGERY RARELY IMPROVES COUGH, ASTHMA, OR LARYNGITIS

GERD has been implicated as a cause of chronic cough, asthma, and laryngitis, although each of these has many potential causes.^44–46 Despite these associations, the evidence for therapeutic benefit from antireflux therapy is weak.

PPI therapy shows no benefit over placebo for chronic cough of uncertain etiology, but some benefit if GERD is objectively demonstrated.⁴⁷ Laryngitis resolved in just 15% of patients on esomeprazole vs 16% of patients on placebo after excluding patients with moderate to severe heartburn.⁴⁸

In a large randomized controlled trial in patients with asthma, there was no overall improvement in peak flow for the PPI group vs the placebo group, although significant improvement occurred in patients with heartburn and nocturnal respiratory symptoms.⁴⁶

Potent antisecretory therapy seems to improve extraesophageal symptoms when typical GERD symptoms are also present, but it otherwise has shown little evidence of benefit.

The evidence for a benefit from antireflux surgery in patients with extraesophageal GERD syndromes is even more limited. Although one systematic review⁴⁹ found that cough and other laryngeal symptoms improved in 60% to 100% of patients with objective evidence of GERD who underwent fundoplication, virtually all of the studies were uncontrolled case series.⁴⁹

The lone randomized controlled trial in the systematic review compared Nissen fundoplication with ranitidine (Zantac) or antacids only for patients with asthma and GERD, and found no significant difference in peak expiratory flow among the three groups after 2 years. However, asthma symptom scores improved in 75% of the surgical group, 9% of the medical group, and 4% of the control group.⁵⁰

In a study that was not included in the prior systematic review, patients with laryngopharyngeal reflux unresponsive to aggressive acid suppression who subsequently underwent fundoplication fared no better than those who did not.⁵¹

Thus, based on the available data, antireflux surgery is only rarely indicated for extraesophageal symptoms, especially in patients who have no typical GERD symptoms or in patients whose symptoms are refractory to medical therapy.

 

SURGERY FOR EROSIVE ESOPHAGITIS OR BARRETT ESOPHAGUS IF PPI FAILS

Lifelong antireflux therapy is indicated for patients with severe erosive esophagitis or Barrett esophagus. Erosive esophagitis recurs in more than 80% within 12 months of discontinuing antisecretory therapy.⁵² Both Barrett esophagus and esophageal adenocarcinoma are strongly associated with GERD, and nearly 10% of patients with chronic reflux have Barrett esophagus.^53,54 It is suspected that suppressing reflux reduces the rate of progression of Barrett esophagus to esophageal adenocarcinoma, but this remains to be proven.

Perhaps the strongest indication for surgery in the PPI era is for patients who have persistent symptoms and severe erosive esophagitis (Los Angeles grade C or D) despite high-dose PPI therapy. If other causes of persistent esophagitis have been ruled out, fundoplication can induce healing and improve symptoms.^55,56 In these cases, surgery is done to induce remission of the disease when maximal medical therapy has been truly unsuccessful.

Randomized controlled trials suggest that medical and surgical therapies are equally effective for preventing the recurrence of erosive esophagitis or the progression of Barrett esophagus. In a study of 225 patients, at 7 years of follow-up, esophagitis had recurred in 10.4% of patients on omeprazole vs 11.8% of those who had undergone antireflux surgery.⁴⁰ Similarly, open Nissen fundoplication was no different from drug therapy (histamine-2 receptor antagonist or PPI) for progression of Barrett esophagus over a median of 5 years.⁵⁷ A meta-analysis with nearly 5,000 person-years each in the medical and surgical groups also found no significant difference in rates of cancer progression.⁵⁸

Notably, symptoms such as dysphagia, flatulence, and the inability to burp occurred significantly more often in the surgical groups in these studies.

In view of these data, antireflux surgery has no significant advantage over medical therapy for maintaining healing of erosive esophagitis or preventing progression of Barrett esophagus. Thus, it should be reserved for patients who do not desire lifelong drug therapy, provided they understand that there is no therapeutic advantage for their esophagitis or for Barrett esophagus.

SPECIFIC INDICATIONS FOR ANTIREFLUX SURGERY

Now that we have PPIs, several situations remain in which surgery for GERD is either indicated or worth considering.

Antireflux surgery is clearly indicated for:

• Patients with erosive esophagitis that does not heal with maximal drug therapy
• Patients with volume regurgitation, particularly if it occurs at night or if there is evidence of aspiration
• Patients who require lifelong treatment for reflux but who have had a serious adverse event related to PPI therapy, such as refractory Clostridium difficile infection.

Antireflux surgery is also worth considering in patients who for personal reasons wish to avoid long-term or lifelong drug therapy.

Patients should be informed, however, that antireflux surgery has not been shown to be better than medical therapy for maintaining remission of symptoms, for preventing progression of Barrett esophagus, or for maintaining healing of erosive esophagitis. Medical therapy is still the first option for these patients.

Surgery may also be considered in patients with persistent symptoms who have a partial response to medical therapy, who show persistent acidic or weakly acidic reflux on MII-pH testing, and whose symptoms have been correlated with reflux events. Although surgery is not sure to improve their symptoms, benefit is more likely in this patient population compared with those without these characteristics.

Extraesophageal GERD

In patients suspected of having extraesophageal GERD, surgery should be considered if typical GERD symptoms are present and improve with PPI therapy, if the extraesophageal syndrome partially responds to PPI therapy, and if MII-pH testing demonstrates a correlation between symptoms and reflux. Surgery may have a stronger indication in this setting if the patient has nocturnal reflux or extraesophageal symptoms.

When is surgery not an option?

In general, surgery should not be considered in patients who do not have a partial response to PPI therapy or who do not have a strong symptom-reflux correlation on MII-pH testing. In all cases of failed medical therapy without persistent severe erosive disease, the threshold for opting for surgery should be high, given the uncertain response of these patients to surgery.

Peristaltic dysfunction is a relative but not an absolute contraindication to surgery.⁵⁹

RISKS, BENEFITS OF SURGERY FOR GERD

The patient’s preference for surgery over drug therapy should always be balanced against the risks of surgery, including both short-term and long-term adverse events, to allow the patient to make an adequately informed decision (Table 2).^2,26

Adverse events associated with PPI therapy are rare and in many cases the association is debatable.²⁶ Nonetheless, long-term PPI therapy has been most strongly associated with an increased risk of C difficile infection and other enteric infections, although the absolute risk of these events remains low.

Complication rates after antireflux surgery depend on the surgeon’s experience and technique. Death is exceedingly rare. In most high-volume centers, the need to convert from laparoscopic to open fundoplication occurs in fewer than 2.4% of patients.²

Potential perioperative complications include perforation (4%), wound infection (3%), and pneumothorax (2%).²

Antireflux surgery is also associated with a significant risk of dysphagia, bloating, an inability to burp, and excessive flatulence, all of which can markedly impair the quality of life.

A major consideration is that fundoplication is generally irreversible. Reoperation rates have been reported to range from 0% to 15%.² Furthermore, up to 50% of patients still need medical therapy after surgery.^60,61 Of note, only about 25% of patients on medical therapy after surgery will actually have an abnormal pH study.⁶¹

MORE STUDY NEEDED

Future studies directly comparing medical and surgical therapy for carefully selected patients with extraesophageal manifestations of GERD and refractory symptoms should help further delineate outcome in this difficult group of patients.

Under development are new drugs that may inhibit transient relaxation of the lower esophageal sphincter, as well as minimally invasive procedures, which may alter the indications for surgery in coming years.³⁶
 

---

Acknowledgment: The research for this article was supported in part by a grant from the National Institutes of Health (T32 DK07634).

A 29-year-old white man with no chronic medical problems presents to the emergency department with shortness of breath, left-sided pleuritic chest pain, cough, and hemoptysis. These symptoms began abruptly 1 day ago and have persisted. He also has mild pain and swelling in both calves. He denies having any fever, night sweats, or chills. On further questioning, he reports having taken a long, nonstop driving trip that lasted 8 hours 1 week ago.

His medical history is negative, and he specifically reports no history of deep venous thrombosis or pulmonary embolism. He underwent appendectomy 10 years ago but has had no other operations. He does not take any medications. His family history is noncontributory and is negative for venous thromboembolism. He smokes and uses alcohol occasionally but not illicit drugs.

Examination. He appears to be in considerable distress because of his chest pain. His temperature is 100.4°F (38.0°C), blood pressure 125/70 mm Hg, heart rate 125 beats per minute, respiratory rate 26 breaths per minute, oxygen saturation 92% on room air, and body mass index 19 kg/m².

Chest examination reveals diminished vesicular breathing in the left base, which is normal to percussion without added sounds. Both calves are swollen and tender to palpation without skin discoloration. The rest of his examination is normal.

Laboratory values:

• White blood cell count 9.3 × 10⁹/L (reference range 4.5–11.0)
• Hemoglobin 15.9 g/dL (14.0–17.5)
• Platelets 205 × 10⁹/L (150–350)
• Sodium 140 mEq/L (136–142)
• Potassium 3.9 mEq/L (3.5–5.0)
• Chloride 108 mEq/L (96–106)
• Bicarbonate 23 mEq/L (21–28)
• Blood urea nitrogen 14 mg/dL (8–23)
• Creatinine 0.9 mg/dL (0.6–1.2)
• Glucose 95 mg/dL (70–110)
• International normalized ratio (INR) 0.90 (0.00–1.2)
• Partial thromboplastin time 27.5 seconds (24.6–31.8)
• Creatine phosphokinase 205 U/L (39–308)
• Troponin T < 0.015 ng/mL (0.01–0.045).

Pulmonary embolism is diagnosed

Electrocardiography shows sinus tachycardia. Chest radiography shows small atelectatic changes at the left lung base (Figure 1). Pulmonary embolism is suspected, and a serum Ddimer level is obtained; it is 4,054 ng/mL (reference range < 500). Computed tomography of the chest confirms bilateral acute pulmonary emboli (Figure 2). Doppler ultrasonography of both legs reveals bilateral deep venous thrombosis. Echocardiography shows mildly elevated right ventricular systolic pressure at 47 mm Hg.

Factor V Leiden is diagnosed, and the patient recovers with treatment

Anticoagulation is started in the emergency department.

Given this patient’s young age and clot burden, a hypercoagulable state is suspected. Thrombophilia screening is performed, with tests for the factor V Leiden mutation, the prothrombin G20210A mutation, and antiphospholipid and lupus anticoagulant antibodies. The rest of the thrombophilia panel, including antithrombin III, factor VIII, protein C, and protein S, is deferred because the levels of these substances would be expected to change during the acute thrombosis.

The direct test for factor V Leiden mutation is positive for the heterozygous type. The test for the prothrombin G20210A mutation is negative, and his antiphospholipid antibody levels, including the lupus anticoagulant titer, are within normal limits.

The patient is kept on a standard regimen of unfractionated heparin, overlapped with warfarin (Coumadin) until his INR is 2.0 to 3.0 on 2 consecutive days. His hospital course is uneventful and his condition gradually improves.

He is discharged home to continue on oral anticoagulation for 6 months with a target INR of 2.0 to 3.0. Two weeks after completing his anticoagulation therapy, his levels of antithrombin III, factor VIII, protein C, and protein S are all within normal limits.

FACTOR V LEIDEN IS COMMON

Factor V Leiden is the most common inherited thrombophilia, with a prevalence of 3% to 7% in the general US population,¹ approximately 5% in whites, 2.2% in Hispanics, and 1.2% in blacks.² Its prevalence in patients with venous thromboembolism, however, is 50%.^1,3 The annual incidence of venous thromboembolism in patients with factor V Leiden is 0.5%.^4,5

 

MORE COAGULATION, LESS ANTICOAGULATION

Factor V has a critical position in both the coagulant and anticoagulant pathways. Factor V Leiden results in a hypercoagulable state by both increasing coagulation and decreasing anticoagulation.

This mutation causes factor V to be resistant to being cleaved and inactivated by activated protein C, a condition known as APC resistance. As a result, more factor Va is available within the prothrombinase complex, increasing coagulation by increased generation of thrombin.^6–8

Furthermore, a cofactor formed by cleavage of factor V at position 506 is thought to support activated protein C in degrading factor VIIIa (in the tenase complex), along with protein S. People with factor V Leiden lack this cleavage product and thus have less anticoagulant activity from activated protein C. The increased coagulation and decreased anticoagulation appear to contribute equally to the hypercoagulable state in factor V Leiden-associated APC resistance.^9–11

Heterozygosity for the factor V Leiden mutation accounts for 90% to 95% of cases of APC resistance. A much smaller number of people are homozygous for it.¹

People who are homozygous for factor V Leiden are at higher risk of venous thromboembolism than those who are heterozygous for it, since the latter group’s blood contains both factor V Leiden and normal factor V. The normal factor V allows anticoagulation via the second pathway of inactivation of factor VIIIa by activated protein C, giving some protection against thrombosis. In people who are homozygous for factor V Leiden, the lack of normal factor V acting as an anticoagulant protein results in a higher thrombotic risk.^9–11

Other factor V mutations may also cause APC resistance

Although factor V Leiden is the only genetic defect for which a causal relationship with APC resistance has been clearly determined, other, rarer hereditary factor V mutations or polymorphisms have been described, such as factor V Cambridge (Arg306Thr)¹² and factor V Hong Kong (Arg306Gly).¹³ These mutations may result in APC resistance, but their clinical association with thrombosis is less clear.¹⁴ Factor V Liverpool (Ile359Thr) is associated with a higher risk of thrombosis, apparently because of reduced APC-mediated inactivation of factor Va and because it is a poor cofactor with activated protein C for the inactivation of factor VIIIa.¹⁵

An R2 haplotype has also been described in association with APC resistance.^16,17 The phenomenon may be due to a reduction in activated protein C cofactor activity.⁹ However, not all studies have been convincing regarding the role of this haplotype in clinical disease.¹⁸ Coinheritance of this haplotype with factor V Leiden may increase the risk of venous thromboembolism above that associated with factor V Leiden alone.¹⁹

Although factor V Leiden is the most common cause of inherited APC resistance, other changes in hemostasis cause acquired APC resistance and may contribute to the thrombotic tendency in these patients.^20–22 The most common causes of acquired APC resistance include elevated factor VIII levels,^23–25 pregnancy,^26–28 use of oral contraceptives,^29,30 and antiphospholipid antibodies.³¹

USUALLY MANIFESTS AS DEEP VEIN THROMBOSIS

Factor V Leiden usually manifests as deep vein thrombosis with or without pulmonary embolism, but thrombosis in unusual locations also occurs.³²

The risk of a first episode of venous thromboembolism is two to five times higher with heterozygous factor V Leiden. However, even though the relative risk is high, the absolute risk is low. Furthermore, despite the higher risk of venous thrombosis, there is no evidence that heterozygosity for factor V Leiden increases the overall mortality rate.^4,33–36

In people with homozygous factor V Leiden or with combined inherited thrombophilias, the risk of venous thromboembolism is increased to a greater degree: it is 20 to 50 times higher.^7,8,37–39 However, whether the risk of death is higher is not clear.

VENOUS THROMBOEMBOLISM IS MULTIFACTORIAL

The pathogenesis of venous thromboembolism is multifactorial and involves an interaction between inherited and acquired factors. Very often, people with factor V Leiden have additional risk factors that contribute to the development of venous clots, and it is very unusual for them to have thrombosis in the absence of these additional factors.

These factors include older age, surgery, obesity, prolonged travel, immobility, hospitalization, oral contraceptive use, hormonal replacement therapy, pregnancy, and malignancy. They increase the risk of venous thrombosis in normal individuals as well, but more so in people with factor V Leiden.^40–43

Testing for other known causes of thrombophilia may also be pursued. These include elevated homocysteine levels, the factor II (prothrombin) G20210A mutation, anticardiolipin antibody, lupus anticoagulant, and deficiencies of antithrombin III, protein C, and protein S.

Factor V Leiden by itself does not appear to increase the risk of arterial thrombosis, ie, heart attack and stroke.^{33,38,44–46}

Family history: A risk indicator for venous thrombosis

Family history is an important indicator of risk for a first venous thromboembolic event, regardless of other risk factors identified. The risk of a first event is two to three times higher in people with a family history of thrombosis in a first-degree relative. The risk is four times higher when multiple family members are affected, at least one of them before age 50.⁴⁷

In people with genetic thrombophilia, the risk of thrombosis (especially unprovoked thrombosis at a young age) is also higher in those with a strong family history than in those without a family history. In those with factor V Leiden, the risk of venous thromboembolism is three to four times higher if there is a positive family history. The risk is five times higher in carriers of factor V Leiden with a family history of venous thromboembolism before age 50, and 13 times higher in those with more than one affected family member.⁴⁷

Possible shared environmental factors or coinheritance of other unidentified genetic factors may also contribute to the higher susceptibility in thrombosis-prone families.

TESTING FOR APC RESISTANCE AND FACTOR V LEIDEN

The factor V Leiden mutation can be detected directly by genetic testing of peripheral blood mononuclear cells. This method is relatively time-consuming and expensive, however.

At present, the most cost-effective approach is to test first for APC resistance using a second-generation coagulation assay—the modified APC sensitivity test. In this clot-based method, the patient’s sample is prediluted with factor V-deficient plasma to eliminate the effect of lupus anticoagulants and factor deficiencies that could prolong the baseline clotting time, and heparin is inactivated by polybrene. Then either an augmented partial-thromboplastin-time-based assay or a tissue-factor-dependent factor V assay is performed.

This test is nearly 100% sensitive and specific for factor V Leiden, in contrast to the first-generation, or classic, APC sensitivity test, which lacked specificity and sensitivity for it.^{9–11,48–60} This modification also permits testing of patients receiving anticoagulants or who have abnormal augmented partial thromboplastin times due to coagulation factor deficiencies.

A positive result on the modified APC sensitivity test should be confirmed by a direct genetic test for the factor V Leiden mutation. An APC resistance assay is unnecessary if a direct genetic test is used initially.

 

HOW LONG TO GIVE ANTICOAGULATION AFTER VENOUS THROMBOEMBOLISM?

Patients who have had an episode of venous thromboembolism have to be treated with anticoagulants.

In general, the initial management of venous thromboembolism in patients with heritable thrombophilias is no different from that in any other patient with a clot. Anticoagulants such as warfarin are given at a target INR of 2.5 (range 2.0–3.0).³² The duration of treatment is based on the risk factors that resulted in the thrombotic event.

After a first event, some authorities recommend anticoagulant therapy for 6 months.³² A shorter period (3 months) is recommended if there is a transient risk factor (eg, surgery, oral contraceptive use, travel, pregnancy, the puerperium) and the thrombosis is confined to distal veins (eg, the calf veins).³²

Factor V Leiden does not necessarily increase the risk of recurrent events in patients who have a transient risk factor. Therefore, people who are heterozygous for this mutation do not usually need to be treated lifelong with anticoagulants if they have had only one episode of deep vein thrombosis or pulmonary embolism, given the risk of bleeding associated with anticoagulation, unless they have additional risk factors.

Conditions in which indefinite anticoagulation may be required after careful consideration of the risks and benefits are:

• Life-threatening events such as near-fatal pulmonary embolism
• Cerebral or visceral vein thrombosis
• Recurrent thrombotic events
• Additional persistent risk factors (eg, active malignant neoplasm, extremity paresis, and antiphospholipid antibodies)
• Combined thrombophilias (eg, combined heterozygosity for factor V Leiden and the prothrombin G20210A mutation)
• Homozygosity for factor V Leiden.^32,46,48

Factor V Leiden by itself or combined with other thrombophilic abnormalities is not associated with a higher risk of recurrent venous thromboembolism during warfarin therapy (a possible exception is the combination of factor V Leiden plus antiphospholipid antibodies).^32,34 Furthermore, current evidence suggests that no thrombophilic defect is a clinically important risk factor for recurrent venous thromboembolism after anticoagulant therapy is stopped. All these facts indicate that clinical factors are probably more important than laboratory abnormalities in determining the duration of anticoagulation therapy.^{32,35,36,61–63}

PRIMARY PROPHYLAXIS IN PATIENTS WITH FACTOR V LEIDEN

Factor V Leiden is only one of many risk factors for deep vein thrombosis or pulmonary embolism. If carriers of factor V Leiden have never had a blood clot, then they are not routinely treated with an anticoagulant. Rather, they should be counseled about reducing or eliminating other factors that may add to their risk of developing a clot in the future.

Usually, the effect of risk factors is additive: the more risk factors present, the higher the risk.^46,50 Sometimes, however, the effect of multiple risk factors is more than additive.

Some risk factors, such as genetics or age, are not alterable, but many can be controlled by medications or lifestyle modifications. Therefore, general measures and precautions are recommended to minimize the risk of thrombosis. For example:

Losing weight (if the patient is overweight) is an important intervention for risk reduction, since obesity is probably the most common modifiable risk factor for developing blood clots.

Avoiding long periods of immobility is recommended. For example, if the patient is taking a long car ride (more than 2 hours), then stopping every few hours and walking around for a few minutes is a good way to keep the blood circulating. If the patient has a desk job, getting up and walking around the office periodically is advised. On long airplane trips, a walk in the aisle every so often and preventing dehydration by drinking plenty of fluids and avoiding alcohol are recommended.

Wearing elastic stockings with a graduated elastic pressure may prevent deep venous thrombosis from developing on long flights.^63–65

Staying active and getting regular exercise through such activities as walking, bicycling, or swimming are helpful.

Avoiding smoking is critical.^50,63

Thromboprophylaxis is recommended for most acutely ill hospitalized patients, especially those confined to bed with additional risk factors. Guidelines for prophylaxis are based on an individualized risk assessment and not on thrombophilia status. Prophylactic anticoagulation is routinely recommended for patients undergoing major high-risk surgery, such as an orthopedic, urologic, gynecologic, or bariatric procedure. Any excess thrombotic risk conferred by thrombophilia is likely small compared with the risk of surgery, and recommendations on the duration and intensity of thromboprophylaxis are not based on thrombophilic status.^46,48

Education. Pain, swelling, redness of a limb, unexplained shortness of breath, and chest pain are the most common symptoms of deep vein thrombosis and pulmonary embolism.^46,50 It is crucial to teach patients with factor V Leiden to recognize these symptoms and to seek early medical attention in case they experience any of them.

SCREENING FAMILY MEMBERS FOR THE FACTOR V LEIDEN MUTATION

Factor V Leiden by itself is a relatively mild thrombophilic defect that does not cause thrombosis in all carriers, and there is no evidence that early diagnosis reduces rates of morbidity or mortality. Therefore, routine screening of all asymptomatic relatives of affected patients with venous thrombosis is not recommended. Rather, the decision to screen should be made on an individual basis.^50,66

Screening may be beneficial in selected cases, especially when patients have a strong family history of recurrent venous thrombosis at a young age (younger than 50 years) and the family member has additional risk factors for venous thromboembolism such as oral contraception or is planning for pregnancy.^32,48,49,66

A 29-year-old white man with no chronic medical problems presents to the emergency department with shortness of breath, left-sided pleuritic chest pain, cough, and hemoptysis. These symptoms began abruptly 1 day ago and have persisted. He also has mild pain and swelling in both calves. He denies having any fever, night sweats, or chills. On further questioning, he reports having taken a long, nonstop driving trip that lasted 8 hours 1 week ago.

His medical history is negative, and he specifically reports no history of deep venous thrombosis or pulmonary embolism. He underwent appendectomy 10 years ago but has had no other operations. He does not take any medications. His family history is noncontributory and is negative for venous thromboembolism. He smokes and uses alcohol occasionally but not illicit drugs.

Examination. He appears to be in considerable distress because of his chest pain. His temperature is 100.4°F (38.0°C), blood pressure 125/70 mm Hg, heart rate 125 beats per minute, respiratory rate 26 breaths per minute, oxygen saturation 92% on room air, and body mass index 19 kg/m².

Chest examination reveals diminished vesicular breathing in the left base, which is normal to percussion without added sounds. Both calves are swollen and tender to palpation without skin discoloration. The rest of his examination is normal.

Laboratory values:

• White blood cell count 9.3 × 10⁹/L (reference range 4.5–11.0)
• Hemoglobin 15.9 g/dL (14.0–17.5)
• Platelets 205 × 10⁹/L (150–350)
• Sodium 140 mEq/L (136–142)
• Potassium 3.9 mEq/L (3.5–5.0)
• Chloride 108 mEq/L (96–106)
• Bicarbonate 23 mEq/L (21–28)
• Blood urea nitrogen 14 mg/dL (8–23)
• Creatinine 0.9 mg/dL (0.6–1.2)
• Glucose 95 mg/dL (70–110)
• International normalized ratio (INR) 0.90 (0.00–1.2)
• Partial thromboplastin time 27.5 seconds (24.6–31.8)
• Creatine phosphokinase 205 U/L (39–308)
• Troponin T < 0.015 ng/mL (0.01–0.045).

Pulmonary embolism is diagnosed

Electrocardiography shows sinus tachycardia. Chest radiography shows small atelectatic changes at the left lung base (Figure 1). Pulmonary embolism is suspected, and a serum Ddimer level is obtained; it is 4,054 ng/mL (reference range < 500). Computed tomography of the chest confirms bilateral acute pulmonary emboli (Figure 2). Doppler ultrasonography of both legs reveals bilateral deep venous thrombosis. Echocardiography shows mildly elevated right ventricular systolic pressure at 47 mm Hg.

Factor V Leiden is diagnosed, and the patient recovers with treatment

Anticoagulation is started in the emergency department.

Given this patient’s young age and clot burden, a hypercoagulable state is suspected. Thrombophilia screening is performed, with tests for the factor V Leiden mutation, the prothrombin G20210A mutation, and antiphospholipid and lupus anticoagulant antibodies. The rest of the thrombophilia panel, including antithrombin III, factor VIII, protein C, and protein S, is deferred because the levels of these substances would be expected to change during the acute thrombosis.

The direct test for factor V Leiden mutation is positive for the heterozygous type. The test for the prothrombin G20210A mutation is negative, and his antiphospholipid antibody levels, including the lupus anticoagulant titer, are within normal limits.

The patient is kept on a standard regimen of unfractionated heparin, overlapped with warfarin (Coumadin) until his INR is 2.0 to 3.0 on 2 consecutive days. His hospital course is uneventful and his condition gradually improves.

He is discharged home to continue on oral anticoagulation for 6 months with a target INR of 2.0 to 3.0. Two weeks after completing his anticoagulation therapy, his levels of antithrombin III, factor VIII, protein C, and protein S are all within normal limits.

FACTOR V LEIDEN IS COMMON

Factor V Leiden is the most common inherited thrombophilia, with a prevalence of 3% to 7% in the general US population,¹ approximately 5% in whites, 2.2% in Hispanics, and 1.2% in blacks.² Its prevalence in patients with venous thromboembolism, however, is 50%.^1,3 The annual incidence of venous thromboembolism in patients with factor V Leiden is 0.5%.^4,5

 

MORE COAGULATION, LESS ANTICOAGULATION

Factor V has a critical position in both the coagulant and anticoagulant pathways. Factor V Leiden results in a hypercoagulable state by both increasing coagulation and decreasing anticoagulation.

This mutation causes factor V to be resistant to being cleaved and inactivated by activated protein C, a condition known as APC resistance. As a result, more factor Va is available within the prothrombinase complex, increasing coagulation by increased generation of thrombin.^6–8

Furthermore, a cofactor formed by cleavage of factor V at position 506 is thought to support activated protein C in degrading factor VIIIa (in the tenase complex), along with protein S. People with factor V Leiden lack this cleavage product and thus have less anticoagulant activity from activated protein C. The increased coagulation and decreased anticoagulation appear to contribute equally to the hypercoagulable state in factor V Leiden-associated APC resistance.^9–11

Heterozygosity for the factor V Leiden mutation accounts for 90% to 95% of cases of APC resistance. A much smaller number of people are homozygous for it.¹

People who are homozygous for factor V Leiden are at higher risk of venous thromboembolism than those who are heterozygous for it, since the latter group’s blood contains both factor V Leiden and normal factor V. The normal factor V allows anticoagulation via the second pathway of inactivation of factor VIIIa by activated protein C, giving some protection against thrombosis. In people who are homozygous for factor V Leiden, the lack of normal factor V acting as an anticoagulant protein results in a higher thrombotic risk.^9–11

Other factor V mutations may also cause APC resistance

Although factor V Leiden is the only genetic defect for which a causal relationship with APC resistance has been clearly determined, other, rarer hereditary factor V mutations or polymorphisms have been described, such as factor V Cambridge (Arg306Thr)¹² and factor V Hong Kong (Arg306Gly).¹³ These mutations may result in APC resistance, but their clinical association with thrombosis is less clear.¹⁴ Factor V Liverpool (Ile359Thr) is associated with a higher risk of thrombosis, apparently because of reduced APC-mediated inactivation of factor Va and because it is a poor cofactor with activated protein C for the inactivation of factor VIIIa.¹⁵

An R2 haplotype has also been described in association with APC resistance.^16,17 The phenomenon may be due to a reduction in activated protein C cofactor activity.⁹ However, not all studies have been convincing regarding the role of this haplotype in clinical disease.¹⁸ Coinheritance of this haplotype with factor V Leiden may increase the risk of venous thromboembolism above that associated with factor V Leiden alone.¹⁹

Although factor V Leiden is the most common cause of inherited APC resistance, other changes in hemostasis cause acquired APC resistance and may contribute to the thrombotic tendency in these patients.^20–22 The most common causes of acquired APC resistance include elevated factor VIII levels,^23–25 pregnancy,^26–28 use of oral contraceptives,^29,30 and antiphospholipid antibodies.³¹

USUALLY MANIFESTS AS DEEP VEIN THROMBOSIS

Factor V Leiden usually manifests as deep vein thrombosis with or without pulmonary embolism, but thrombosis in unusual locations also occurs.³²

The risk of a first episode of venous thromboembolism is two to five times higher with heterozygous factor V Leiden. However, even though the relative risk is high, the absolute risk is low. Furthermore, despite the higher risk of venous thrombosis, there is no evidence that heterozygosity for factor V Leiden increases the overall mortality rate.^4,33–36

In people with homozygous factor V Leiden or with combined inherited thrombophilias, the risk of venous thromboembolism is increased to a greater degree: it is 20 to 50 times higher.^7,8,37–39 However, whether the risk of death is higher is not clear.

VENOUS THROMBOEMBOLISM IS MULTIFACTORIAL

The pathogenesis of venous thromboembolism is multifactorial and involves an interaction between inherited and acquired factors. Very often, people with factor V Leiden have additional risk factors that contribute to the development of venous clots, and it is very unusual for them to have thrombosis in the absence of these additional factors.

These factors include older age, surgery, obesity, prolonged travel, immobility, hospitalization, oral contraceptive use, hormonal replacement therapy, pregnancy, and malignancy. They increase the risk of venous thrombosis in normal individuals as well, but more so in people with factor V Leiden.^40–43

Testing for other known causes of thrombophilia may also be pursued. These include elevated homocysteine levels, the factor II (prothrombin) G20210A mutation, anticardiolipin antibody, lupus anticoagulant, and deficiencies of antithrombin III, protein C, and protein S.

Factor V Leiden by itself does not appear to increase the risk of arterial thrombosis, ie, heart attack and stroke.^{33,38,44–46}

Family history: A risk indicator for venous thrombosis

Family history is an important indicator of risk for a first venous thromboembolic event, regardless of other risk factors identified. The risk of a first event is two to three times higher in people with a family history of thrombosis in a first-degree relative. The risk is four times higher when multiple family members are affected, at least one of them before age 50.⁴⁷

In people with genetic thrombophilia, the risk of thrombosis (especially unprovoked thrombosis at a young age) is also higher in those with a strong family history than in those without a family history. In those with factor V Leiden, the risk of venous thromboembolism is three to four times higher if there is a positive family history. The risk is five times higher in carriers of factor V Leiden with a family history of venous thromboembolism before age 50, and 13 times higher in those with more than one affected family member.⁴⁷

Possible shared environmental factors or coinheritance of other unidentified genetic factors may also contribute to the higher susceptibility in thrombosis-prone families.

TESTING FOR APC RESISTANCE AND FACTOR V LEIDEN

The factor V Leiden mutation can be detected directly by genetic testing of peripheral blood mononuclear cells. This method is relatively time-consuming and expensive, however.

At present, the most cost-effective approach is to test first for APC resistance using a second-generation coagulation assay—the modified APC sensitivity test. In this clot-based method, the patient’s sample is prediluted with factor V-deficient plasma to eliminate the effect of lupus anticoagulants and factor deficiencies that could prolong the baseline clotting time, and heparin is inactivated by polybrene. Then either an augmented partial-thromboplastin-time-based assay or a tissue-factor-dependent factor V assay is performed.

This test is nearly 100% sensitive and specific for factor V Leiden, in contrast to the first-generation, or classic, APC sensitivity test, which lacked specificity and sensitivity for it.^{9–11,48–60} This modification also permits testing of patients receiving anticoagulants or who have abnormal augmented partial thromboplastin times due to coagulation factor deficiencies.

A positive result on the modified APC sensitivity test should be confirmed by a direct genetic test for the factor V Leiden mutation. An APC resistance assay is unnecessary if a direct genetic test is used initially.

 

HOW LONG TO GIVE ANTICOAGULATION AFTER VENOUS THROMBOEMBOLISM?

Patients who have had an episode of venous thromboembolism have to be treated with anticoagulants.

In general, the initial management of venous thromboembolism in patients with heritable thrombophilias is no different from that in any other patient with a clot. Anticoagulants such as warfarin are given at a target INR of 2.5 (range 2.0–3.0).³² The duration of treatment is based on the risk factors that resulted in the thrombotic event.

After a first event, some authorities recommend anticoagulant therapy for 6 months.³² A shorter period (3 months) is recommended if there is a transient risk factor (eg, surgery, oral contraceptive use, travel, pregnancy, the puerperium) and the thrombosis is confined to distal veins (eg, the calf veins).³²

Factor V Leiden does not necessarily increase the risk of recurrent events in patients who have a transient risk factor. Therefore, people who are heterozygous for this mutation do not usually need to be treated lifelong with anticoagulants if they have had only one episode of deep vein thrombosis or pulmonary embolism, given the risk of bleeding associated with anticoagulation, unless they have additional risk factors.

Conditions in which indefinite anticoagulation may be required after careful consideration of the risks and benefits are:

• Life-threatening events such as near-fatal pulmonary embolism
• Cerebral or visceral vein thrombosis
• Recurrent thrombotic events
• Additional persistent risk factors (eg, active malignant neoplasm, extremity paresis, and antiphospholipid antibodies)
• Combined thrombophilias (eg, combined heterozygosity for factor V Leiden and the prothrombin G20210A mutation)
• Homozygosity for factor V Leiden.^32,46,48

Factor V Leiden by itself or combined with other thrombophilic abnormalities is not associated with a higher risk of recurrent venous thromboembolism during warfarin therapy (a possible exception is the combination of factor V Leiden plus antiphospholipid antibodies).^32,34 Furthermore, current evidence suggests that no thrombophilic defect is a clinically important risk factor for recurrent venous thromboembolism after anticoagulant therapy is stopped. All these facts indicate that clinical factors are probably more important than laboratory abnormalities in determining the duration of anticoagulation therapy.^{32,35,36,61–63}

PRIMARY PROPHYLAXIS IN PATIENTS WITH FACTOR V LEIDEN

Factor V Leiden is only one of many risk factors for deep vein thrombosis or pulmonary embolism. If carriers of factor V Leiden have never had a blood clot, then they are not routinely treated with an anticoagulant. Rather, they should be counseled about reducing or eliminating other factors that may add to their risk of developing a clot in the future.

Usually, the effect of risk factors is additive: the more risk factors present, the higher the risk.^46,50 Sometimes, however, the effect of multiple risk factors is more than additive.

Some risk factors, such as genetics or age, are not alterable, but many can be controlled by medications or lifestyle modifications. Therefore, general measures and precautions are recommended to minimize the risk of thrombosis. For example:

Losing weight (if the patient is overweight) is an important intervention for risk reduction, since obesity is probably the most common modifiable risk factor for developing blood clots.

Avoiding long periods of immobility is recommended. For example, if the patient is taking a long car ride (more than 2 hours), then stopping every few hours and walking around for a few minutes is a good way to keep the blood circulating. If the patient has a desk job, getting up and walking around the office periodically is advised. On long airplane trips, a walk in the aisle every so often and preventing dehydration by drinking plenty of fluids and avoiding alcohol are recommended.

Wearing elastic stockings with a graduated elastic pressure may prevent deep venous thrombosis from developing on long flights.^63–65

Staying active and getting regular exercise through such activities as walking, bicycling, or swimming are helpful.

Avoiding smoking is critical.^50,63

Thromboprophylaxis is recommended for most acutely ill hospitalized patients, especially those confined to bed with additional risk factors. Guidelines for prophylaxis are based on an individualized risk assessment and not on thrombophilia status. Prophylactic anticoagulation is routinely recommended for patients undergoing major high-risk surgery, such as an orthopedic, urologic, gynecologic, or bariatric procedure. Any excess thrombotic risk conferred by thrombophilia is likely small compared with the risk of surgery, and recommendations on the duration and intensity of thromboprophylaxis are not based on thrombophilic status.^46,48

Education. Pain, swelling, redness of a limb, unexplained shortness of breath, and chest pain are the most common symptoms of deep vein thrombosis and pulmonary embolism.^46,50 It is crucial to teach patients with factor V Leiden to recognize these symptoms and to seek early medical attention in case they experience any of them.

SCREENING FAMILY MEMBERS FOR THE FACTOR V LEIDEN MUTATION

Factor V Leiden by itself is a relatively mild thrombophilic defect that does not cause thrombosis in all carriers, and there is no evidence that early diagnosis reduces rates of morbidity or mortality. Therefore, routine screening of all asymptomatic relatives of affected patients with venous thrombosis is not recommended. Rather, the decision to screen should be made on an individual basis.^50,66

Screening may be beneficial in selected cases, especially when patients have a strong family history of recurrent venous thrombosis at a young age (younger than 50 years) and the family member has additional risk factors for venous thromboembolism such as oral contraception or is planning for pregnancy.^32,48,49,66

A 29-year-old white man with no chronic medical problems presents to the emergency department with shortness of breath, left-sided pleuritic chest pain, cough, and hemoptysis. These symptoms began abruptly 1 day ago and have persisted. He also has mild pain and swelling in both calves. He denies having any fever, night sweats, or chills. On further questioning, he reports having taken a long, nonstop driving trip that lasted 8 hours 1 week ago.

His medical history is negative, and he specifically reports no history of deep venous thrombosis or pulmonary embolism. He underwent appendectomy 10 years ago but has had no other operations. He does not take any medications. His family history is noncontributory and is negative for venous thromboembolism. He smokes and uses alcohol occasionally but not illicit drugs.

Examination. He appears to be in considerable distress because of his chest pain. His temperature is 100.4°F (38.0°C), blood pressure 125/70 mm Hg, heart rate 125 beats per minute, respiratory rate 26 breaths per minute, oxygen saturation 92% on room air, and body mass index 19 kg/m².

Chest examination reveals diminished vesicular breathing in the left base, which is normal to percussion without added sounds. Both calves are swollen and tender to palpation without skin discoloration. The rest of his examination is normal.

Laboratory values:

• White blood cell count 9.3 × 10⁹/L (reference range 4.5–11.0)
• Hemoglobin 15.9 g/dL (14.0–17.5)
• Platelets 205 × 10⁹/L (150–350)
• Sodium 140 mEq/L (136–142)
• Potassium 3.9 mEq/L (3.5–5.0)
• Chloride 108 mEq/L (96–106)
• Bicarbonate 23 mEq/L (21–28)
• Blood urea nitrogen 14 mg/dL (8–23)
• Creatinine 0.9 mg/dL (0.6–1.2)
• Glucose 95 mg/dL (70–110)
• International normalized ratio (INR) 0.90 (0.00–1.2)
• Partial thromboplastin time 27.5 seconds (24.6–31.8)
• Creatine phosphokinase 205 U/L (39–308)
• Troponin T < 0.015 ng/mL (0.01–0.045).

Pulmonary embolism is diagnosed

Electrocardiography shows sinus tachycardia. Chest radiography shows small atelectatic changes at the left lung base (Figure 1). Pulmonary embolism is suspected, and a serum Ddimer level is obtained; it is 4,054 ng/mL (reference range < 500). Computed tomography of the chest confirms bilateral acute pulmonary emboli (Figure 2). Doppler ultrasonography of both legs reveals bilateral deep venous thrombosis. Echocardiography shows mildly elevated right ventricular systolic pressure at 47 mm Hg.

Factor V Leiden is diagnosed, and the patient recovers with treatment

Anticoagulation is started in the emergency department.

Given this patient’s young age and clot burden, a hypercoagulable state is suspected. Thrombophilia screening is performed, with tests for the factor V Leiden mutation, the prothrombin G20210A mutation, and antiphospholipid and lupus anticoagulant antibodies. The rest of the thrombophilia panel, including antithrombin III, factor VIII, protein C, and protein S, is deferred because the levels of these substances would be expected to change during the acute thrombosis.

The direct test for factor V Leiden mutation is positive for the heterozygous type. The test for the prothrombin G20210A mutation is negative, and his antiphospholipid antibody levels, including the lupus anticoagulant titer, are within normal limits.

The patient is kept on a standard regimen of unfractionated heparin, overlapped with warfarin (Coumadin) until his INR is 2.0 to 3.0 on 2 consecutive days. His hospital course is uneventful and his condition gradually improves.

He is discharged home to continue on oral anticoagulation for 6 months with a target INR of 2.0 to 3.0. Two weeks after completing his anticoagulation therapy, his levels of antithrombin III, factor VIII, protein C, and protein S are all within normal limits.

FACTOR V LEIDEN IS COMMON

Factor V Leiden is the most common inherited thrombophilia, with a prevalence of 3% to 7% in the general US population,¹ approximately 5% in whites, 2.2% in Hispanics, and 1.2% in blacks.² Its prevalence in patients with venous thromboembolism, however, is 50%.^1,3 The annual incidence of venous thromboembolism in patients with factor V Leiden is 0.5%.^4,5

 

MORE COAGULATION, LESS ANTICOAGULATION

Factor V has a critical position in both the coagulant and anticoagulant pathways. Factor V Leiden results in a hypercoagulable state by both increasing coagulation and decreasing anticoagulation.

This mutation causes factor V to be resistant to being cleaved and inactivated by activated protein C, a condition known as APC resistance. As a result, more factor Va is available within the prothrombinase complex, increasing coagulation by increased generation of thrombin.^6–8

Furthermore, a cofactor formed by cleavage of factor V at position 506 is thought to support activated protein C in degrading factor VIIIa (in the tenase complex), along with protein S. People with factor V Leiden lack this cleavage product and thus have less anticoagulant activity from activated protein C. The increased coagulation and decreased anticoagulation appear to contribute equally to the hypercoagulable state in factor V Leiden-associated APC resistance.^9–11

Heterozygosity for the factor V Leiden mutation accounts for 90% to 95% of cases of APC resistance. A much smaller number of people are homozygous for it.¹

People who are homozygous for factor V Leiden are at higher risk of venous thromboembolism than those who are heterozygous for it, since the latter group’s blood contains both factor V Leiden and normal factor V. The normal factor V allows anticoagulation via the second pathway of inactivation of factor VIIIa by activated protein C, giving some protection against thrombosis. In people who are homozygous for factor V Leiden, the lack of normal factor V acting as an anticoagulant protein results in a higher thrombotic risk.^9–11

Other factor V mutations may also cause APC resistance

Although factor V Leiden is the only genetic defect for which a causal relationship with APC resistance has been clearly determined, other, rarer hereditary factor V mutations or polymorphisms have been described, such as factor V Cambridge (Arg306Thr)¹² and factor V Hong Kong (Arg306Gly).¹³ These mutations may result in APC resistance, but their clinical association with thrombosis is less clear.¹⁴ Factor V Liverpool (Ile359Thr) is associated with a higher risk of thrombosis, apparently because of reduced APC-mediated inactivation of factor Va and because it is a poor cofactor with activated protein C for the inactivation of factor VIIIa.¹⁵

An R2 haplotype has also been described in association with APC resistance.^16,17 The phenomenon may be due to a reduction in activated protein C cofactor activity.⁹ However, not all studies have been convincing regarding the role of this haplotype in clinical disease.¹⁸ Coinheritance of this haplotype with factor V Leiden may increase the risk of venous thromboembolism above that associated with factor V Leiden alone.¹⁹

Although factor V Leiden is the most common cause of inherited APC resistance, other changes in hemostasis cause acquired APC resistance and may contribute to the thrombotic tendency in these patients.^20–22 The most common causes of acquired APC resistance include elevated factor VIII levels,^23–25 pregnancy,^26–28 use of oral contraceptives,^29,30 and antiphospholipid antibodies.³¹

USUALLY MANIFESTS AS DEEP VEIN THROMBOSIS

Factor V Leiden usually manifests as deep vein thrombosis with or without pulmonary embolism, but thrombosis in unusual locations also occurs.³²

The risk of a first episode of venous thromboembolism is two to five times higher with heterozygous factor V Leiden. However, even though the relative risk is high, the absolute risk is low. Furthermore, despite the higher risk of venous thrombosis, there is no evidence that heterozygosity for factor V Leiden increases the overall mortality rate.^4,33–36

In people with homozygous factor V Leiden or with combined inherited thrombophilias, the risk of venous thromboembolism is increased to a greater degree: it is 20 to 50 times higher.^7,8,37–39 However, whether the risk of death is higher is not clear.

VENOUS THROMBOEMBOLISM IS MULTIFACTORIAL

The pathogenesis of venous thromboembolism is multifactorial and involves an interaction between inherited and acquired factors. Very often, people with factor V Leiden have additional risk factors that contribute to the development of venous clots, and it is very unusual for them to have thrombosis in the absence of these additional factors.

These factors include older age, surgery, obesity, prolonged travel, immobility, hospitalization, oral contraceptive use, hormonal replacement therapy, pregnancy, and malignancy. They increase the risk of venous thrombosis in normal individuals as well, but more so in people with factor V Leiden.^40–43

Testing for other known causes of thrombophilia may also be pursued. These include elevated homocysteine levels, the factor II (prothrombin) G20210A mutation, anticardiolipin antibody, lupus anticoagulant, and deficiencies of antithrombin III, protein C, and protein S.

Factor V Leiden by itself does not appear to increase the risk of arterial thrombosis, ie, heart attack and stroke.^{33,38,44–46}

Family history: A risk indicator for venous thrombosis

Family history is an important indicator of risk for a first venous thromboembolic event, regardless of other risk factors identified. The risk of a first event is two to three times higher in people with a family history of thrombosis in a first-degree relative. The risk is four times higher when multiple family members are affected, at least one of them before age 50.⁴⁷

In people with genetic thrombophilia, the risk of thrombosis (especially unprovoked thrombosis at a young age) is also higher in those with a strong family history than in those without a family history. In those with factor V Leiden, the risk of venous thromboembolism is three to four times higher if there is a positive family history. The risk is five times higher in carriers of factor V Leiden with a family history of venous thromboembolism before age 50, and 13 times higher in those with more than one affected family member.⁴⁷

Possible shared environmental factors or coinheritance of other unidentified genetic factors may also contribute to the higher susceptibility in thrombosis-prone families.

TESTING FOR APC RESISTANCE AND FACTOR V LEIDEN

The factor V Leiden mutation can be detected directly by genetic testing of peripheral blood mononuclear cells. This method is relatively time-consuming and expensive, however.

At present, the most cost-effective approach is to test first for APC resistance using a second-generation coagulation assay—the modified APC sensitivity test. In this clot-based method, the patient’s sample is prediluted with factor V-deficient plasma to eliminate the effect of lupus anticoagulants and factor deficiencies that could prolong the baseline clotting time, and heparin is inactivated by polybrene. Then either an augmented partial-thromboplastin-time-based assay or a tissue-factor-dependent factor V assay is performed.

This test is nearly 100% sensitive and specific for factor V Leiden, in contrast to the first-generation, or classic, APC sensitivity test, which lacked specificity and sensitivity for it.^{9–11,48–60} This modification also permits testing of patients receiving anticoagulants or who have abnormal augmented partial thromboplastin times due to coagulation factor deficiencies.

A positive result on the modified APC sensitivity test should be confirmed by a direct genetic test for the factor V Leiden mutation. An APC resistance assay is unnecessary if a direct genetic test is used initially.

 

HOW LONG TO GIVE ANTICOAGULATION AFTER VENOUS THROMBOEMBOLISM?

Patients who have had an episode of venous thromboembolism have to be treated with anticoagulants.

In general, the initial management of venous thromboembolism in patients with heritable thrombophilias is no different from that in any other patient with a clot. Anticoagulants such as warfarin are given at a target INR of 2.5 (range 2.0–3.0).³² The duration of treatment is based on the risk factors that resulted in the thrombotic event.

After a first event, some authorities recommend anticoagulant therapy for 6 months.³² A shorter period (3 months) is recommended if there is a transient risk factor (eg, surgery, oral contraceptive use, travel, pregnancy, the puerperium) and the thrombosis is confined to distal veins (eg, the calf veins).³²

Factor V Leiden does not necessarily increase the risk of recurrent events in patients who have a transient risk factor. Therefore, people who are heterozygous for this mutation do not usually need to be treated lifelong with anticoagulants if they have had only one episode of deep vein thrombosis or pulmonary embolism, given the risk of bleeding associated with anticoagulation, unless they have additional risk factors.

Conditions in which indefinite anticoagulation may be required after careful consideration of the risks and benefits are:

• Life-threatening events such as near-fatal pulmonary embolism
• Cerebral or visceral vein thrombosis
• Recurrent thrombotic events
• Additional persistent risk factors (eg, active malignant neoplasm, extremity paresis, and antiphospholipid antibodies)
• Combined thrombophilias (eg, combined heterozygosity for factor V Leiden and the prothrombin G20210A mutation)
• Homozygosity for factor V Leiden.^32,46,48

Factor V Leiden by itself or combined with other thrombophilic abnormalities is not associated with a higher risk of recurrent venous thromboembolism during warfarin therapy (a possible exception is the combination of factor V Leiden plus antiphospholipid antibodies).^32,34 Furthermore, current evidence suggests that no thrombophilic defect is a clinically important risk factor for recurrent venous thromboembolism after anticoagulant therapy is stopped. All these facts indicate that clinical factors are probably more important than laboratory abnormalities in determining the duration of anticoagulation therapy.^{32,35,36,61–63}

PRIMARY PROPHYLAXIS IN PATIENTS WITH FACTOR V LEIDEN

Factor V Leiden is only one of many risk factors for deep vein thrombosis or pulmonary embolism. If carriers of factor V Leiden have never had a blood clot, then they are not routinely treated with an anticoagulant. Rather, they should be counseled about reducing or eliminating other factors that may add to their risk of developing a clot in the future.

Usually, the effect of risk factors is additive: the more risk factors present, the higher the risk.^46,50 Sometimes, however, the effect of multiple risk factors is more than additive.

Some risk factors, such as genetics or age, are not alterable, but many can be controlled by medications or lifestyle modifications. Therefore, general measures and precautions are recommended to minimize the risk of thrombosis. For example:

Losing weight (if the patient is overweight) is an important intervention for risk reduction, since obesity is probably the most common modifiable risk factor for developing blood clots.

Avoiding long periods of immobility is recommended. For example, if the patient is taking a long car ride (more than 2 hours), then stopping every few hours and walking around for a few minutes is a good way to keep the blood circulating. If the patient has a desk job, getting up and walking around the office periodically is advised. On long airplane trips, a walk in the aisle every so often and preventing dehydration by drinking plenty of fluids and avoiding alcohol are recommended.

Wearing elastic stockings with a graduated elastic pressure may prevent deep venous thrombosis from developing on long flights.^63–65

Staying active and getting regular exercise through such activities as walking, bicycling, or swimming are helpful.

Avoiding smoking is critical.^50,63

Thromboprophylaxis is recommended for most acutely ill hospitalized patients, especially those confined to bed with additional risk factors. Guidelines for prophylaxis are based on an individualized risk assessment and not on thrombophilia status. Prophylactic anticoagulation is routinely recommended for patients undergoing major high-risk surgery, such as an orthopedic, urologic, gynecologic, or bariatric procedure. Any excess thrombotic risk conferred by thrombophilia is likely small compared with the risk of surgery, and recommendations on the duration and intensity of thromboprophylaxis are not based on thrombophilic status.^46,48

Education. Pain, swelling, redness of a limb, unexplained shortness of breath, and chest pain are the most common symptoms of deep vein thrombosis and pulmonary embolism.^46,50 It is crucial to teach patients with factor V Leiden to recognize these symptoms and to seek early medical attention in case they experience any of them.

SCREENING FAMILY MEMBERS FOR THE FACTOR V LEIDEN MUTATION

Factor V Leiden by itself is a relatively mild thrombophilic defect that does not cause thrombosis in all carriers, and there is no evidence that early diagnosis reduces rates of morbidity or mortality. Therefore, routine screening of all asymptomatic relatives of affected patients with venous thrombosis is not recommended. Rather, the decision to screen should be made on an individual basis.^50,66

Screening may be beneficial in selected cases, especially when patients have a strong family history of recurrent venous thrombosis at a young age (younger than 50 years) and the family member has additional risk factors for venous thromboembolism such as oral contraception or is planning for pregnancy.^32,48,49,66

A 70-year-old woman presents with 3 days of fever (temperatures up to 38°C), abdominal pain, and purple-colored urine (Figure 1). She has stage 4 chronic kidney disease secondary to diabetes and hypertension. Her diabetes is controlled with insulin, and her hypertension with irbesartan (Avapro) 150 mg daily. She also has neurogenic bladder, managed by a urinary catheter for the last 6 months.

On examination, her blood pressure is 138/70 mm Hg, respiratory rate 18 breaths/minute, and heart rate 80 beats/minute. Her abdomen is soft. She has never undergone abdominal surgery. She is not taking any medications that may have caused urine discoloration.

Plain radiography of the abdomen reveals no abnormal gas. Laboratory test results are as follows:

• White blood cell count 15.1 × 10⁹/L (reference range 4–11), with 85% neutrophils (reference range 39.5%–74%)
• C-reactive protein 6.27 mg/dL (reference range 0.0–1.0)
• Blood urea nitrogen 54 mg/dL (reference range 8–25)
• Serum creatinine 2.5 mg/dL (0.70–1.40)
• Estimated glomerular filtration rate 20 mL/min/1.73 m² (< 60 is sufficient for the diagnosis of chronic kidney disease)
• Liver function tests are normal
• Urine pH 8.0 (4.80–7.80); urine is positive for nitrates and for marked pyuria and bacteriuria.

Urine culture yields more than 100,000 colony-forming units of Pseudomonas aeruginosa, Morganella morganii, and Proteus vulgaris. These results and the patient’s presentation point to a diagnosis of purple urine bag syndrome. After placement of a new urinary catheter and 7 days of intravenous ciprofloxacin (Cipro) 250 mg every 12 hours, the color of her urine returns to normal.

PURPLE URINE BAG SYNDROME

Purple urine bag syndrome is rare, and catheter-associated urinary tract infection is the main cause.¹ However, it has also been associated with intestinal intussusception.² In our patient, the examination and radiography ruled out intussusception.

Factors reported to be involved in the development of this syndrome include older age, female sex, chronic constipation, chronic urinary catheterization, alkaline (common) or acidic (uncommon) urine, and a higher bacterial load in the urine.^3,4

The pathogenesis of purple-colored urine^4,5 is thought to start with the metabolism of dietary tryptophan by intestinal bacteria to indole. Indole is then absorbed into the portal circulation and is converted to indoxyl sulfate, which is excreted into the urine. In vitro experiments^4,5 have shown that certain bacteria in the urine produce indoxyl sulfatase and indoxyl phosphatase, which break down indoxyl sulfate to indoxyl. Indoxyl can then be converted to indigo or indirubin in alkaline⁵ or acidic⁴ urine. When blue indigo and red indirubin mix together, the result is purple.^4,5

Bacteria that possess indoxyl sulfatase or indoxyl phosphatase include P aeruginosa, M morganii, P vulgaris, Escherichia coli, and Providencia species.^5,6 However, not all bacteria of the same species produce the enzymes required for the formation of purple urine.⁵ This may explain the rarity of this syndrome despite the common occurrence of urinary tract infection in patients with risk factors for purple urine bag syndrome.

CHRONIC KIDNEY DISEASE: A POTENTIAL RISK FACTOR

Chronic kidney disease was shown to be a risk factor for purple urine bag syndrome in a small cohort study of Taiwanese patients.⁷ The serum and urine levels of indoxyl sulfate increased markedly in patients who had chronic kidney disease or who were undergoing dialysis because of impaired renal clearance.⁶ Furthermore, indoxyl sulfate, which plays an important role in this syndrome, is also cytotoxic and may increase the rate of renal failure in uremic rats.⁴

Although purple urine itself is usually considered benign,³ it should prompt an evaluation for urinary tract infection, especially in patients with kidney disease. Failure to treat the underlying infection can lead to septicemia or Fourier gangrene.^1,3

A 70-year-old woman presents with 3 days of fever (temperatures up to 38°C), abdominal pain, and purple-colored urine (Figure 1). She has stage 4 chronic kidney disease secondary to diabetes and hypertension. Her diabetes is controlled with insulin, and her hypertension with irbesartan (Avapro) 150 mg daily. She also has neurogenic bladder, managed by a urinary catheter for the last 6 months.

On examination, her blood pressure is 138/70 mm Hg, respiratory rate 18 breaths/minute, and heart rate 80 beats/minute. Her abdomen is soft. She has never undergone abdominal surgery. She is not taking any medications that may have caused urine discoloration.

Plain radiography of the abdomen reveals no abnormal gas. Laboratory test results are as follows:

• White blood cell count 15.1 × 10⁹/L (reference range 4–11), with 85% neutrophils (reference range 39.5%–74%)
• C-reactive protein 6.27 mg/dL (reference range 0.0–1.0)
• Blood urea nitrogen 54 mg/dL (reference range 8–25)
• Serum creatinine 2.5 mg/dL (0.70–1.40)
• Estimated glomerular filtration rate 20 mL/min/1.73 m² (< 60 is sufficient for the diagnosis of chronic kidney disease)
• Liver function tests are normal
• Urine pH 8.0 (4.80–7.80); urine is positive for nitrates and for marked pyuria and bacteriuria.

Urine culture yields more than 100,000 colony-forming units of Pseudomonas aeruginosa, Morganella morganii, and Proteus vulgaris. These results and the patient’s presentation point to a diagnosis of purple urine bag syndrome. After placement of a new urinary catheter and 7 days of intravenous ciprofloxacin (Cipro) 250 mg every 12 hours, the color of her urine returns to normal.

PURPLE URINE BAG SYNDROME

Purple urine bag syndrome is rare, and catheter-associated urinary tract infection is the main cause.¹ However, it has also been associated with intestinal intussusception.² In our patient, the examination and radiography ruled out intussusception.

Factors reported to be involved in the development of this syndrome include older age, female sex, chronic constipation, chronic urinary catheterization, alkaline (common) or acidic (uncommon) urine, and a higher bacterial load in the urine.^3,4

The pathogenesis of purple-colored urine^4,5 is thought to start with the metabolism of dietary tryptophan by intestinal bacteria to indole. Indole is then absorbed into the portal circulation and is converted to indoxyl sulfate, which is excreted into the urine. In vitro experiments^4,5 have shown that certain bacteria in the urine produce indoxyl sulfatase and indoxyl phosphatase, which break down indoxyl sulfate to indoxyl. Indoxyl can then be converted to indigo or indirubin in alkaline⁵ or acidic⁴ urine. When blue indigo and red indirubin mix together, the result is purple.^4,5

Bacteria that possess indoxyl sulfatase or indoxyl phosphatase include P aeruginosa, M morganii, P vulgaris, Escherichia coli, and Providencia species.^5,6 However, not all bacteria of the same species produce the enzymes required for the formation of purple urine.⁵ This may explain the rarity of this syndrome despite the common occurrence of urinary tract infection in patients with risk factors for purple urine bag syndrome.

CHRONIC KIDNEY DISEASE: A POTENTIAL RISK FACTOR

Chronic kidney disease was shown to be a risk factor for purple urine bag syndrome in a small cohort study of Taiwanese patients.⁷ The serum and urine levels of indoxyl sulfate increased markedly in patients who had chronic kidney disease or who were undergoing dialysis because of impaired renal clearance.⁶ Furthermore, indoxyl sulfate, which plays an important role in this syndrome, is also cytotoxic and may increase the rate of renal failure in uremic rats.⁴

Although purple urine itself is usually considered benign,³ it should prompt an evaluation for urinary tract infection, especially in patients with kidney disease. Failure to treat the underlying infection can lead to septicemia or Fourier gangrene.^1,3

A 70-year-old woman presents with 3 days of fever (temperatures up to 38°C), abdominal pain, and purple-colored urine (Figure 1). She has stage 4 chronic kidney disease secondary to diabetes and hypertension. Her diabetes is controlled with insulin, and her hypertension with irbesartan (Avapro) 150 mg daily. She also has neurogenic bladder, managed by a urinary catheter for the last 6 months.

On examination, her blood pressure is 138/70 mm Hg, respiratory rate 18 breaths/minute, and heart rate 80 beats/minute. Her abdomen is soft. She has never undergone abdominal surgery. She is not taking any medications that may have caused urine discoloration.

Plain radiography of the abdomen reveals no abnormal gas. Laboratory test results are as follows:

• White blood cell count 15.1 × 10⁹/L (reference range 4–11), with 85% neutrophils (reference range 39.5%–74%)
• C-reactive protein 6.27 mg/dL (reference range 0.0–1.0)
• Blood urea nitrogen 54 mg/dL (reference range 8–25)
• Serum creatinine 2.5 mg/dL (0.70–1.40)
• Estimated glomerular filtration rate 20 mL/min/1.73 m² (< 60 is sufficient for the diagnosis of chronic kidney disease)
• Liver function tests are normal
• Urine pH 8.0 (4.80–7.80); urine is positive for nitrates and for marked pyuria and bacteriuria.

Urine culture yields more than 100,000 colony-forming units of Pseudomonas aeruginosa, Morganella morganii, and Proteus vulgaris. These results and the patient’s presentation point to a diagnosis of purple urine bag syndrome. After placement of a new urinary catheter and 7 days of intravenous ciprofloxacin (Cipro) 250 mg every 12 hours, the color of her urine returns to normal.

PURPLE URINE BAG SYNDROME

Purple urine bag syndrome is rare, and catheter-associated urinary tract infection is the main cause.¹ However, it has also been associated with intestinal intussusception.² In our patient, the examination and radiography ruled out intussusception.

Factors reported to be involved in the development of this syndrome include older age, female sex, chronic constipation, chronic urinary catheterization, alkaline (common) or acidic (uncommon) urine, and a higher bacterial load in the urine.^3,4

The pathogenesis of purple-colored urine^4,5 is thought to start with the metabolism of dietary tryptophan by intestinal bacteria to indole. Indole is then absorbed into the portal circulation and is converted to indoxyl sulfate, which is excreted into the urine. In vitro experiments^4,5 have shown that certain bacteria in the urine produce indoxyl sulfatase and indoxyl phosphatase, which break down indoxyl sulfate to indoxyl. Indoxyl can then be converted to indigo or indirubin in alkaline⁵ or acidic⁴ urine. When blue indigo and red indirubin mix together, the result is purple.^4,5

Bacteria that possess indoxyl sulfatase or indoxyl phosphatase include P aeruginosa, M morganii, P vulgaris, Escherichia coli, and Providencia species.^5,6 However, not all bacteria of the same species produce the enzymes required for the formation of purple urine.⁵ This may explain the rarity of this syndrome despite the common occurrence of urinary tract infection in patients with risk factors for purple urine bag syndrome.

CHRONIC KIDNEY DISEASE: A POTENTIAL RISK FACTOR

Chronic kidney disease was shown to be a risk factor for purple urine bag syndrome in a small cohort study of Taiwanese patients.⁷ The serum and urine levels of indoxyl sulfate increased markedly in patients who had chronic kidney disease or who were undergoing dialysis because of impaired renal clearance.⁶ Furthermore, indoxyl sulfate, which plays an important role in this syndrome, is also cytotoxic and may increase the rate of renal failure in uremic rats.⁴

Although purple urine itself is usually considered benign,³ it should prompt an evaluation for urinary tract infection, especially in patients with kidney disease. Failure to treat the underlying infection can lead to septicemia or Fourier gangrene.^1,3

A 75-year-old man was admitted to the hospital with new-onset atrial fibrillation. He underwent rate control, and a heparin infusion was started. Warfarin (Coumadin) 10 mg was added on the second hospital day. Two days later, the heparin infusion was discontinued when the international normalized ratio (INR) was in the therapeutic range.

On day 5, he developed a painful lesion on the left elbow, which progressed to multiple lesions on the forearms, abdomen, and lower legs. No history of trauma was noted. His INR was 5.2, and wound cultures were negative (Figure 1).

Q: Which is the most likely diagnosis?

• Pyoderma gangrenosum
• Cutaneous vasculitis
• Warfarin-induced skin necrosis
• Ecthyma gangrenosum
• Dermatitis herpetiformis

A: The most likely diagnosis is warfarin-induced skin necrosis, a rare paradoxical complication that occurs in 0.01% to 0.1% of patients receiving this drug.¹ Microthrombosis leads to necrosis of the skin and subcutaneous tissues, arising within 2 to 10 days after the start of anticoagulation therapy, although in rare cases it can occur months to years later.^2,3

The most common risk factors include the unopposed use of warfarin (ie, unopposed by heparin at the start of therapy), using higher doses of warfarin during the initiation of anticoagulation, and inadequate overlap with an effective parenteral anticoagulant. Patients with protein C or S deficiency, heparin-induced thrombocytopenia,⁴ resistance to activated protein C, antithrombin deficiency, and lupus anticoagulant have also been reported to be at risk.

The most common sites affected are areas with high subcutaneous fat content, such as the abdomen, thighs, breasts, and buttocks. Skin presentations can vary from dermal plaques to petechial lesions, which rapidly progress to well-demarcated, bluish-black, painful lesions and eventually to hemorrhagic bullae and necrosis.¹

At the start of warfarin therapy, the levels of protein C and factor VII (with half-lives of 5 to 8 hours) fall faster than those of other vitamin-K-dependent factors (ie, factors II, IX, and X). This causes a transient imbalance in procoagulant and anticoagulant pathways favoring thrombosis of the microvasculature, with resulting necrosis. Patients with hereditary protein C deficiency are at higher risk.⁵

Histologic review of lesions often shows venous thrombosis and diffuse necrosis of the dermis and subcutaneous tissue.²

Promptly stopping the warfarin and choosing alternative anticoagulation may help prevent further progression of this condition. Wound care, debridement, and sometimes skin grafting may be necessary, depending on the extent of the lesions. A rechallenge with warfarin is often difficult, but cases have been reported in which treatment was resumed without adverse consequences.⁶ Avoiding large loading doses of warfarin, gradually increasing doses over an extended period (about 10 days),³ and starting warfarin with a heparin bridge for at least 5 days (which was not done in this patient) would prevent the condition.

Early recognition, differentiation, and diagnosis are essential to minimize morbidity and to prevent death.

CASE CONTINUED

Warfarin was discontinued once the patient developed the skin lesions. He received vitamin K and fresh frozen plasma to normalize his INR, and he was started on a heparin infusion, after which the lesions began to heal. The patient refused a skin biopsy. Platelet counts remained stable during his hospital course. Protein C levels were not checked, given his recent use of warfarin. He was started on dabigatran (Pradaxa) and was discharged a week later.

THE OTHER DIAGNOSTIC CHOICES

Pyoderma gangrenosum is an uncommon ulcerative skin condition often associated with autoimmune disease. It usually starts at the site of a minor injury, more commonly on the legs, and gradually progresses to a painful ulcer.

Cutaneous vasculitis is an inflammation of small blood vessels characterized by palpable purpura. The lesions can resemble urticaria, petechia, or erythema multiforme. It is commonly associated with infection, drug therapy, inflammatory disease, and malignancy.

Ecthyma gangrenosum is an infection of skin caused by Pseudomonas aeruginosa. Usually, it presents as hemorrhagic pustules or infarct-like areas with surrounding erythema that evolve into necrotic ulcers surrounded by erythema.

Dermatitis herpetiformis is a chronic skin condition, presenting with fluid-filled blisters and commonly involving the neck, back, scalp, and elbows. This condition is associated with celiac disease, and the lesions are extremely pruritic.

A 75-year-old man was admitted to the hospital with new-onset atrial fibrillation. He underwent rate control, and a heparin infusion was started. Warfarin (Coumadin) 10 mg was added on the second hospital day. Two days later, the heparin infusion was discontinued when the international normalized ratio (INR) was in the therapeutic range.

On day 5, he developed a painful lesion on the left elbow, which progressed to multiple lesions on the forearms, abdomen, and lower legs. No history of trauma was noted. His INR was 5.2, and wound cultures were negative (Figure 1).

Q: Which is the most likely diagnosis?

• Pyoderma gangrenosum
• Cutaneous vasculitis
• Warfarin-induced skin necrosis
• Ecthyma gangrenosum
• Dermatitis herpetiformis

A: The most likely diagnosis is warfarin-induced skin necrosis, a rare paradoxical complication that occurs in 0.01% to 0.1% of patients receiving this drug.¹ Microthrombosis leads to necrosis of the skin and subcutaneous tissues, arising within 2 to 10 days after the start of anticoagulation therapy, although in rare cases it can occur months to years later.^2,3

The most common risk factors include the unopposed use of warfarin (ie, unopposed by heparin at the start of therapy), using higher doses of warfarin during the initiation of anticoagulation, and inadequate overlap with an effective parenteral anticoagulant. Patients with protein C or S deficiency, heparin-induced thrombocytopenia,⁴ resistance to activated protein C, antithrombin deficiency, and lupus anticoagulant have also been reported to be at risk.

The most common sites affected are areas with high subcutaneous fat content, such as the abdomen, thighs, breasts, and buttocks. Skin presentations can vary from dermal plaques to petechial lesions, which rapidly progress to well-demarcated, bluish-black, painful lesions and eventually to hemorrhagic bullae and necrosis.¹

At the start of warfarin therapy, the levels of protein C and factor VII (with half-lives of 5 to 8 hours) fall faster than those of other vitamin-K-dependent factors (ie, factors II, IX, and X). This causes a transient imbalance in procoagulant and anticoagulant pathways favoring thrombosis of the microvasculature, with resulting necrosis. Patients with hereditary protein C deficiency are at higher risk.⁵

Histologic review of lesions often shows venous thrombosis and diffuse necrosis of the dermis and subcutaneous tissue.²

Promptly stopping the warfarin and choosing alternative anticoagulation may help prevent further progression of this condition. Wound care, debridement, and sometimes skin grafting may be necessary, depending on the extent of the lesions. A rechallenge with warfarin is often difficult, but cases have been reported in which treatment was resumed without adverse consequences.⁶ Avoiding large loading doses of warfarin, gradually increasing doses over an extended period (about 10 days),³ and starting warfarin with a heparin bridge for at least 5 days (which was not done in this patient) would prevent the condition.

Early recognition, differentiation, and diagnosis are essential to minimize morbidity and to prevent death.

CASE CONTINUED

Warfarin was discontinued once the patient developed the skin lesions. He received vitamin K and fresh frozen plasma to normalize his INR, and he was started on a heparin infusion, after which the lesions began to heal. The patient refused a skin biopsy. Platelet counts remained stable during his hospital course. Protein C levels were not checked, given his recent use of warfarin. He was started on dabigatran (Pradaxa) and was discharged a week later.

THE OTHER DIAGNOSTIC CHOICES

Pyoderma gangrenosum is an uncommon ulcerative skin condition often associated with autoimmune disease. It usually starts at the site of a minor injury, more commonly on the legs, and gradually progresses to a painful ulcer.

Cutaneous vasculitis is an inflammation of small blood vessels characterized by palpable purpura. The lesions can resemble urticaria, petechia, or erythema multiforme. It is commonly associated with infection, drug therapy, inflammatory disease, and malignancy.

Ecthyma gangrenosum is an infection of skin caused by Pseudomonas aeruginosa. Usually, it presents as hemorrhagic pustules or infarct-like areas with surrounding erythema that evolve into necrotic ulcers surrounded by erythema.

Dermatitis herpetiformis is a chronic skin condition, presenting with fluid-filled blisters and commonly involving the neck, back, scalp, and elbows. This condition is associated with celiac disease, and the lesions are extremely pruritic.

A 75-year-old man was admitted to the hospital with new-onset atrial fibrillation. He underwent rate control, and a heparin infusion was started. Warfarin (Coumadin) 10 mg was added on the second hospital day. Two days later, the heparin infusion was discontinued when the international normalized ratio (INR) was in the therapeutic range.

On day 5, he developed a painful lesion on the left elbow, which progressed to multiple lesions on the forearms, abdomen, and lower legs. No history of trauma was noted. His INR was 5.2, and wound cultures were negative (Figure 1).

Q: Which is the most likely diagnosis?

• Pyoderma gangrenosum
• Cutaneous vasculitis
• Warfarin-induced skin necrosis
• Ecthyma gangrenosum
• Dermatitis herpetiformis

A: The most likely diagnosis is warfarin-induced skin necrosis, a rare paradoxical complication that occurs in 0.01% to 0.1% of patients receiving this drug.¹ Microthrombosis leads to necrosis of the skin and subcutaneous tissues, arising within 2 to 10 days after the start of anticoagulation therapy, although in rare cases it can occur months to years later.^2,3

The most common risk factors include the unopposed use of warfarin (ie, unopposed by heparin at the start of therapy), using higher doses of warfarin during the initiation of anticoagulation, and inadequate overlap with an effective parenteral anticoagulant. Patients with protein C or S deficiency, heparin-induced thrombocytopenia,⁴ resistance to activated protein C, antithrombin deficiency, and lupus anticoagulant have also been reported to be at risk.

The most common sites affected are areas with high subcutaneous fat content, such as the abdomen, thighs, breasts, and buttocks. Skin presentations can vary from dermal plaques to petechial lesions, which rapidly progress to well-demarcated, bluish-black, painful lesions and eventually to hemorrhagic bullae and necrosis.¹

At the start of warfarin therapy, the levels of protein C and factor VII (with half-lives of 5 to 8 hours) fall faster than those of other vitamin-K-dependent factors (ie, factors II, IX, and X). This causes a transient imbalance in procoagulant and anticoagulant pathways favoring thrombosis of the microvasculature, with resulting necrosis. Patients with hereditary protein C deficiency are at higher risk.⁵

Histologic review of lesions often shows venous thrombosis and diffuse necrosis of the dermis and subcutaneous tissue.²

Promptly stopping the warfarin and choosing alternative anticoagulation may help prevent further progression of this condition. Wound care, debridement, and sometimes skin grafting may be necessary, depending on the extent of the lesions. A rechallenge with warfarin is often difficult, but cases have been reported in which treatment was resumed without adverse consequences.⁶ Avoiding large loading doses of warfarin, gradually increasing doses over an extended period (about 10 days),³ and starting warfarin with a heparin bridge for at least 5 days (which was not done in this patient) would prevent the condition.

Early recognition, differentiation, and diagnosis are essential to minimize morbidity and to prevent death.

CASE CONTINUED

Warfarin was discontinued once the patient developed the skin lesions. He received vitamin K and fresh frozen plasma to normalize his INR, and he was started on a heparin infusion, after which the lesions began to heal. The patient refused a skin biopsy. Platelet counts remained stable during his hospital course. Protein C levels were not checked, given his recent use of warfarin. He was started on dabigatran (Pradaxa) and was discharged a week later.

THE OTHER DIAGNOSTIC CHOICES

Pyoderma gangrenosum is an uncommon ulcerative skin condition often associated with autoimmune disease. It usually starts at the site of a minor injury, more commonly on the legs, and gradually progresses to a painful ulcer.

Cutaneous vasculitis is an inflammation of small blood vessels characterized by palpable purpura. The lesions can resemble urticaria, petechia, or erythema multiforme. It is commonly associated with infection, drug therapy, inflammatory disease, and malignancy.

Ecthyma gangrenosum is an infection of skin caused by Pseudomonas aeruginosa. Usually, it presents as hemorrhagic pustules or infarct-like areas with surrounding erythema that evolve into necrotic ulcers surrounded by erythema.

Dermatitis herpetiformis is a chronic skin condition, presenting with fluid-filled blisters and commonly involving the neck, back, scalp, and elbows. This condition is associated with celiac disease, and the lesions are extremely pruritic.

I have always been irked when doctors reflexively order panels of immunologic tests when evaluating patients with “arthritis,” possible vasculitis, or other autoimmune diseases. The serologic marker of an immune response to an often nonpathogenic antigen should not define a clinical diagnosis. Experienced clinicians, well-versed in the nuances of systemic autoimmune diseases such as myositis or scleroderma that have distinguishable clinical subsets, can use specific serologic tests to help focus the diagnosis and the approach to follow-up. But indiscreet ordering of batteries of antinuclear antibody tests, “screening tests for vasculitis,” or rheumatoid factor tests to evaluate arthritis that has not been carefully clinically characterized is neither cost-effective nor clinically wise.

We rheumatologists may have inadvertently encouraged this practice. We teach about the prevalence of specific autoantibodies in patients with specific, accurately diagnosed autoimmune disorders as opposed to that in the general population (ie, the test’s sensitivity and specificity). But that is different than using a test to diagnose a specific disease in an ill patient with a heretofore undiagnosed condition (ie, the test’s predictive value). When I ask trainees or nonrheumatologists, “Why order all those tests?” the response I often get is that they thought the rheumatologist would want them when he or she was consulted. The fact that I also see our rheumatology fellows requesting the same tests before fully evaluating the patient clinically suggests that we have not done a great job at explaining the clinical utility and limitations of these tests. A serologic test should be used to strengthen or refute the clinician’s preliminary diagnosis, depending on the test’s specificity and sensitivity. It should not be used to generate a diagnosis.

So with these concerns, why would we invite a paper encouraging the use of the relatively new anti-cyclic citrullinated peptide (anti-CCP) test to evaluate patients with possible rheumatoid arthritis (Bose and Calabrese)?

As discussed in that paper, this test has characteristics that are useful when evaluating patients with polyarthritis compatible with the diagnosis of rheumatoid arthritis. Specifically, this test, unlike the traditional test for rheumatoid factor, can help discern whether the arthritis is a reaction to an infection like hepatitis C or endocarditis. Like rheumatoid factor, anti-CCP may precede the appearance of clinically meaningful arthritis and helps to predict prognosis in established rheumatoid arthritis. But, like other serologic tests, the anti-CCP test cannot supplant the listening ears and examining fingers of the clinician in establishing the pretest likelihood of the diagnosis. Clinical evaluation must precede laboratory testing.

I have always been irked when doctors reflexively order panels of immunologic tests when evaluating patients with “arthritis,” possible vasculitis, or other autoimmune diseases. The serologic marker of an immune response to an often nonpathogenic antigen should not define a clinical diagnosis. Experienced clinicians, well-versed in the nuances of systemic autoimmune diseases such as myositis or scleroderma that have distinguishable clinical subsets, can use specific serologic tests to help focus the diagnosis and the approach to follow-up. But indiscreet ordering of batteries of antinuclear antibody tests, “screening tests for vasculitis,” or rheumatoid factor tests to evaluate arthritis that has not been carefully clinically characterized is neither cost-effective nor clinically wise.

We rheumatologists may have inadvertently encouraged this practice. We teach about the prevalence of specific autoantibodies in patients with specific, accurately diagnosed autoimmune disorders as opposed to that in the general population (ie, the test’s sensitivity and specificity). But that is different than using a test to diagnose a specific disease in an ill patient with a heretofore undiagnosed condition (ie, the test’s predictive value). When I ask trainees or nonrheumatologists, “Why order all those tests?” the response I often get is that they thought the rheumatologist would want them when he or she was consulted. The fact that I also see our rheumatology fellows requesting the same tests before fully evaluating the patient clinically suggests that we have not done a great job at explaining the clinical utility and limitations of these tests. A serologic test should be used to strengthen or refute the clinician’s preliminary diagnosis, depending on the test’s specificity and sensitivity. It should not be used to generate a diagnosis.

So with these concerns, why would we invite a paper encouraging the use of the relatively new anti-cyclic citrullinated peptide (anti-CCP) test to evaluate patients with possible rheumatoid arthritis (Bose and Calabrese)?

As discussed in that paper, this test has characteristics that are useful when evaluating patients with polyarthritis compatible with the diagnosis of rheumatoid arthritis. Specifically, this test, unlike the traditional test for rheumatoid factor, can help discern whether the arthritis is a reaction to an infection like hepatitis C or endocarditis. Like rheumatoid factor, anti-CCP may precede the appearance of clinically meaningful arthritis and helps to predict prognosis in established rheumatoid arthritis. But, like other serologic tests, the anti-CCP test cannot supplant the listening ears and examining fingers of the clinician in establishing the pretest likelihood of the diagnosis. Clinical evaluation must precede laboratory testing.

I have always been irked when doctors reflexively order panels of immunologic tests when evaluating patients with “arthritis,” possible vasculitis, or other autoimmune diseases. The serologic marker of an immune response to an often nonpathogenic antigen should not define a clinical diagnosis. Experienced clinicians, well-versed in the nuances of systemic autoimmune diseases such as myositis or scleroderma that have distinguishable clinical subsets, can use specific serologic tests to help focus the diagnosis and the approach to follow-up. But indiscreet ordering of batteries of antinuclear antibody tests, “screening tests for vasculitis,” or rheumatoid factor tests to evaluate arthritis that has not been carefully clinically characterized is neither cost-effective nor clinically wise.

We rheumatologists may have inadvertently encouraged this practice. We teach about the prevalence of specific autoantibodies in patients with specific, accurately diagnosed autoimmune disorders as opposed to that in the general population (ie, the test’s sensitivity and specificity). But that is different than using a test to diagnose a specific disease in an ill patient with a heretofore undiagnosed condition (ie, the test’s predictive value). When I ask trainees or nonrheumatologists, “Why order all those tests?” the response I often get is that they thought the rheumatologist would want them when he or she was consulted. The fact that I also see our rheumatology fellows requesting the same tests before fully evaluating the patient clinically suggests that we have not done a great job at explaining the clinical utility and limitations of these tests. A serologic test should be used to strengthen or refute the clinician’s preliminary diagnosis, depending on the test’s specificity and sensitivity. It should not be used to generate a diagnosis.

So with these concerns, why would we invite a paper encouraging the use of the relatively new anti-cyclic citrullinated peptide (anti-CCP) test to evaluate patients with possible rheumatoid arthritis (Bose and Calabrese)?

As discussed in that paper, this test has characteristics that are useful when evaluating patients with polyarthritis compatible with the diagnosis of rheumatoid arthritis. Specifically, this test, unlike the traditional test for rheumatoid factor, can help discern whether the arthritis is a reaction to an infection like hepatitis C or endocarditis. Like rheumatoid factor, anti-CCP may precede the appearance of clinically meaningful arthritis and helps to predict prognosis in established rheumatoid arthritis. But, like other serologic tests, the anti-CCP test cannot supplant the listening ears and examining fingers of the clinician in establishing the pretest likelihood of the diagnosis. Clinical evaluation must precede laboratory testing.