The burden of shift-work disorder (SWD) is multifactorial—affecting relationships, health, and work performance. Lack of support, research, and treatment for SWD has economic and safety consequences for society in general. In this supplement, sleep experts suggest practical steps to relieve the adverse effects of SWD.

The burden of shift-work disorder (SWD) is multifactorial—affecting relationships, health, and work performance. Lack of support, research, and treatment for SWD has economic and safety consequences for society in general. In this supplement, sleep experts suggest practical steps to relieve the adverse effects of SWD.

The burden of shift-work disorder (SWD) is multifactorial—affecting relationships, health, and work performance. Lack of support, research, and treatment for SWD has economic and safety consequences for society in general. In this supplement, sleep experts suggest practical steps to relieve the adverse effects of SWD.

Yes. Obesity hypoventilation syndrome (OHS) is often undiagnosed and greatly increases perioperative risk. Therefore, we recommend trying to detect OHS in a timely manner. Treatment should begin without delay to avoid adverse perioperative outcomes, which can include acute-on-chronic respiratory failure requiring intensive-care monitoring and invasive mechanical ventilation, or death.

ALSO CALLED PICKWICKIAN SYNDROME

OHS is also known as Pickwickian syndrome, named for a character—a “fat boy” who is constantly falling asleep—in The Posthumous Papers of the Pickwick Club by Charles Dickens.

Salient features of OHS are:

• Obesity (body mass index ≥ 30 kg/m²)
• Sleep-disordered breathing (most patients with OHS are morbidly obese and have severe obstructive sleep apnea1)
• Chronic daytime alveolar hypoventilation: ie, Paco₂ ≥ 45 mm Hg (normal range 35–45 mm Hg) and Pao₂ < 70 mm Hg1 (normal range 85–95 mm Hg)
• No other identifiable cause of hypoventilation such as pulmonary disease (severe obstructive or restrictive), chest wall deformities, severe hypothyroidism, or neuromuscular disease.

WHY SCREEN FOR OHS?

Both obstructive sleep apnea and OHS worsen quality of life and increase the risk of serious disease and death.^2–3 Patients with severe sleep apnea, particularly those with hypercapnia (ie, OHS) are at higher risk of cardiopulmonary complications in the perioperative period.

Compared with eucapnic patients with obstructive sleep apnea, patients with OHS have higher health care expenses, are at higher risk of developing serious cardiovascular diseases such as pulmonary hypertension and congestive heart failure, and are more likely to die sooner.^4,5

Nowbar et al⁵ prospectively followed a group of severely obese patients after hospital discharge. At 18 months, 23% of those with OHS had died, compared with 9% of those without OHS. The groups were well matched for body mass index, age, and a number of comorbid conditions. Most of the deaths occurred in the first 3 months after hospital discharge. During the hospital stay, more patients with OHS were admitted to the intensive care unit and needed endotracheal intubation and mechanical ventilation, and more were discharged to a long-term facility.

A high level of suspicion can lead to early recognition and treatment, which may reduce the rate of adverse outcomes associated with undiagnosed and untreated OHS. Routine screening for hypercapnia in patients with sleep apnea might help to identify patients with OHS and allow for modifications in surgical approach, anesthetic technique, and postoperative monitoring, increasing patient safety.

HOW PREVALENT IS OHS?

Obstructive sleep apnea affects up to 20% of US adults and is undiagnosed and untreated in up to 90% of cases.⁶ Simple screening questionnaires have been shown to reliably identify patients at risk.^7,8

To date, no population-based prevalence studies of OHS have been done.

The overall prevalence of OHS in patients with obstructive sleep apnea is better studied: multiple prospective and retrospective studies across various geographic regions with a variety of racial or ethnic populations have shown it to be between 10% and 20%.^1,9 This range is very consistent among studies performed in Europe, the United States, and Japan, whether retrospective or prospective, and whether large or small.

The prevalence of OHS in the general adult population in the United States can, however, be estimated. If approximately 5% of the general US population has severe obesity (body mass index ≤ 40 kg/m²), if half of patients with severe obesity have obstructive sleep apnea,¹⁰ and if 15% of severely obese patients with sleep apnea have OHS, then a conservative estimated prevalence of OHS in the general adult US population is 0.37% (1 in 270 adults).

WHAT CAN BE DONE BEFORE ELECTIVE SURGERY?

Patients with OHS have an elevated serum bicarbonate level due to metabolic compensation for chronic respiratory acidosis. Moreover, they may have mild hypoxemia during wakefulness as measured by finger pulse oximetry.

The serum venous bicarbonate level is an easy and reasonable test to screen for hypercapnia in obese patients with obstructive sleep apnea because it is readily available, physiologically sensible, and less invasive than arterial puncture to measure blood gases.⁹

Arterial blood gas measurements, however, should be obtained to confirm the presence and severity of daytime hypercapnia in obese patients with hypoxemia during wakefulness or an elevated serum bicarbonate level.

Pulmonary function testing and chest imaging can exclude other causes of hypercapnia if hypercapnia is confirmed.

An overnight, attended polysomnographic study in a sleep laboratory is ultimately needed to establish the diagnosis and severity of obstructive sleep apnea and to titrate continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BPAP) therapy. Since most patients with OHS have severe obstructive sleep apnea, in-laboratory attended polysomnography allows the clinician to both diagnose and intervene with PAP therapy (a “split-night” study). Home titration with an auto-CPAP device is not recommended because it does not have the ability to titrate PAP pressures in response to hypoxemia or hypoventilation. Patients with OHS require attended, laboratory-based PAP titration with or without supplemental oxygen.

CPAP or BPAP therapy should be started during the few days or weeks before surgery, and adherence should be emphasized. Anesthesiologists might reconsider the choice of anesthetic technique in favor of regional anesthesia and modify postoperative pain management to reduce opioid requirements. Reinstituting CPAP or BPAP therapy upon extubation or arrival in the postoperative recovery unit can further reduce the risk of respiratory complications. Additional monitoring such as continuous pulse oximetry when the patient is on the general ward should be considered.

Yes. Obesity hypoventilation syndrome (OHS) is often undiagnosed and greatly increases perioperative risk. Therefore, we recommend trying to detect OHS in a timely manner. Treatment should begin without delay to avoid adverse perioperative outcomes, which can include acute-on-chronic respiratory failure requiring intensive-care monitoring and invasive mechanical ventilation, or death.

ALSO CALLED PICKWICKIAN SYNDROME

OHS is also known as Pickwickian syndrome, named for a character—a “fat boy” who is constantly falling asleep—in The Posthumous Papers of the Pickwick Club by Charles Dickens.

Salient features of OHS are:

• Obesity (body mass index ≥ 30 kg/m²)
• Sleep-disordered breathing (most patients with OHS are morbidly obese and have severe obstructive sleep apnea1)
• Chronic daytime alveolar hypoventilation: ie, Paco₂ ≥ 45 mm Hg (normal range 35–45 mm Hg) and Pao₂ < 70 mm Hg1 (normal range 85–95 mm Hg)
• No other identifiable cause of hypoventilation such as pulmonary disease (severe obstructive or restrictive), chest wall deformities, severe hypothyroidism, or neuromuscular disease.

WHY SCREEN FOR OHS?

Both obstructive sleep apnea and OHS worsen quality of life and increase the risk of serious disease and death.^2–3 Patients with severe sleep apnea, particularly those with hypercapnia (ie, OHS) are at higher risk of cardiopulmonary complications in the perioperative period.

Compared with eucapnic patients with obstructive sleep apnea, patients with OHS have higher health care expenses, are at higher risk of developing serious cardiovascular diseases such as pulmonary hypertension and congestive heart failure, and are more likely to die sooner.^4,5

Nowbar et al⁵ prospectively followed a group of severely obese patients after hospital discharge. At 18 months, 23% of those with OHS had died, compared with 9% of those without OHS. The groups were well matched for body mass index, age, and a number of comorbid conditions. Most of the deaths occurred in the first 3 months after hospital discharge. During the hospital stay, more patients with OHS were admitted to the intensive care unit and needed endotracheal intubation and mechanical ventilation, and more were discharged to a long-term facility.

A high level of suspicion can lead to early recognition and treatment, which may reduce the rate of adverse outcomes associated with undiagnosed and untreated OHS. Routine screening for hypercapnia in patients with sleep apnea might help to identify patients with OHS and allow for modifications in surgical approach, anesthetic technique, and postoperative monitoring, increasing patient safety.

HOW PREVALENT IS OHS?

Obstructive sleep apnea affects up to 20% of US adults and is undiagnosed and untreated in up to 90% of cases.⁶ Simple screening questionnaires have been shown to reliably identify patients at risk.^7,8

To date, no population-based prevalence studies of OHS have been done.

The overall prevalence of OHS in patients with obstructive sleep apnea is better studied: multiple prospective and retrospective studies across various geographic regions with a variety of racial or ethnic populations have shown it to be between 10% and 20%.^1,9 This range is very consistent among studies performed in Europe, the United States, and Japan, whether retrospective or prospective, and whether large or small.

The prevalence of OHS in the general adult population in the United States can, however, be estimated. If approximately 5% of the general US population has severe obesity (body mass index ≤ 40 kg/m²), if half of patients with severe obesity have obstructive sleep apnea,¹⁰ and if 15% of severely obese patients with sleep apnea have OHS, then a conservative estimated prevalence of OHS in the general adult US population is 0.37% (1 in 270 adults).

WHAT CAN BE DONE BEFORE ELECTIVE SURGERY?

Patients with OHS have an elevated serum bicarbonate level due to metabolic compensation for chronic respiratory acidosis. Moreover, they may have mild hypoxemia during wakefulness as measured by finger pulse oximetry.

The serum venous bicarbonate level is an easy and reasonable test to screen for hypercapnia in obese patients with obstructive sleep apnea because it is readily available, physiologically sensible, and less invasive than arterial puncture to measure blood gases.⁹

Arterial blood gas measurements, however, should be obtained to confirm the presence and severity of daytime hypercapnia in obese patients with hypoxemia during wakefulness or an elevated serum bicarbonate level.

Pulmonary function testing and chest imaging can exclude other causes of hypercapnia if hypercapnia is confirmed.

An overnight, attended polysomnographic study in a sleep laboratory is ultimately needed to establish the diagnosis and severity of obstructive sleep apnea and to titrate continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BPAP) therapy. Since most patients with OHS have severe obstructive sleep apnea, in-laboratory attended polysomnography allows the clinician to both diagnose and intervene with PAP therapy (a “split-night” study). Home titration with an auto-CPAP device is not recommended because it does not have the ability to titrate PAP pressures in response to hypoxemia or hypoventilation. Patients with OHS require attended, laboratory-based PAP titration with or without supplemental oxygen.

CPAP or BPAP therapy should be started during the few days or weeks before surgery, and adherence should be emphasized. Anesthesiologists might reconsider the choice of anesthetic technique in favor of regional anesthesia and modify postoperative pain management to reduce opioid requirements. Reinstituting CPAP or BPAP therapy upon extubation or arrival in the postoperative recovery unit can further reduce the risk of respiratory complications. Additional monitoring such as continuous pulse oximetry when the patient is on the general ward should be considered.

Yes. Obesity hypoventilation syndrome (OHS) is often undiagnosed and greatly increases perioperative risk. Therefore, we recommend trying to detect OHS in a timely manner. Treatment should begin without delay to avoid adverse perioperative outcomes, which can include acute-on-chronic respiratory failure requiring intensive-care monitoring and invasive mechanical ventilation, or death.

ALSO CALLED PICKWICKIAN SYNDROME

OHS is also known as Pickwickian syndrome, named for a character—a “fat boy” who is constantly falling asleep—in The Posthumous Papers of the Pickwick Club by Charles Dickens.

Salient features of OHS are:

• Obesity (body mass index ≥ 30 kg/m²)
• Sleep-disordered breathing (most patients with OHS are morbidly obese and have severe obstructive sleep apnea1)
• Chronic daytime alveolar hypoventilation: ie, Paco₂ ≥ 45 mm Hg (normal range 35–45 mm Hg) and Pao₂ < 70 mm Hg1 (normal range 85–95 mm Hg)
• No other identifiable cause of hypoventilation such as pulmonary disease (severe obstructive or restrictive), chest wall deformities, severe hypothyroidism, or neuromuscular disease.

WHY SCREEN FOR OHS?

Both obstructive sleep apnea and OHS worsen quality of life and increase the risk of serious disease and death.^2–3 Patients with severe sleep apnea, particularly those with hypercapnia (ie, OHS) are at higher risk of cardiopulmonary complications in the perioperative period.

Compared with eucapnic patients with obstructive sleep apnea, patients with OHS have higher health care expenses, are at higher risk of developing serious cardiovascular diseases such as pulmonary hypertension and congestive heart failure, and are more likely to die sooner.^4,5

Nowbar et al⁵ prospectively followed a group of severely obese patients after hospital discharge. At 18 months, 23% of those with OHS had died, compared with 9% of those without OHS. The groups were well matched for body mass index, age, and a number of comorbid conditions. Most of the deaths occurred in the first 3 months after hospital discharge. During the hospital stay, more patients with OHS were admitted to the intensive care unit and needed endotracheal intubation and mechanical ventilation, and more were discharged to a long-term facility.

A high level of suspicion can lead to early recognition and treatment, which may reduce the rate of adverse outcomes associated with undiagnosed and untreated OHS. Routine screening for hypercapnia in patients with sleep apnea might help to identify patients with OHS and allow for modifications in surgical approach, anesthetic technique, and postoperative monitoring, increasing patient safety.

HOW PREVALENT IS OHS?

Obstructive sleep apnea affects up to 20% of US adults and is undiagnosed and untreated in up to 90% of cases.⁶ Simple screening questionnaires have been shown to reliably identify patients at risk.^7,8

To date, no population-based prevalence studies of OHS have been done.

The overall prevalence of OHS in patients with obstructive sleep apnea is better studied: multiple prospective and retrospective studies across various geographic regions with a variety of racial or ethnic populations have shown it to be between 10% and 20%.^1,9 This range is very consistent among studies performed in Europe, the United States, and Japan, whether retrospective or prospective, and whether large or small.

The prevalence of OHS in the general adult population in the United States can, however, be estimated. If approximately 5% of the general US population has severe obesity (body mass index ≤ 40 kg/m²), if half of patients with severe obesity have obstructive sleep apnea,¹⁰ and if 15% of severely obese patients with sleep apnea have OHS, then a conservative estimated prevalence of OHS in the general adult US population is 0.37% (1 in 270 adults).

WHAT CAN BE DONE BEFORE ELECTIVE SURGERY?

Patients with OHS have an elevated serum bicarbonate level due to metabolic compensation for chronic respiratory acidosis. Moreover, they may have mild hypoxemia during wakefulness as measured by finger pulse oximetry.

The serum venous bicarbonate level is an easy and reasonable test to screen for hypercapnia in obese patients with obstructive sleep apnea because it is readily available, physiologically sensible, and less invasive than arterial puncture to measure blood gases.⁹

Arterial blood gas measurements, however, should be obtained to confirm the presence and severity of daytime hypercapnia in obese patients with hypoxemia during wakefulness or an elevated serum bicarbonate level.

Pulmonary function testing and chest imaging can exclude other causes of hypercapnia if hypercapnia is confirmed.

An overnight, attended polysomnographic study in a sleep laboratory is ultimately needed to establish the diagnosis and severity of obstructive sleep apnea and to titrate continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BPAP) therapy. Since most patients with OHS have severe obstructive sleep apnea, in-laboratory attended polysomnography allows the clinician to both diagnose and intervene with PAP therapy (a “split-night” study). Home titration with an auto-CPAP device is not recommended because it does not have the ability to titrate PAP pressures in response to hypoxemia or hypoventilation. Patients with OHS require attended, laboratory-based PAP titration with or without supplemental oxygen.

CPAP or BPAP therapy should be started during the few days or weeks before surgery, and adherence should be emphasized. Anesthesiologists might reconsider the choice of anesthetic technique in favor of regional anesthesia and modify postoperative pain management to reduce opioid requirements. Reinstituting CPAP or BPAP therapy upon extubation or arrival in the postoperative recovery unit can further reduce the risk of respiratory complications. Additional monitoring such as continuous pulse oximetry when the patient is on the general ward should be considered.

More children and even adults seem to be allergic to various foods these days than in the past. Also apparently on the rise is a linked condition, eosinophilic esophagitis.

The reason for these increases is not clear. This article confines itself to what we know about the mechanisms of food allergies and eosinophilic esophagitis, how to diagnose them, and how to treat them.

FOOD ALLERGIES ARE COMMON, AND MORE PREVALENT THAN EVER

Food allergies—abnormal immune responses to food proteins¹—affect an estimated 6% to 8% of young children and 3% to 4% of adults in the United States,^2,3 and their prevalence appears to be rising in developed countries. Studies in US and British children indicate that peanut allergy has doubled in the past decade. ⁴

Any food can provoke a reaction, but only a few foods account for most of the significant allergic reactions: cow’s milk, soy, wheat, eggs, peanuts, tree nuts, fish, and shellfish.

Approximately 80% of allergies to milk, egg, wheat, and soy resolve by the time the patient reaches early adolescence.⁶ Fewer cases resolve in children with tree nut allergies (approximately 9%) or peanut allergy (20%),^7,8 and allergies to fish and shellfish often develop or persist in adulthood.

A family history of an atopic disease such as asthma, allergic rhinitis, eczema, or food allergy is a risk factor for developing a food allergy. ³ Considering that the rate of peanut allergy has doubled in children over the past 10 years, environmental factors may also play a role.³

How we tolerate foods or become allergic to them

The gut, the largest mucosal organ in the body, is exposed to large quantities of foreign proteins daily. Most protein is broken down by stomach acid and digestive enzymes into lessantigenic peptides or is bound by secretory immunoglobulin A (IgA), which prevents it from being absorbed. Further, the epithelial cells lining the gut do not allow large molecules to pass easily, having tight intracellular junctions and being covered with mucus.

For these reasons, less than 2% of the protein in food is absorbed in an allergenic form.⁹ The reason food allergies are more prevalent in children is most likely that children have an immature gut barrier, lower IgA levels, a higher gastric pH, and lower proteolytic enzyme levels.

When dietary proteins do cross the gut barrier, the immune system normally suppresses the allergic response. Regulatory T cells, dendritic cells, and local immune responses play critical roles in the development of tolerance. Several types of regulatory T cells, such as Tr1 cells (which secrete interleukin 10), TH3 cells (which secrete transforming growth factor beta), CD4+CD25+ regulatory T cells, gamma-delta T cells, and CD8+ suppressor cells can all contribute to suppressing allergic responses.¹⁰ Dendritic cells also help induce tolerance by stimulating CD4+ T cells to secrete transforming growth factor beta, which leads to the production of interleukin 10 and additional transforming growth factor beta.¹¹

Factors that contribute to food allergy

Many factors may contribute to whether a person becomes tolerant to or sensitized to a specific food protein.

The dose of antigen. Tolerance can develop after either high or low doses of antigens, but by different mechanisms.

The antigen structure. Soluble antigens are less sensitizing than particulate antigens.^12,13

Processing of foods. Dry-roasted peanuts are more allergenic than raw or boiled peanuts, partly because they are less soluble.¹³

The route of initial exposure. Sensitization to food proteins can occur directly through the gut or the skin. Alternatively, it can occur indirectly via the respiratory tract. Skin exposure may be especially sensitizing in children with atopic dermatitis.^14,15

The gut flora. When mice are raised in a germ-free environment, they fail to develop normal tolerance.¹⁶ They are also more likely to become sensitized if they are treated with antibiotics or if they lack toll-like receptors that recognize bacterial lipopolysaccharides.¹⁷ Furthermore, human studies suggest that probiotics promote tolerance, especially in preventing atopic dermatitis, although the studies have had conflicting results.^18–21

The gastric pH. Murine and human studies reveal that antacid medications increase the risk of food allergy.^22,23

Genetic susceptibility. A child with a sibling who is allergic to peanuts is approximately 10 times more likely to be allergic to peanuts than predicted by the rate in the general population. Although no risk-conferring gene has been identified, a study of twins showed concordance for peanut allergy in 64.3% of identical twins vs 6.8% of fraternal twins.²⁴

 

 

Three types of immune responses to food

Immunologic reactions to foods can be divided into three categories: mediated by immunoglobulin E (IgE), non-IgE-mediated, and mixed. Therefore, these disorders can present as an acute, potentially life-threatening reaction or as a chronic disease such as eosinophilic gastoenteropathy.

IgE-mediated reactions are immediate hypersensitivity responses. In most patients, an IgE-mediated mechanism can be confirmed by a positive skin test or a test for food-specific IgE in the serum. In this article, the term “food allergy” refers to an IgE-mediated reaction to a food, unless otherwise indicated.

Non-IgE-mediated reactions have a delayed onset and chronic symptoms. Commonly, they are confined to the gastrointestinal tract; examples are food-protein-induced enterocolitis, proctitis, and proctocolitis and celiac disease.^3,26,27 However, other diseases such as contact dermatitis, dermatitis herpetiformis, and food-induced pulmonary hemosiderosis (Heiner syndrome) are also considered non-IgE-mediated allergies.

Mixed-reaction disorders are chronic and include the eosinophilic gastroenteropathies, ie, eosinophilic proctocolitis, eosinophilic gastroenteritis, and eosinophilic esophagitis.²⁸ The pathophysiology of these diseases is poorly understood. Many patients have evidence of allergic sensitivities to food or to environmental allergens, or both, but whether these sensitivities have a causal role in these disorders is not clear.

Atopic dermatitis, another complicated disease process, may be associated with mixedreaction food allergy, as approximately 35% of young children with moderate to severe atopic dermatitis have food allergies.²⁹

Diagnosis of IgE-mediated food allergies

A thorough history and physical examination are key to diagnosing an IgE-mediated food allergy.

The history should include potential culprit foods, the quantity eaten, the timing of the onset of symptoms, and related factors such as exercise, alcohol intake, or medication use. Symptoms of an IgE-mediated reaction are generally rapid in onset but may be delayed up to a few hours, while non-IgE mediated symptoms may present several hours to days later.

Food challenge. A double-blind, placebocontrolled oral food challenge is the gold standard for the diagnosis of food allergies. (The food to be tested is hidden in other food or in capsules.) However, this test poses significant risks, and other diagnostic methods are more practical for screening.

Skin-prick tests with commercially available extracts are a rapid and sensitive method of screening for allergy to several foods.

Negative skin-prick tests have an estimated negative predictive value of more than 95% and can therefore exclude IgE-mediated food allergies.

A positive test indicates the presence of IgE against a specific food allergen and suggests a clinical food allergy, although the specificity of the test is only about 50%, making a positive result difficult to interpret. Although the size of the skin-test response does not necessarily correlate with the potential severity of a reaction, a response larger than 3 mm does indicate a greater likelihood of clinical reactivity. A positive test is most helpful in confirming the diagnosis of IgE-mediated food allergy when combined with a clear history of food-induced symptoms.

The proteins in commercially based extracts of most fruits and vegetables are often labile; therefore, skin testing with fresh fruits and vegetables may be indicated.³⁰

Immunoassays. Radioallergosorbent tests (RASTs) and fluorescent enzyme immunoassays are used to identity food-specific IgE antibodies in the serum. The commercially available tests do not use radioactivity, but the term “RAST” is still commonly used.

Immunoassays are generally less sensitive and more costly than skin-prick tests, and their results are not immediately available, unlike those of skin-prick testing. However, these in vitro tests are not affected by antihistamine use and are useful in patients with severe dermatologic conditions or severe anaphylaxis, for whom skin-prick testing would not be appropriate.

However, unlike a negative skin-prick test, an undetectable serum food-specific IgE level has a low negative predictive value, and an undetectable level may be associated with symptoms of an allergic reaction for 10% to 25% of patients.²⁹ Therefore, if one suspects an allergic reaction but no food-specific IgE can be detected in the serum, confirming the absence of a clinical allergy must be done with a skin-prick test or with a physician-supervised oral challenge, or both.

Managing food allergy by avoiding the allergen

Food allergies are managed by strictly avoiding food allergens and by taking medications such as self-injectable epinephrine for anaphylactic symptoms.

Patients and caregivers must be educated about reading food labels, avoiding high-risk situations such as eating at buffets and other restaurants with high risk of cross-contamination, wearing a medical-alert bracelet, recognizing and managing early symptoms of an allergic reaction, and calling for emergency services if they are having an allergic reaction. Since January 2006, the US Food and Drug Administration has required food manufacturers to list common food allergens on food labels (cow’s milk, soy, wheat, egg, peanut, tree nuts, fish, and shellfish), and the labeling must use simple, easily understood terms, such as “milk” instead of “whey.” However, it is still prudent to read all ingredients listed on the label.

 

 

Experimental treatments for food allergies

Humanized monoclonal anti-IgE antibodies such as talizumab (also known as TNX-901) and omalizumab (Xolair) have been developed, but their use in food allergy has been limited. In a study in patients with peanut allergy, injections of talizumab increased the threshold for sensitivity to peanuts in most patients, but 25% of the patients did not have any improvement.³² A study of omalizumab in patients with peanut allergy was stopped after adverse reactions developed during oral peanut challenges.³³

Oral immunotherapy. Recent studies suggest it may be possible to induce oral tolerance in patients with IgE-mediated food allergy. Pilot studies have shown that frequent, increasing doses of food allergens (egg, milk, and peanut) may raise the threshold at which symptoms occur.^34–36 Though these studies suggest that oral immunotherapy may protect some patients against a reaction if they accidentally ingest a food they are allergic to, some patients could not reach the goal doses because allergic symptoms were provoked.

At this early stage, these strategies must be considered investigational, and more randomized, placebo-controlled studies are needed. Further studies will also be needed to assess whether oral immunotherapy induces only short-term desensitization (in which case the allergen needs to be ingested daily to prevent reactions) or sustained tolerance (in which case the antigenic protein can be ingested without symptoms despite periods of abstinence).

THE ROLE OF FOOD ALLERGY IN EOSINOPHILIC ESOPHAGITIS

Eosinophilic esophagitis has been recognized with increasing frequency in both children and adults over the past several years. Symptoms can include difficulty feeding, failure to thrive, vomiting, epigastric or chest pain, dysphagia, and food impaction.

Diagnostic criteria for eosinophilic esophagitis are³⁷:

• Clinical symptoms of esophageal dysfunction
• At least 15 eosinophils per high-power field in at least one esophageal biopsy specimen
• No response to a proton-pump inhibitor in high doses (up to 2 mg/kg/day) for 1 to 2 months, or normal results on pH probe monitoring of the esophagus (the reason for this criterion is that patients with gastroesophageal reflux disease can also have large numbers of eosinophils in the esophagus—more than 100 per highpower field³⁸)
• Exclusion of other causes.

Though the cause of eosinophilic esophagitis is not completely understood, atopy has been strongly implicated as a factor. More than 50% of patients with eosinophilic esophagitis also have an atopic condition (eg, atopic dermatitis, allergic rhinitis, asthma), as well as positive results on skin-prick testing or measurement of antigen-specific IgE in the serum.^39–41 Also, since most patients improve with either dietary restriction or elemental diets, food sensitization appears to play a considerable role.

As with atopic conditions such as asthma, atopic dermatitis, allergic rhinitis, and food allergy, eosinophilic esophagitis has been linked with immune responses involving helper T cell 2 (T_H2). Adults and children with eosinophilic esophagitis have been found to have elevated eosinophil counts and total IgE levels in peripheral blood.³⁷ In the esophagus, patients have elevated levels of the T_H2 cytokines often seen in atopic patients (eg, interleukins 4, 5, and 13) and mast cells.^42,43 In mice, eosinophilic esophagitis can be induced by allergen exposure and overexpression of T_H2 cytokines.^44,45 Expression of eotaxin-3, a potent eosinophil chemoattractant, was noted to be higher in children with eosinophilic esophagitis than in controls.⁴⁶

Of interest, some patients with eosinophilic esophagitis say their symptoms vary with the seasons, correlating with seasonal changes in esophageal eosinophil levels.^47,48

Studies linking eosinophilic esophagitis and food allergy in children

Kelly et al⁴⁹ reported that 10 children with chronic symptomatic gastroesophageal reflux and eosinophilic esophagitis all had partial or complete resolution of symptoms on an elemental diet.

Markowitz et al⁵⁰ found that symptoms of chronic reflux disease and eosinophilic esophagitis improved in 49 of 51 children on an elemental diet, and the number of eosinophils in the distal esophagus decreased significantly.

Liacouras et al³⁹ reported similar findings in a 10-year experience. Of 132 children who had eosinophilic esophagitis, 75 improved with dietary restriction based on results of skin-prick and patch testing. The 57 patients who did not respond and 115 others were started on an elemental diet. Of the 164 patients who complied with the elemental diet, 160 had significant improvement of symptoms and a significant decrease in the number of eosinophils in the esophagus. Individual foods were reintroduced approximately every 5 days, and esophagogastroduodenoscopy with biopsies was performed 4 to 8 weeks after the last was reintroduced into the diet.

In a retrospective study, Kagalwalla et al⁵¹ reported that 60 children with eosinophilic esophagitis were treated with either an elemental diet or a six-food elimination diet (no milk, soy, wheat, egg, peanut, or seafood). The two groups showed similar clinical and histologic improvements.

Collectively, these studies in pediatric patients imply that food allergy is a significant factor in the pathogenesis of eosinophilic esophagitis.

 

 

Studies in adults

Fewer studies of the link between food allergy and eosinophilic esophagitis have been done in adults.

In a preliminary study, 18 adults followed the six-food elimination diet. Symptoms improved in 17 (94%), and histologic findings improved in 14 (78%).⁵²

On the other hand, in six adult patients with eosinophilic esophagitis, Simon et al⁵³ found that only one had improvement in symptoms after eliminating wheat and rye from the diet, and none had significant changes in the number of eosinophils in the esophagus.

In a 37-year-old man with eosinophilic esophagitis, symptoms improved after eliminating egg from his diet.⁵⁴

Yamazaki et al⁵⁵ measured expression of interleukin 5 and interleukin 13 in 15 adult patients with eosinophilic esophagitis. Food and aeroallergens that included milk, soy, dust mite, ragweed, and Aspergillus induced significantly more interleukin 5 production in these patients than in atopic controls, suggesting that both foods and aeroallergens may have a role in the pathogenesis of eosinophilic esophagitis in adults.

How to identify potential food triggers of eosinophilic esophagitis

Though elemental diets have been associated with a decrease in symptoms and esophageal eosinophilia, elemental formulas are expensive and unpalatable and pose a risk of nutritional deprivation. Identifying specific food allergens to eliminate from the diet in patients with eosinophilic esophagitis may be less expensive and more desirable than a very limited or elemental diet.

However, potential food triggers have been hard to identify in eosinophilic esophagitis. A recent consensus report did not recommend in vitro food allergy testing,³⁷ owing to a lack of positive or negative predictive values for food-specific IgE level testing in eosinophilic esophagitis. Furthermore, the absence of IgE does not eliminate a food as a potential trigger, since non-IgE mechanisms may play a role.

Skin-prick testing is one of the currently validated diagnostic methods. Several studies have used skin-prick testing of foods in patients with eosinophilic esophagitis. In these studies, approximately two-thirds of patients had positive test reactions to at least one food, most often to common food allergens such as cow’s milk, egg, soy, wheat, and peanut, but also to rye, beef, and bean.³⁷ In a recent article,⁵⁶ 81% of adult patients with eosinophilic esophagitis had one or more allergens identified by skin-prick testing, and 50% of the patients tested positive for one or more food allergens.

Atopy patch testing. The combination of skin-prick testing and atopy patch testing may be more effective than skin-prick testing alone in identifying potential food triggers. Atopy patch testing has been used in the diagnosis of non-IgE cell-mediated (delayed) immune responses, in which T cells may play a significant role.

Atopy patch testing is similar to patch testing for contact dermatitis. It involves placing a small quantity of food on the skin and evaluating for a local delayed reaction after a set time.

In two studies,^50,57 146 children with biopsy-proven eosinophilic esophagitis had foods eliminated from the diet on the basis of positive skin-prick tests and atopy patch tests. Approximately 77% of the children had significant reduction of esophageal eosinophils in biopsy specimens (from 20 per high-power field to 1.1). The foods most commonly implicated by skin-prick testing were cow’s milk, egg, wheat, peanut, shellfish, peas, beef, fish, rye, and tomato; those identified by atopy patch testing were cow’s milk, egg, wheat, corn, beef, milk, soy, rye, chicken, oats, and potato. The combination of both types of testing had a negative predictive value of 88% to 100% for all foods except milk, while the positive predictive value was greater than 74% for the most common foods causing eosinophilic esophagitis.⁵⁸

Though atopy patch testing shows some usefulness in identifying foods that may elicit non-IgE-mediated reactions, currently these tests are not validated and have been evaluated in only a small number of studies. Currently, no standardized testing materials, methods of application, or interpretation of results exist, and no studies have included a control population to validate atopy patch testing. More studies are needed to validate atopy patch testing as a reliable diagnostic tool before it can be recommended as a component of routine diagnostic evaluation in patients with eosinophilic esophagitis.

More children and even adults seem to be allergic to various foods these days than in the past. Also apparently on the rise is a linked condition, eosinophilic esophagitis.

The reason for these increases is not clear. This article confines itself to what we know about the mechanisms of food allergies and eosinophilic esophagitis, how to diagnose them, and how to treat them.

FOOD ALLERGIES ARE COMMON, AND MORE PREVALENT THAN EVER

Food allergies—abnormal immune responses to food proteins¹—affect an estimated 6% to 8% of young children and 3% to 4% of adults in the United States,^2,3 and their prevalence appears to be rising in developed countries. Studies in US and British children indicate that peanut allergy has doubled in the past decade. ⁴

Any food can provoke a reaction, but only a few foods account for most of the significant allergic reactions: cow’s milk, soy, wheat, eggs, peanuts, tree nuts, fish, and shellfish.

Approximately 80% of allergies to milk, egg, wheat, and soy resolve by the time the patient reaches early adolescence.⁶ Fewer cases resolve in children with tree nut allergies (approximately 9%) or peanut allergy (20%),^7,8 and allergies to fish and shellfish often develop or persist in adulthood.

A family history of an atopic disease such as asthma, allergic rhinitis, eczema, or food allergy is a risk factor for developing a food allergy. ³ Considering that the rate of peanut allergy has doubled in children over the past 10 years, environmental factors may also play a role.³

How we tolerate foods or become allergic to them

The gut, the largest mucosal organ in the body, is exposed to large quantities of foreign proteins daily. Most protein is broken down by stomach acid and digestive enzymes into lessantigenic peptides or is bound by secretory immunoglobulin A (IgA), which prevents it from being absorbed. Further, the epithelial cells lining the gut do not allow large molecules to pass easily, having tight intracellular junctions and being covered with mucus.

For these reasons, less than 2% of the protein in food is absorbed in an allergenic form.⁹ The reason food allergies are more prevalent in children is most likely that children have an immature gut barrier, lower IgA levels, a higher gastric pH, and lower proteolytic enzyme levels.

When dietary proteins do cross the gut barrier, the immune system normally suppresses the allergic response. Regulatory T cells, dendritic cells, and local immune responses play critical roles in the development of tolerance. Several types of regulatory T cells, such as Tr1 cells (which secrete interleukin 10), TH3 cells (which secrete transforming growth factor beta), CD4+CD25+ regulatory T cells, gamma-delta T cells, and CD8+ suppressor cells can all contribute to suppressing allergic responses.¹⁰ Dendritic cells also help induce tolerance by stimulating CD4+ T cells to secrete transforming growth factor beta, which leads to the production of interleukin 10 and additional transforming growth factor beta.¹¹

Factors that contribute to food allergy

Many factors may contribute to whether a person becomes tolerant to or sensitized to a specific food protein.

The dose of antigen. Tolerance can develop after either high or low doses of antigens, but by different mechanisms.

The antigen structure. Soluble antigens are less sensitizing than particulate antigens.^12,13

Processing of foods. Dry-roasted peanuts are more allergenic than raw or boiled peanuts, partly because they are less soluble.¹³

The route of initial exposure. Sensitization to food proteins can occur directly through the gut or the skin. Alternatively, it can occur indirectly via the respiratory tract. Skin exposure may be especially sensitizing in children with atopic dermatitis.^14,15

The gut flora. When mice are raised in a germ-free environment, they fail to develop normal tolerance.¹⁶ They are also more likely to become sensitized if they are treated with antibiotics or if they lack toll-like receptors that recognize bacterial lipopolysaccharides.¹⁷ Furthermore, human studies suggest that probiotics promote tolerance, especially in preventing atopic dermatitis, although the studies have had conflicting results.^18–21

The gastric pH. Murine and human studies reveal that antacid medications increase the risk of food allergy.^22,23

Genetic susceptibility. A child with a sibling who is allergic to peanuts is approximately 10 times more likely to be allergic to peanuts than predicted by the rate in the general population. Although no risk-conferring gene has been identified, a study of twins showed concordance for peanut allergy in 64.3% of identical twins vs 6.8% of fraternal twins.²⁴

 

 

Three types of immune responses to food

Immunologic reactions to foods can be divided into three categories: mediated by immunoglobulin E (IgE), non-IgE-mediated, and mixed. Therefore, these disorders can present as an acute, potentially life-threatening reaction or as a chronic disease such as eosinophilic gastoenteropathy.

IgE-mediated reactions are immediate hypersensitivity responses. In most patients, an IgE-mediated mechanism can be confirmed by a positive skin test or a test for food-specific IgE in the serum. In this article, the term “food allergy” refers to an IgE-mediated reaction to a food, unless otherwise indicated.

Non-IgE-mediated reactions have a delayed onset and chronic symptoms. Commonly, they are confined to the gastrointestinal tract; examples are food-protein-induced enterocolitis, proctitis, and proctocolitis and celiac disease.^3,26,27 However, other diseases such as contact dermatitis, dermatitis herpetiformis, and food-induced pulmonary hemosiderosis (Heiner syndrome) are also considered non-IgE-mediated allergies.

Mixed-reaction disorders are chronic and include the eosinophilic gastroenteropathies, ie, eosinophilic proctocolitis, eosinophilic gastroenteritis, and eosinophilic esophagitis.²⁸ The pathophysiology of these diseases is poorly understood. Many patients have evidence of allergic sensitivities to food or to environmental allergens, or both, but whether these sensitivities have a causal role in these disorders is not clear.

Atopic dermatitis, another complicated disease process, may be associated with mixedreaction food allergy, as approximately 35% of young children with moderate to severe atopic dermatitis have food allergies.²⁹

Diagnosis of IgE-mediated food allergies

A thorough history and physical examination are key to diagnosing an IgE-mediated food allergy.

The history should include potential culprit foods, the quantity eaten, the timing of the onset of symptoms, and related factors such as exercise, alcohol intake, or medication use. Symptoms of an IgE-mediated reaction are generally rapid in onset but may be delayed up to a few hours, while non-IgE mediated symptoms may present several hours to days later.

Food challenge. A double-blind, placebocontrolled oral food challenge is the gold standard for the diagnosis of food allergies. (The food to be tested is hidden in other food or in capsules.) However, this test poses significant risks, and other diagnostic methods are more practical for screening.

Skin-prick tests with commercially available extracts are a rapid and sensitive method of screening for allergy to several foods.

Negative skin-prick tests have an estimated negative predictive value of more than 95% and can therefore exclude IgE-mediated food allergies.

A positive test indicates the presence of IgE against a specific food allergen and suggests a clinical food allergy, although the specificity of the test is only about 50%, making a positive result difficult to interpret. Although the size of the skin-test response does not necessarily correlate with the potential severity of a reaction, a response larger than 3 mm does indicate a greater likelihood of clinical reactivity. A positive test is most helpful in confirming the diagnosis of IgE-mediated food allergy when combined with a clear history of food-induced symptoms.

The proteins in commercially based extracts of most fruits and vegetables are often labile; therefore, skin testing with fresh fruits and vegetables may be indicated.³⁰

Immunoassays. Radioallergosorbent tests (RASTs) and fluorescent enzyme immunoassays are used to identity food-specific IgE antibodies in the serum. The commercially available tests do not use radioactivity, but the term “RAST” is still commonly used.

Immunoassays are generally less sensitive and more costly than skin-prick tests, and their results are not immediately available, unlike those of skin-prick testing. However, these in vitro tests are not affected by antihistamine use and are useful in patients with severe dermatologic conditions or severe anaphylaxis, for whom skin-prick testing would not be appropriate.

However, unlike a negative skin-prick test, an undetectable serum food-specific IgE level has a low negative predictive value, and an undetectable level may be associated with symptoms of an allergic reaction for 10% to 25% of patients.²⁹ Therefore, if one suspects an allergic reaction but no food-specific IgE can be detected in the serum, confirming the absence of a clinical allergy must be done with a skin-prick test or with a physician-supervised oral challenge, or both.

Managing food allergy by avoiding the allergen

Food allergies are managed by strictly avoiding food allergens and by taking medications such as self-injectable epinephrine for anaphylactic symptoms.

Patients and caregivers must be educated about reading food labels, avoiding high-risk situations such as eating at buffets and other restaurants with high risk of cross-contamination, wearing a medical-alert bracelet, recognizing and managing early symptoms of an allergic reaction, and calling for emergency services if they are having an allergic reaction. Since January 2006, the US Food and Drug Administration has required food manufacturers to list common food allergens on food labels (cow’s milk, soy, wheat, egg, peanut, tree nuts, fish, and shellfish), and the labeling must use simple, easily understood terms, such as “milk” instead of “whey.” However, it is still prudent to read all ingredients listed on the label.

 

 

Experimental treatments for food allergies

Humanized monoclonal anti-IgE antibodies such as talizumab (also known as TNX-901) and omalizumab (Xolair) have been developed, but their use in food allergy has been limited. In a study in patients with peanut allergy, injections of talizumab increased the threshold for sensitivity to peanuts in most patients, but 25% of the patients did not have any improvement.³² A study of omalizumab in patients with peanut allergy was stopped after adverse reactions developed during oral peanut challenges.³³

Oral immunotherapy. Recent studies suggest it may be possible to induce oral tolerance in patients with IgE-mediated food allergy. Pilot studies have shown that frequent, increasing doses of food allergens (egg, milk, and peanut) may raise the threshold at which symptoms occur.^34–36 Though these studies suggest that oral immunotherapy may protect some patients against a reaction if they accidentally ingest a food they are allergic to, some patients could not reach the goal doses because allergic symptoms were provoked.

At this early stage, these strategies must be considered investigational, and more randomized, placebo-controlled studies are needed. Further studies will also be needed to assess whether oral immunotherapy induces only short-term desensitization (in which case the allergen needs to be ingested daily to prevent reactions) or sustained tolerance (in which case the antigenic protein can be ingested without symptoms despite periods of abstinence).

THE ROLE OF FOOD ALLERGY IN EOSINOPHILIC ESOPHAGITIS

Eosinophilic esophagitis has been recognized with increasing frequency in both children and adults over the past several years. Symptoms can include difficulty feeding, failure to thrive, vomiting, epigastric or chest pain, dysphagia, and food impaction.

Diagnostic criteria for eosinophilic esophagitis are³⁷:

• Clinical symptoms of esophageal dysfunction
• At least 15 eosinophils per high-power field in at least one esophageal biopsy specimen
• No response to a proton-pump inhibitor in high doses (up to 2 mg/kg/day) for 1 to 2 months, or normal results on pH probe monitoring of the esophagus (the reason for this criterion is that patients with gastroesophageal reflux disease can also have large numbers of eosinophils in the esophagus—more than 100 per highpower field³⁸)
• Exclusion of other causes.

Though the cause of eosinophilic esophagitis is not completely understood, atopy has been strongly implicated as a factor. More than 50% of patients with eosinophilic esophagitis also have an atopic condition (eg, atopic dermatitis, allergic rhinitis, asthma), as well as positive results on skin-prick testing or measurement of antigen-specific IgE in the serum.^39–41 Also, since most patients improve with either dietary restriction or elemental diets, food sensitization appears to play a considerable role.

As with atopic conditions such as asthma, atopic dermatitis, allergic rhinitis, and food allergy, eosinophilic esophagitis has been linked with immune responses involving helper T cell 2 (T_H2). Adults and children with eosinophilic esophagitis have been found to have elevated eosinophil counts and total IgE levels in peripheral blood.³⁷ In the esophagus, patients have elevated levels of the T_H2 cytokines often seen in atopic patients (eg, interleukins 4, 5, and 13) and mast cells.^42,43 In mice, eosinophilic esophagitis can be induced by allergen exposure and overexpression of T_H2 cytokines.^44,45 Expression of eotaxin-3, a potent eosinophil chemoattractant, was noted to be higher in children with eosinophilic esophagitis than in controls.⁴⁶

Of interest, some patients with eosinophilic esophagitis say their symptoms vary with the seasons, correlating with seasonal changes in esophageal eosinophil levels.^47,48

Studies linking eosinophilic esophagitis and food allergy in children

Kelly et al⁴⁹ reported that 10 children with chronic symptomatic gastroesophageal reflux and eosinophilic esophagitis all had partial or complete resolution of symptoms on an elemental diet.

Markowitz et al⁵⁰ found that symptoms of chronic reflux disease and eosinophilic esophagitis improved in 49 of 51 children on an elemental diet, and the number of eosinophils in the distal esophagus decreased significantly.

Liacouras et al³⁹ reported similar findings in a 10-year experience. Of 132 children who had eosinophilic esophagitis, 75 improved with dietary restriction based on results of skin-prick and patch testing. The 57 patients who did not respond and 115 others were started on an elemental diet. Of the 164 patients who complied with the elemental diet, 160 had significant improvement of symptoms and a significant decrease in the number of eosinophils in the esophagus. Individual foods were reintroduced approximately every 5 days, and esophagogastroduodenoscopy with biopsies was performed 4 to 8 weeks after the last was reintroduced into the diet.

In a retrospective study, Kagalwalla et al⁵¹ reported that 60 children with eosinophilic esophagitis were treated with either an elemental diet or a six-food elimination diet (no milk, soy, wheat, egg, peanut, or seafood). The two groups showed similar clinical and histologic improvements.

Collectively, these studies in pediatric patients imply that food allergy is a significant factor in the pathogenesis of eosinophilic esophagitis.

 

 

Studies in adults

Fewer studies of the link between food allergy and eosinophilic esophagitis have been done in adults.

In a preliminary study, 18 adults followed the six-food elimination diet. Symptoms improved in 17 (94%), and histologic findings improved in 14 (78%).⁵²

On the other hand, in six adult patients with eosinophilic esophagitis, Simon et al⁵³ found that only one had improvement in symptoms after eliminating wheat and rye from the diet, and none had significant changes in the number of eosinophils in the esophagus.

In a 37-year-old man with eosinophilic esophagitis, symptoms improved after eliminating egg from his diet.⁵⁴

Yamazaki et al⁵⁵ measured expression of interleukin 5 and interleukin 13 in 15 adult patients with eosinophilic esophagitis. Food and aeroallergens that included milk, soy, dust mite, ragweed, and Aspergillus induced significantly more interleukin 5 production in these patients than in atopic controls, suggesting that both foods and aeroallergens may have a role in the pathogenesis of eosinophilic esophagitis in adults.

How to identify potential food triggers of eosinophilic esophagitis

Though elemental diets have been associated with a decrease in symptoms and esophageal eosinophilia, elemental formulas are expensive and unpalatable and pose a risk of nutritional deprivation. Identifying specific food allergens to eliminate from the diet in patients with eosinophilic esophagitis may be less expensive and more desirable than a very limited or elemental diet.

However, potential food triggers have been hard to identify in eosinophilic esophagitis. A recent consensus report did not recommend in vitro food allergy testing,³⁷ owing to a lack of positive or negative predictive values for food-specific IgE level testing in eosinophilic esophagitis. Furthermore, the absence of IgE does not eliminate a food as a potential trigger, since non-IgE mechanisms may play a role.

Skin-prick testing is one of the currently validated diagnostic methods. Several studies have used skin-prick testing of foods in patients with eosinophilic esophagitis. In these studies, approximately two-thirds of patients had positive test reactions to at least one food, most often to common food allergens such as cow’s milk, egg, soy, wheat, and peanut, but also to rye, beef, and bean.³⁷ In a recent article,⁵⁶ 81% of adult patients with eosinophilic esophagitis had one or more allergens identified by skin-prick testing, and 50% of the patients tested positive for one or more food allergens.

Atopy patch testing. The combination of skin-prick testing and atopy patch testing may be more effective than skin-prick testing alone in identifying potential food triggers. Atopy patch testing has been used in the diagnosis of non-IgE cell-mediated (delayed) immune responses, in which T cells may play a significant role.

Atopy patch testing is similar to patch testing for contact dermatitis. It involves placing a small quantity of food on the skin and evaluating for a local delayed reaction after a set time.

In two studies,^50,57 146 children with biopsy-proven eosinophilic esophagitis had foods eliminated from the diet on the basis of positive skin-prick tests and atopy patch tests. Approximately 77% of the children had significant reduction of esophageal eosinophils in biopsy specimens (from 20 per high-power field to 1.1). The foods most commonly implicated by skin-prick testing were cow’s milk, egg, wheat, peanut, shellfish, peas, beef, fish, rye, and tomato; those identified by atopy patch testing were cow’s milk, egg, wheat, corn, beef, milk, soy, rye, chicken, oats, and potato. The combination of both types of testing had a negative predictive value of 88% to 100% for all foods except milk, while the positive predictive value was greater than 74% for the most common foods causing eosinophilic esophagitis.⁵⁸

Though atopy patch testing shows some usefulness in identifying foods that may elicit non-IgE-mediated reactions, currently these tests are not validated and have been evaluated in only a small number of studies. Currently, no standardized testing materials, methods of application, or interpretation of results exist, and no studies have included a control population to validate atopy patch testing. More studies are needed to validate atopy patch testing as a reliable diagnostic tool before it can be recommended as a component of routine diagnostic evaluation in patients with eosinophilic esophagitis.

More children and even adults seem to be allergic to various foods these days than in the past. Also apparently on the rise is a linked condition, eosinophilic esophagitis.

The reason for these increases is not clear. This article confines itself to what we know about the mechanisms of food allergies and eosinophilic esophagitis, how to diagnose them, and how to treat them.

FOOD ALLERGIES ARE COMMON, AND MORE PREVALENT THAN EVER

Food allergies—abnormal immune responses to food proteins¹—affect an estimated 6% to 8% of young children and 3% to 4% of adults in the United States,^2,3 and their prevalence appears to be rising in developed countries. Studies in US and British children indicate that peanut allergy has doubled in the past decade. ⁴

Any food can provoke a reaction, but only a few foods account for most of the significant allergic reactions: cow’s milk, soy, wheat, eggs, peanuts, tree nuts, fish, and shellfish.

Approximately 80% of allergies to milk, egg, wheat, and soy resolve by the time the patient reaches early adolescence.⁶ Fewer cases resolve in children with tree nut allergies (approximately 9%) or peanut allergy (20%),^7,8 and allergies to fish and shellfish often develop or persist in adulthood.

A family history of an atopic disease such as asthma, allergic rhinitis, eczema, or food allergy is a risk factor for developing a food allergy. ³ Considering that the rate of peanut allergy has doubled in children over the past 10 years, environmental factors may also play a role.³

How we tolerate foods or become allergic to them

The gut, the largest mucosal organ in the body, is exposed to large quantities of foreign proteins daily. Most protein is broken down by stomach acid and digestive enzymes into lessantigenic peptides or is bound by secretory immunoglobulin A (IgA), which prevents it from being absorbed. Further, the epithelial cells lining the gut do not allow large molecules to pass easily, having tight intracellular junctions and being covered with mucus.

For these reasons, less than 2% of the protein in food is absorbed in an allergenic form.⁹ The reason food allergies are more prevalent in children is most likely that children have an immature gut barrier, lower IgA levels, a higher gastric pH, and lower proteolytic enzyme levels.

When dietary proteins do cross the gut barrier, the immune system normally suppresses the allergic response. Regulatory T cells, dendritic cells, and local immune responses play critical roles in the development of tolerance. Several types of regulatory T cells, such as Tr1 cells (which secrete interleukin 10), TH3 cells (which secrete transforming growth factor beta), CD4+CD25+ regulatory T cells, gamma-delta T cells, and CD8+ suppressor cells can all contribute to suppressing allergic responses.¹⁰ Dendritic cells also help induce tolerance by stimulating CD4+ T cells to secrete transforming growth factor beta, which leads to the production of interleukin 10 and additional transforming growth factor beta.¹¹

Factors that contribute to food allergy

Many factors may contribute to whether a person becomes tolerant to or sensitized to a specific food protein.

The dose of antigen. Tolerance can develop after either high or low doses of antigens, but by different mechanisms.

The antigen structure. Soluble antigens are less sensitizing than particulate antigens.^12,13

Processing of foods. Dry-roasted peanuts are more allergenic than raw or boiled peanuts, partly because they are less soluble.¹³

The route of initial exposure. Sensitization to food proteins can occur directly through the gut or the skin. Alternatively, it can occur indirectly via the respiratory tract. Skin exposure may be especially sensitizing in children with atopic dermatitis.^14,15

The gut flora. When mice are raised in a germ-free environment, they fail to develop normal tolerance.¹⁶ They are also more likely to become sensitized if they are treated with antibiotics or if they lack toll-like receptors that recognize bacterial lipopolysaccharides.¹⁷ Furthermore, human studies suggest that probiotics promote tolerance, especially in preventing atopic dermatitis, although the studies have had conflicting results.^18–21

The gastric pH. Murine and human studies reveal that antacid medications increase the risk of food allergy.^22,23

Genetic susceptibility. A child with a sibling who is allergic to peanuts is approximately 10 times more likely to be allergic to peanuts than predicted by the rate in the general population. Although no risk-conferring gene has been identified, a study of twins showed concordance for peanut allergy in 64.3% of identical twins vs 6.8% of fraternal twins.²⁴

 

 

Three types of immune responses to food

Immunologic reactions to foods can be divided into three categories: mediated by immunoglobulin E (IgE), non-IgE-mediated, and mixed. Therefore, these disorders can present as an acute, potentially life-threatening reaction or as a chronic disease such as eosinophilic gastoenteropathy.

IgE-mediated reactions are immediate hypersensitivity responses. In most patients, an IgE-mediated mechanism can be confirmed by a positive skin test or a test for food-specific IgE in the serum. In this article, the term “food allergy” refers to an IgE-mediated reaction to a food, unless otherwise indicated.

Non-IgE-mediated reactions have a delayed onset and chronic symptoms. Commonly, they are confined to the gastrointestinal tract; examples are food-protein-induced enterocolitis, proctitis, and proctocolitis and celiac disease.^3,26,27 However, other diseases such as contact dermatitis, dermatitis herpetiformis, and food-induced pulmonary hemosiderosis (Heiner syndrome) are also considered non-IgE-mediated allergies.

Mixed-reaction disorders are chronic and include the eosinophilic gastroenteropathies, ie, eosinophilic proctocolitis, eosinophilic gastroenteritis, and eosinophilic esophagitis.²⁸ The pathophysiology of these diseases is poorly understood. Many patients have evidence of allergic sensitivities to food or to environmental allergens, or both, but whether these sensitivities have a causal role in these disorders is not clear.

Atopic dermatitis, another complicated disease process, may be associated with mixedreaction food allergy, as approximately 35% of young children with moderate to severe atopic dermatitis have food allergies.²⁹

Diagnosis of IgE-mediated food allergies

A thorough history and physical examination are key to diagnosing an IgE-mediated food allergy.

The history should include potential culprit foods, the quantity eaten, the timing of the onset of symptoms, and related factors such as exercise, alcohol intake, or medication use. Symptoms of an IgE-mediated reaction are generally rapid in onset but may be delayed up to a few hours, while non-IgE mediated symptoms may present several hours to days later.

Food challenge. A double-blind, placebocontrolled oral food challenge is the gold standard for the diagnosis of food allergies. (The food to be tested is hidden in other food or in capsules.) However, this test poses significant risks, and other diagnostic methods are more practical for screening.

Skin-prick tests with commercially available extracts are a rapid and sensitive method of screening for allergy to several foods.

Negative skin-prick tests have an estimated negative predictive value of more than 95% and can therefore exclude IgE-mediated food allergies.

A positive test indicates the presence of IgE against a specific food allergen and suggests a clinical food allergy, although the specificity of the test is only about 50%, making a positive result difficult to interpret. Although the size of the skin-test response does not necessarily correlate with the potential severity of a reaction, a response larger than 3 mm does indicate a greater likelihood of clinical reactivity. A positive test is most helpful in confirming the diagnosis of IgE-mediated food allergy when combined with a clear history of food-induced symptoms.

The proteins in commercially based extracts of most fruits and vegetables are often labile; therefore, skin testing with fresh fruits and vegetables may be indicated.³⁰

Immunoassays. Radioallergosorbent tests (RASTs) and fluorescent enzyme immunoassays are used to identity food-specific IgE antibodies in the serum. The commercially available tests do not use radioactivity, but the term “RAST” is still commonly used.

Immunoassays are generally less sensitive and more costly than skin-prick tests, and their results are not immediately available, unlike those of skin-prick testing. However, these in vitro tests are not affected by antihistamine use and are useful in patients with severe dermatologic conditions or severe anaphylaxis, for whom skin-prick testing would not be appropriate.

However, unlike a negative skin-prick test, an undetectable serum food-specific IgE level has a low negative predictive value, and an undetectable level may be associated with symptoms of an allergic reaction for 10% to 25% of patients.²⁹ Therefore, if one suspects an allergic reaction but no food-specific IgE can be detected in the serum, confirming the absence of a clinical allergy must be done with a skin-prick test or with a physician-supervised oral challenge, or both.

Managing food allergy by avoiding the allergen

Food allergies are managed by strictly avoiding food allergens and by taking medications such as self-injectable epinephrine for anaphylactic symptoms.

Patients and caregivers must be educated about reading food labels, avoiding high-risk situations such as eating at buffets and other restaurants with high risk of cross-contamination, wearing a medical-alert bracelet, recognizing and managing early symptoms of an allergic reaction, and calling for emergency services if they are having an allergic reaction. Since January 2006, the US Food and Drug Administration has required food manufacturers to list common food allergens on food labels (cow’s milk, soy, wheat, egg, peanut, tree nuts, fish, and shellfish), and the labeling must use simple, easily understood terms, such as “milk” instead of “whey.” However, it is still prudent to read all ingredients listed on the label.

 

 

Experimental treatments for food allergies

Humanized monoclonal anti-IgE antibodies such as talizumab (also known as TNX-901) and omalizumab (Xolair) have been developed, but their use in food allergy has been limited. In a study in patients with peanut allergy, injections of talizumab increased the threshold for sensitivity to peanuts in most patients, but 25% of the patients did not have any improvement.³² A study of omalizumab in patients with peanut allergy was stopped after adverse reactions developed during oral peanut challenges.³³

Oral immunotherapy. Recent studies suggest it may be possible to induce oral tolerance in patients with IgE-mediated food allergy. Pilot studies have shown that frequent, increasing doses of food allergens (egg, milk, and peanut) may raise the threshold at which symptoms occur.^34–36 Though these studies suggest that oral immunotherapy may protect some patients against a reaction if they accidentally ingest a food they are allergic to, some patients could not reach the goal doses because allergic symptoms were provoked.

At this early stage, these strategies must be considered investigational, and more randomized, placebo-controlled studies are needed. Further studies will also be needed to assess whether oral immunotherapy induces only short-term desensitization (in which case the allergen needs to be ingested daily to prevent reactions) or sustained tolerance (in which case the antigenic protein can be ingested without symptoms despite periods of abstinence).

THE ROLE OF FOOD ALLERGY IN EOSINOPHILIC ESOPHAGITIS

Eosinophilic esophagitis has been recognized with increasing frequency in both children and adults over the past several years. Symptoms can include difficulty feeding, failure to thrive, vomiting, epigastric or chest pain, dysphagia, and food impaction.

Diagnostic criteria for eosinophilic esophagitis are³⁷:

• Clinical symptoms of esophageal dysfunction
• At least 15 eosinophils per high-power field in at least one esophageal biopsy specimen
• No response to a proton-pump inhibitor in high doses (up to 2 mg/kg/day) for 1 to 2 months, or normal results on pH probe monitoring of the esophagus (the reason for this criterion is that patients with gastroesophageal reflux disease can also have large numbers of eosinophils in the esophagus—more than 100 per highpower field³⁸)
• Exclusion of other causes.

Though the cause of eosinophilic esophagitis is not completely understood, atopy has been strongly implicated as a factor. More than 50% of patients with eosinophilic esophagitis also have an atopic condition (eg, atopic dermatitis, allergic rhinitis, asthma), as well as positive results on skin-prick testing or measurement of antigen-specific IgE in the serum.^39–41 Also, since most patients improve with either dietary restriction or elemental diets, food sensitization appears to play a considerable role.

As with atopic conditions such as asthma, atopic dermatitis, allergic rhinitis, and food allergy, eosinophilic esophagitis has been linked with immune responses involving helper T cell 2 (T_H2). Adults and children with eosinophilic esophagitis have been found to have elevated eosinophil counts and total IgE levels in peripheral blood.³⁷ In the esophagus, patients have elevated levels of the T_H2 cytokines often seen in atopic patients (eg, interleukins 4, 5, and 13) and mast cells.^42,43 In mice, eosinophilic esophagitis can be induced by allergen exposure and overexpression of T_H2 cytokines.^44,45 Expression of eotaxin-3, a potent eosinophil chemoattractant, was noted to be higher in children with eosinophilic esophagitis than in controls.⁴⁶

Of interest, some patients with eosinophilic esophagitis say their symptoms vary with the seasons, correlating with seasonal changes in esophageal eosinophil levels.^47,48

Studies linking eosinophilic esophagitis and food allergy in children

Kelly et al⁴⁹ reported that 10 children with chronic symptomatic gastroesophageal reflux and eosinophilic esophagitis all had partial or complete resolution of symptoms on an elemental diet.

Markowitz et al⁵⁰ found that symptoms of chronic reflux disease and eosinophilic esophagitis improved in 49 of 51 children on an elemental diet, and the number of eosinophils in the distal esophagus decreased significantly.

Liacouras et al³⁹ reported similar findings in a 10-year experience. Of 132 children who had eosinophilic esophagitis, 75 improved with dietary restriction based on results of skin-prick and patch testing. The 57 patients who did not respond and 115 others were started on an elemental diet. Of the 164 patients who complied with the elemental diet, 160 had significant improvement of symptoms and a significant decrease in the number of eosinophils in the esophagus. Individual foods were reintroduced approximately every 5 days, and esophagogastroduodenoscopy with biopsies was performed 4 to 8 weeks after the last was reintroduced into the diet.

In a retrospective study, Kagalwalla et al⁵¹ reported that 60 children with eosinophilic esophagitis were treated with either an elemental diet or a six-food elimination diet (no milk, soy, wheat, egg, peanut, or seafood). The two groups showed similar clinical and histologic improvements.

Collectively, these studies in pediatric patients imply that food allergy is a significant factor in the pathogenesis of eosinophilic esophagitis.

 

 

Studies in adults

Fewer studies of the link between food allergy and eosinophilic esophagitis have been done in adults.

In a preliminary study, 18 adults followed the six-food elimination diet. Symptoms improved in 17 (94%), and histologic findings improved in 14 (78%).⁵²

On the other hand, in six adult patients with eosinophilic esophagitis, Simon et al⁵³ found that only one had improvement in symptoms after eliminating wheat and rye from the diet, and none had significant changes in the number of eosinophils in the esophagus.

In a 37-year-old man with eosinophilic esophagitis, symptoms improved after eliminating egg from his diet.⁵⁴

Yamazaki et al⁵⁵ measured expression of interleukin 5 and interleukin 13 in 15 adult patients with eosinophilic esophagitis. Food and aeroallergens that included milk, soy, dust mite, ragweed, and Aspergillus induced significantly more interleukin 5 production in these patients than in atopic controls, suggesting that both foods and aeroallergens may have a role in the pathogenesis of eosinophilic esophagitis in adults.

How to identify potential food triggers of eosinophilic esophagitis

Though elemental diets have been associated with a decrease in symptoms and esophageal eosinophilia, elemental formulas are expensive and unpalatable and pose a risk of nutritional deprivation. Identifying specific food allergens to eliminate from the diet in patients with eosinophilic esophagitis may be less expensive and more desirable than a very limited or elemental diet.

However, potential food triggers have been hard to identify in eosinophilic esophagitis. A recent consensus report did not recommend in vitro food allergy testing,³⁷ owing to a lack of positive or negative predictive values for food-specific IgE level testing in eosinophilic esophagitis. Furthermore, the absence of IgE does not eliminate a food as a potential trigger, since non-IgE mechanisms may play a role.

Skin-prick testing is one of the currently validated diagnostic methods. Several studies have used skin-prick testing of foods in patients with eosinophilic esophagitis. In these studies, approximately two-thirds of patients had positive test reactions to at least one food, most often to common food allergens such as cow’s milk, egg, soy, wheat, and peanut, but also to rye, beef, and bean.³⁷ In a recent article,⁵⁶ 81% of adult patients with eosinophilic esophagitis had one or more allergens identified by skin-prick testing, and 50% of the patients tested positive for one or more food allergens.

Atopy patch testing. The combination of skin-prick testing and atopy patch testing may be more effective than skin-prick testing alone in identifying potential food triggers. Atopy patch testing has been used in the diagnosis of non-IgE cell-mediated (delayed) immune responses, in which T cells may play a significant role.

Atopy patch testing is similar to patch testing for contact dermatitis. It involves placing a small quantity of food on the skin and evaluating for a local delayed reaction after a set time.

In two studies,^50,57 146 children with biopsy-proven eosinophilic esophagitis had foods eliminated from the diet on the basis of positive skin-prick tests and atopy patch tests. Approximately 77% of the children had significant reduction of esophageal eosinophils in biopsy specimens (from 20 per high-power field to 1.1). The foods most commonly implicated by skin-prick testing were cow’s milk, egg, wheat, peanut, shellfish, peas, beef, fish, rye, and tomato; those identified by atopy patch testing were cow’s milk, egg, wheat, corn, beef, milk, soy, rye, chicken, oats, and potato. The combination of both types of testing had a negative predictive value of 88% to 100% for all foods except milk, while the positive predictive value was greater than 74% for the most common foods causing eosinophilic esophagitis.⁵⁸

Though atopy patch testing shows some usefulness in identifying foods that may elicit non-IgE-mediated reactions, currently these tests are not validated and have been evaluated in only a small number of studies. Currently, no standardized testing materials, methods of application, or interpretation of results exist, and no studies have included a control population to validate atopy patch testing. More studies are needed to validate atopy patch testing as a reliable diagnostic tool before it can be recommended as a component of routine diagnostic evaluation in patients with eosinophilic esophagitis.

A 20-year-old woman presents to the emergency department with postprandial epigastric and right-upper-quadrant pain, sometimes associated with nausea. She has been having six to eight loose bowel movements every day, with no blood or mucus, and she has lost about 20 lb despite a good appetite. The diarrhea did not improve when she tried omitting milk products and carbohydrates.

Her symptoms began several months ago, but she says that 3 days ago the pain worsened steadily, radiating to the middle of her back, with associated episodes of nonbloody, nonbilious emesis. She cannot keep down liquids or solids. She says she has never had such episodes in the past.

She reports no oral ulcers, urinary symptoms, skin rashes, musculoskeletal pain, or neurologic symptoms, and she denies being anxious or depressed.

She has no history of serious illness, surgery, or hospitalization. She smokes a half pack of cigarettes a day, drinks alcohol occasionally, and smokes marijuana occasionally. She is employed as a certified nursing assistant.

She is taking ethinyl estradiol-levonorgestrel pills for birth control and takes calcium carbonate as needed for abdominal discomfort. She is taking no other medications, including nonsteroidal anti-inflammatory drugs (NSAIDs).

Her maternal uncle died of colon cancer at age 32, and her mother had colon polyps on colonoscopy. There is no family history of inflammatory bowel disease or celiac sprue. Her father committed suicide.

Her laboratory values

• White blood cell count 10.2 × 10⁹/L (normal range 4–11)
• Red blood cell count 4.71 × 10¹²/L (3.9–5.5)
• Hemoglobin 14.4 g/dL (12–16)
• Hematocrit 42.4% (37%–47%)
• Mean corpuscular volume 90 fL (83–99)
• Mean corpuscular hemoglobin 30.6 pg (27–33)
• Platelet count 230 × 10⁹/L (150–400)
• Red cell distribution width 13.3% (11.5%–14.5%)
• Sodium 140 mmol/L (132–148)
• Potassium 3.3 mmol/L (3.5–5.0)
• Chloride 104 mmol/L (98–111)
• Bicarbonate 28 mmol/L (23–32)
• Blood urea nitrogen 9 mg/dL (8–25)
• Creatinine 0.8 mg/dL (0.7–1.4)
• Glucose 87 mg/dL (65–100)
• Alanine aminotransferase 26 U/L (0–45)
• Aspartate aminotransferase 21 U/L (7–40)
• Alkaline phosphatase 101 U/L (40–150)
• Total bilirubin 0.8 mg/dL (0–1.5)
• Albumin 3.5 g/dL (3.5–5)
• Pregnancy screen negative
• Urine toxicology screen negative.

Physical examination

The patient is very thin and appears quite uncomfortable. Her temperature is 99.7°F (37.6°C), pulse rate 101, respiratory rate 18, blood pressure 111/67 mm Hg, and oxygen saturation 96% on room air. Her skin is warm and dry. Her height is 66 inches, weight 116 lb, and body mass index 18.7.

Examination of the head and neck shows normal dentition, dry mucus membranes, and no oral exudates. The thyroid is normal, and no masses or lymphadenopathy are noted.

Heart sounds and rhythm are normal, and the lungs are clear with no crackles or rubs. The abdomen is scaphoid and soft, with no distention. She has epigastric tenderness but no rebound, guarding, rigidity, palpable mass, or costovertebral angle tenderness. Bowel sounds are normal. The neurologic examination is normal.

NARROWING THE DIAGNOSIS

1. Given the history and findings so far, which is the least likely cause of her symptoms?

• Lactose intolerance
• Celiac disease
• Crohn disease
• Duodenal ulcer
• Eating disorder

This young woman’s presentation has some features found in all of these conditions. However, the least likely is lactose intolerance.

Lactose intolerance results from a shortage of the enzyme lactase, which is normally produced by the cells that line the small intestine. Close to 50 million American adults have lactose intolerance. Common symptoms include nausea, cramps, bloating, gas, and diarrhea, which begin about 30 minutes to 2 hours after eating or drinking foods containing lactose.

Since the patient’s symptoms did not improve when she tried omitting milk products, and since lactose intolerance is rarely associated with pain radiating to the back and with severe vomiting, this is the least likely cause of her symptoms.

Celiac disease presents with a myriad of symptoms—sometimes without gastrointestinal (GI) symptoms. Anemia is the most common laboratory finding, due most often to iron deficiency, but also due to deficiencies of vitamin B₁₂ and folate as a result of malabsorption.¹

Our patient’s laboratory values—especially her red cell indices—do not confirm this finding. One must also remember, however, that hemoglobin tends to be falsely elevated in patients who are dehydrated.

Crohn disease often presents with occult blood loss, low-grade fever, weight loss, and anemia. Though the condition is most often ileocolic, it can affect any part of the gastrointestinal tract. Nevertheless, most patients with gastroduodenal involvement have previously been diagnosed with ileocolic disease, and gastroduodenal involvement manifests later. Nonradiating epigastric pain is very common. Obstructive symptoms due to gastroduodenal strictures (eg, postprandial vomiting, epigastric pain, weight loss, bloating) are also common. ²

Duodenal ulcer. The most important factors responsible for duodenal ulcers are NSAID use and Helicobacter pylori infection.³ Duodenal ulcers have a variety of clinical presentations, ranging from no symptoms to severe pain. Epigastric pain can be sharp, dull, burning, or penetrating. Many patients complain of a feeling of hunger and weight gain—as opposed to gastric ulcer, in which patients experience anorexia and weight loss. Abdominal pain generally occurs several hours after meals and often awakens the patient at night. Pain is often relieved by food, but this phenomenon is present in only 20% to 60% of patients and probably is not specific for duodenal ulcer.

Our patient does not use NSAIDs, but some of her symptoms, such as postprandial pain, epigastric pain radiating to the back, and nausea and vomiting are seen with duodenal ulcer.

Eating disorders. The two main types of eating disorders—anorexia nervosa and bulimia nervosa—have a significant diagnostic overlap,⁴ and a third type, binge-eating disorder, is currently being investigated and defined. Girls and women are 10 times as likely as boys and men to develop an eating disorder.

People with anorexia have a distorted view of their bodies. Even when they are extremely thin, they see themselves as too fat.

Bulimia is characterized by binge-eating, purging, and overexercising to compensate for the excess calories. Patients are often close to normal weight.

Binge-eating disorder involves the consumption of very large amounts of food in a short period of time. About 2% of all young adults in the United States struggle with bingeeating. They are either overweight or obese.

These disorders tend to be associated with other psychiatric disorders such as depression or obsessive-compulsive disorder. Our patient sought medical attention and was appropriately concerned about her weight loss, which make an eating disorder unlikely.

CASE CONTINUED: SHE UNDERGOES CT

2. Which of the following is the most likely diagnosis at this point?

• SMA syndrome
• Chronic mesenteric ischemia involving the SMA
• Megaduodenum due to a connective tissue disorder

SMA syndrome is the most likely diagnosis. Despite its name, this syndrome is not a vascular condition. It is an uncommon cause of proximal intestinal obstruction in which the duodenum is compressed between the SMA and the aorta. First described in 1861, it has also been known as cast syndrome, Wilkie syndrome, and arteriomesenteric duodenal obstruction.⁵

To date, more than 400 cases of this syndrome have been reported, twice as many in women as in men. Most patients are between 20 and 40 years of age at the time of diagnosis. Common presenting symptoms include postprandial abdominal pain, nausea, vomiting, and weight loss, which may further reduce the angle between the SMA and the aorta. Diarrhea is not generally associated with this syndrome, and in our patient’s case the diarrhea was thought to be unrelated to the SMA syndrome, since it subsided spontaneously.

Conditions and events that cause, contribute to, or worsen SMA syndrome include:

• Rapid weight loss (as in cancer or burns) or lean body habitus
• Prolonged bed rest
• Use of a body cast
• Malabsorption
• Spinal disease, deformity, or trauma
• Scoliosis surgery
• Rapid linear growth without compensatory weight gain
• Abnormally high and fixed position of the ligament of Treitz
• Abdominal surgery
• Cardiac cachexia
• Unusually low origin of the SMA.⁷

More common causes of mechanical smallbowel obstruction are adhesions, hernias, and tumors.⁸ Hyperactive, high-pitched peristalsis with rushes coinciding with cramps is typical. Abdominal cramps are centered around the umbilicus or in the epigastrium and are associated with vomiting; obstipation develops in patients with complete obstruction. Patients with partial obstruction may develop diarrhea. Paralytic ileus secondary to hypokalemia is an important consideration in partial obstruction. However, abdominal radiography and CT did not confirm an obstruction, and her symptoms persisted despite correction of the potassium level.

Chronic mesenteric ischemia can be caused by vasculitis, nonocclusive conditions that cause prolonged vasoconstriction (eg, cocaine ingestion), or reduced cardiac output.⁹ Symptoms are due to the gradual reduction in blood flow to the intestine that occurs during eating. Our patient’s toxicology report did not suggest cocaine abuse, and her history and the workup thus far do not suggest heart failure. A workup for vasculitis was negative.

Megaduodenum, SMA-like syndrome. In rare cases, dilation of the duodenum at the level of the SMA may be part of a generalized duodenal dilation caused by something other than obstruction due to mechanical compression. There are conditions, as described below, that cause an SMA-like syndrome.

A compression defect of the duodenum at the site where the SMA crossed the duodenum was found in a series of 11 cases of systemic sclerosis.¹⁰ These patients had definite dilation of the duodenum, but it was a result of atrophy of the muscle layers and replacement by collagenous tissue, changes that result in diminished peristalsis, loss of muscle tone, and dilation. The duodenum yields to pressure in its third portion under the SMA.

Several pathologic conditions, particularly connective tissue disorders, may predispose to the development of a megaduodenum that may result in an imprint on the duodenum at the level of the SMA. The most noteworthy of these conditions is scleroderma. Other conditions that can cause reduced duodenal peristalsis include diabetes, pancreatitis, dermatomyositis, lupus erythematosus, myxedema, and amyloidosis.¹¹

It is important to distinguish SMA syndrome from SMA-like syndromes for several reasons.¹² SMA-like syndromes result in loss of normal peristalsis. Further, the conditions have different outcomes, even though they are managed similarly initially, ie, with rehydration and parenteral nutrition. Surgery is to be avoided if possible in conditions that affect widespread areas of the intestine, such as scleroderma or diabetic neuropathy.

3. Which of the following is helpful in confirming SMA syndrome?

• CT of the abdomen
• Upper GI radiography series
• Upper GI endoscopy

All three can help confirm the diagnosis.

CT of the abdomen is a convenient, safe, rapid, readily available, and relatively noninvasive way to evaluate the aortomesenteric angle and to view retroperitoneal and mesenteric fat.¹³ Rehydration before injecting intravenous dye is important to avoid precipitating renal failure. In this patient, CT findings that helped make the diagnosis included a narrow aortomesenteric angle, compression of the duodenum, and a paucity of fat around the SMA.

An upper GI series can reveal dilation of the first and second portions of the duodenum and abrupt compression of the duodenal mucosal folds. Other findings can include a delay of 4 to 6 hours in gastroduodenal transit and relief of the obstruction when the patient is in the left lateral decubitus position. The Hayes maneuver refers to the disappearance of these radiologic features in the knee-chest position on cinefluoroscopy.¹⁴ The findings mentioned above are best noted in the supine position on both radiography and CT.

Endoscopy is necessary to rule out mechanical causes of duodenal obstruction. A pulsatile extrinsic compression suggests this condition but is found only occasionally.

Other imaging studies, such as ultrasonography, arteriography, and hypotonic duodenography, are used less often.

4. At this time, which of the following would be the most appropriate initial treatment in this patient?

• Conservative treatment
• Narcotics
• Duodenojejunostomy

Conservative treatment is indicated initially in all cases of SMA syndrome.¹⁵ This involves reversing precipitating factors and replacing fluid, electrolytes, and nutrition via total parenteral nutrition and nasogastric decompression.

To avoid keeping the patient on intravenous therapy for a prolonged time, it is important to start enteral feeding once the pain has subsided and the patient can tolerate it. A double-lumen nasojejunal tube is passed distal to the obstruction under fluoroscopic guidance. During feedings, the patient should be in the modified knee-chest, prone, or leftside-down position, all of which increase the aortomesenteric angle.

Delaying the treatment of SMA syndrome can increase the risk of morbidity and mortality by progressive malnutrition, dehydration, oliguria, electrolyte abnormalities (eg, hypokalemia), or intestinal perforation from prolonged ischemia.^16,17

Narcotics and other drugs known to slow gut motility should be avoided.

Symptoms typically improve after restoration of normal body weight. If conservative treatment fails, or if the case is severe or chronic, surgery is required.¹⁸ Fortunately, this is not required often.

Duodenojejunostomy is the most common surgical treatment and involves creation of an alternate route between the duodenum and the jejunum, bypassing the compression between the aorta and the SMA. Other procedures include gastrojejunostomy, laparoscopic duodenojejunostomy, ¹⁹ a Roux-en-Y procedure, robotically assisted duodenojejunostomy, and anterior transposition of the third portion of the duodenum. Cleavage of the ligament of Treitz is another option, enabling the duodenum to drop away from the apex of the sharpened aortomesenteric angle.

WHEN TO CONSIDER SMA SYNDROME

The SMA syndrome is an uncommon cause of a very common presenting symptom, ie, abdominal pain. Nevertheless, it should be considered in the differential diagnosis of abdominal pain, especially in patients who have conditions that cause significant weight loss, such as anorexia nervosa, malabsorption, or hypercatabolic states such as burns, major surgery, severe injuries, or malignancies. The diagnosis is based on a thorough history and on supportive findings from CT and endoscopy.

In our patient, weight loss began with nonspecific diarrhea but perpetuated itself as SMA syndrome occurred.

Appropriate management consists of interrupting the cycle of weight loss and secondary upper gut obstruction. For patients in whom more definitive therapy is not feasible, a gastrostomy tube for decompression with a jejunal extension available for feeding appears to be a reasonable and safe treatment option. Duodenojejunostomy is considered the procedure of choice in severe cases.

CASE CONCLUDED

Fortunately, our patient responded well to conservative management. She was treated with intravenous hydration and correction of electrolytes and 10 days later was able to tolerate a soft diet. She was discharged in stable condition. At a follow-up visit 2 weeks later, she reported minimal abdominal discomfort, was able to tolerate meals, and had gained a few pounds. She continues to do well.

A 20-year-old woman presents to the emergency department with postprandial epigastric and right-upper-quadrant pain, sometimes associated with nausea. She has been having six to eight loose bowel movements every day, with no blood or mucus, and she has lost about 20 lb despite a good appetite. The diarrhea did not improve when she tried omitting milk products and carbohydrates.

Her symptoms began several months ago, but she says that 3 days ago the pain worsened steadily, radiating to the middle of her back, with associated episodes of nonbloody, nonbilious emesis. She cannot keep down liquids or solids. She says she has never had such episodes in the past.

She reports no oral ulcers, urinary symptoms, skin rashes, musculoskeletal pain, or neurologic symptoms, and she denies being anxious or depressed.

She has no history of serious illness, surgery, or hospitalization. She smokes a half pack of cigarettes a day, drinks alcohol occasionally, and smokes marijuana occasionally. She is employed as a certified nursing assistant.

She is taking ethinyl estradiol-levonorgestrel pills for birth control and takes calcium carbonate as needed for abdominal discomfort. She is taking no other medications, including nonsteroidal anti-inflammatory drugs (NSAIDs).

Her maternal uncle died of colon cancer at age 32, and her mother had colon polyps on colonoscopy. There is no family history of inflammatory bowel disease or celiac sprue. Her father committed suicide.

Her laboratory values

• White blood cell count 10.2 × 10⁹/L (normal range 4–11)
• Red blood cell count 4.71 × 10¹²/L (3.9–5.5)
• Hemoglobin 14.4 g/dL (12–16)
• Hematocrit 42.4% (37%–47%)
• Mean corpuscular volume 90 fL (83–99)
• Mean corpuscular hemoglobin 30.6 pg (27–33)
• Platelet count 230 × 10⁹/L (150–400)
• Red cell distribution width 13.3% (11.5%–14.5%)
• Sodium 140 mmol/L (132–148)
• Potassium 3.3 mmol/L (3.5–5.0)
• Chloride 104 mmol/L (98–111)
• Bicarbonate 28 mmol/L (23–32)
• Blood urea nitrogen 9 mg/dL (8–25)
• Creatinine 0.8 mg/dL (0.7–1.4)
• Glucose 87 mg/dL (65–100)
• Alanine aminotransferase 26 U/L (0–45)
• Aspartate aminotransferase 21 U/L (7–40)
• Alkaline phosphatase 101 U/L (40–150)
• Total bilirubin 0.8 mg/dL (0–1.5)
• Albumin 3.5 g/dL (3.5–5)
• Pregnancy screen negative
• Urine toxicology screen negative.

Physical examination

The patient is very thin and appears quite uncomfortable. Her temperature is 99.7°F (37.6°C), pulse rate 101, respiratory rate 18, blood pressure 111/67 mm Hg, and oxygen saturation 96% on room air. Her skin is warm and dry. Her height is 66 inches, weight 116 lb, and body mass index 18.7.

Examination of the head and neck shows normal dentition, dry mucus membranes, and no oral exudates. The thyroid is normal, and no masses or lymphadenopathy are noted.

Heart sounds and rhythm are normal, and the lungs are clear with no crackles or rubs. The abdomen is scaphoid and soft, with no distention. She has epigastric tenderness but no rebound, guarding, rigidity, palpable mass, or costovertebral angle tenderness. Bowel sounds are normal. The neurologic examination is normal.

NARROWING THE DIAGNOSIS

1. Given the history and findings so far, which is the least likely cause of her symptoms?

• Lactose intolerance
• Celiac disease
• Crohn disease
• Duodenal ulcer
• Eating disorder

This young woman’s presentation has some features found in all of these conditions. However, the least likely is lactose intolerance.

Lactose intolerance results from a shortage of the enzyme lactase, which is normally produced by the cells that line the small intestine. Close to 50 million American adults have lactose intolerance. Common symptoms include nausea, cramps, bloating, gas, and diarrhea, which begin about 30 minutes to 2 hours after eating or drinking foods containing lactose.

Since the patient’s symptoms did not improve when she tried omitting milk products, and since lactose intolerance is rarely associated with pain radiating to the back and with severe vomiting, this is the least likely cause of her symptoms.

Celiac disease presents with a myriad of symptoms—sometimes without gastrointestinal (GI) symptoms. Anemia is the most common laboratory finding, due most often to iron deficiency, but also due to deficiencies of vitamin B₁₂ and folate as a result of malabsorption.¹

Our patient’s laboratory values—especially her red cell indices—do not confirm this finding. One must also remember, however, that hemoglobin tends to be falsely elevated in patients who are dehydrated.

Crohn disease often presents with occult blood loss, low-grade fever, weight loss, and anemia. Though the condition is most often ileocolic, it can affect any part of the gastrointestinal tract. Nevertheless, most patients with gastroduodenal involvement have previously been diagnosed with ileocolic disease, and gastroduodenal involvement manifests later. Nonradiating epigastric pain is very common. Obstructive symptoms due to gastroduodenal strictures (eg, postprandial vomiting, epigastric pain, weight loss, bloating) are also common. ²

Duodenal ulcer. The most important factors responsible for duodenal ulcers are NSAID use and Helicobacter pylori infection.³ Duodenal ulcers have a variety of clinical presentations, ranging from no symptoms to severe pain. Epigastric pain can be sharp, dull, burning, or penetrating. Many patients complain of a feeling of hunger and weight gain—as opposed to gastric ulcer, in which patients experience anorexia and weight loss. Abdominal pain generally occurs several hours after meals and often awakens the patient at night. Pain is often relieved by food, but this phenomenon is present in only 20% to 60% of patients and probably is not specific for duodenal ulcer.

Our patient does not use NSAIDs, but some of her symptoms, such as postprandial pain, epigastric pain radiating to the back, and nausea and vomiting are seen with duodenal ulcer.

Eating disorders. The two main types of eating disorders—anorexia nervosa and bulimia nervosa—have a significant diagnostic overlap,⁴ and a third type, binge-eating disorder, is currently being investigated and defined. Girls and women are 10 times as likely as boys and men to develop an eating disorder.

People with anorexia have a distorted view of their bodies. Even when they are extremely thin, they see themselves as too fat.

Bulimia is characterized by binge-eating, purging, and overexercising to compensate for the excess calories. Patients are often close to normal weight.

Binge-eating disorder involves the consumption of very large amounts of food in a short period of time. About 2% of all young adults in the United States struggle with bingeeating. They are either overweight or obese.

These disorders tend to be associated with other psychiatric disorders such as depression or obsessive-compulsive disorder. Our patient sought medical attention and was appropriately concerned about her weight loss, which make an eating disorder unlikely.

CASE CONTINUED: SHE UNDERGOES CT

2. Which of the following is the most likely diagnosis at this point?

• SMA syndrome
• Chronic mesenteric ischemia involving the SMA
• Megaduodenum due to a connective tissue disorder

SMA syndrome is the most likely diagnosis. Despite its name, this syndrome is not a vascular condition. It is an uncommon cause of proximal intestinal obstruction in which the duodenum is compressed between the SMA and the aorta. First described in 1861, it has also been known as cast syndrome, Wilkie syndrome, and arteriomesenteric duodenal obstruction.⁵

To date, more than 400 cases of this syndrome have been reported, twice as many in women as in men. Most patients are between 20 and 40 years of age at the time of diagnosis. Common presenting symptoms include postprandial abdominal pain, nausea, vomiting, and weight loss, which may further reduce the angle between the SMA and the aorta. Diarrhea is not generally associated with this syndrome, and in our patient’s case the diarrhea was thought to be unrelated to the SMA syndrome, since it subsided spontaneously.

Conditions and events that cause, contribute to, or worsen SMA syndrome include:

• Rapid weight loss (as in cancer or burns) or lean body habitus
• Prolonged bed rest
• Use of a body cast
• Malabsorption
• Spinal disease, deformity, or trauma
• Scoliosis surgery
• Rapid linear growth without compensatory weight gain
• Abnormally high and fixed position of the ligament of Treitz
• Abdominal surgery
• Cardiac cachexia
• Unusually low origin of the SMA.⁷

More common causes of mechanical smallbowel obstruction are adhesions, hernias, and tumors.⁸ Hyperactive, high-pitched peristalsis with rushes coinciding with cramps is typical. Abdominal cramps are centered around the umbilicus or in the epigastrium and are associated with vomiting; obstipation develops in patients with complete obstruction. Patients with partial obstruction may develop diarrhea. Paralytic ileus secondary to hypokalemia is an important consideration in partial obstruction. However, abdominal radiography and CT did not confirm an obstruction, and her symptoms persisted despite correction of the potassium level.

Chronic mesenteric ischemia can be caused by vasculitis, nonocclusive conditions that cause prolonged vasoconstriction (eg, cocaine ingestion), or reduced cardiac output.⁹ Symptoms are due to the gradual reduction in blood flow to the intestine that occurs during eating. Our patient’s toxicology report did not suggest cocaine abuse, and her history and the workup thus far do not suggest heart failure. A workup for vasculitis was negative.

Megaduodenum, SMA-like syndrome. In rare cases, dilation of the duodenum at the level of the SMA may be part of a generalized duodenal dilation caused by something other than obstruction due to mechanical compression. There are conditions, as described below, that cause an SMA-like syndrome.

A compression defect of the duodenum at the site where the SMA crossed the duodenum was found in a series of 11 cases of systemic sclerosis.¹⁰ These patients had definite dilation of the duodenum, but it was a result of atrophy of the muscle layers and replacement by collagenous tissue, changes that result in diminished peristalsis, loss of muscle tone, and dilation. The duodenum yields to pressure in its third portion under the SMA.

Several pathologic conditions, particularly connective tissue disorders, may predispose to the development of a megaduodenum that may result in an imprint on the duodenum at the level of the SMA. The most noteworthy of these conditions is scleroderma. Other conditions that can cause reduced duodenal peristalsis include diabetes, pancreatitis, dermatomyositis, lupus erythematosus, myxedema, and amyloidosis.¹¹

It is important to distinguish SMA syndrome from SMA-like syndromes for several reasons.¹² SMA-like syndromes result in loss of normal peristalsis. Further, the conditions have different outcomes, even though they are managed similarly initially, ie, with rehydration and parenteral nutrition. Surgery is to be avoided if possible in conditions that affect widespread areas of the intestine, such as scleroderma or diabetic neuropathy.

3. Which of the following is helpful in confirming SMA syndrome?

• CT of the abdomen
• Upper GI radiography series
• Upper GI endoscopy

All three can help confirm the diagnosis.

CT of the abdomen is a convenient, safe, rapid, readily available, and relatively noninvasive way to evaluate the aortomesenteric angle and to view retroperitoneal and mesenteric fat.¹³ Rehydration before injecting intravenous dye is important to avoid precipitating renal failure. In this patient, CT findings that helped make the diagnosis included a narrow aortomesenteric angle, compression of the duodenum, and a paucity of fat around the SMA.

An upper GI series can reveal dilation of the first and second portions of the duodenum and abrupt compression of the duodenal mucosal folds. Other findings can include a delay of 4 to 6 hours in gastroduodenal transit and relief of the obstruction when the patient is in the left lateral decubitus position. The Hayes maneuver refers to the disappearance of these radiologic features in the knee-chest position on cinefluoroscopy.¹⁴ The findings mentioned above are best noted in the supine position on both radiography and CT.

Endoscopy is necessary to rule out mechanical causes of duodenal obstruction. A pulsatile extrinsic compression suggests this condition but is found only occasionally.

Other imaging studies, such as ultrasonography, arteriography, and hypotonic duodenography, are used less often.

4. At this time, which of the following would be the most appropriate initial treatment in this patient?

• Conservative treatment
• Narcotics
• Duodenojejunostomy

Conservative treatment is indicated initially in all cases of SMA syndrome.¹⁵ This involves reversing precipitating factors and replacing fluid, electrolytes, and nutrition via total parenteral nutrition and nasogastric decompression.

To avoid keeping the patient on intravenous therapy for a prolonged time, it is important to start enteral feeding once the pain has subsided and the patient can tolerate it. A double-lumen nasojejunal tube is passed distal to the obstruction under fluoroscopic guidance. During feedings, the patient should be in the modified knee-chest, prone, or leftside-down position, all of which increase the aortomesenteric angle.

Delaying the treatment of SMA syndrome can increase the risk of morbidity and mortality by progressive malnutrition, dehydration, oliguria, electrolyte abnormalities (eg, hypokalemia), or intestinal perforation from prolonged ischemia.^16,17

Narcotics and other drugs known to slow gut motility should be avoided.

Symptoms typically improve after restoration of normal body weight. If conservative treatment fails, or if the case is severe or chronic, surgery is required.¹⁸ Fortunately, this is not required often.

Duodenojejunostomy is the most common surgical treatment and involves creation of an alternate route between the duodenum and the jejunum, bypassing the compression between the aorta and the SMA. Other procedures include gastrojejunostomy, laparoscopic duodenojejunostomy, ¹⁹ a Roux-en-Y procedure, robotically assisted duodenojejunostomy, and anterior transposition of the third portion of the duodenum. Cleavage of the ligament of Treitz is another option, enabling the duodenum to drop away from the apex of the sharpened aortomesenteric angle.

WHEN TO CONSIDER SMA SYNDROME

The SMA syndrome is an uncommon cause of a very common presenting symptom, ie, abdominal pain. Nevertheless, it should be considered in the differential diagnosis of abdominal pain, especially in patients who have conditions that cause significant weight loss, such as anorexia nervosa, malabsorption, or hypercatabolic states such as burns, major surgery, severe injuries, or malignancies. The diagnosis is based on a thorough history and on supportive findings from CT and endoscopy.

In our patient, weight loss began with nonspecific diarrhea but perpetuated itself as SMA syndrome occurred.

Appropriate management consists of interrupting the cycle of weight loss and secondary upper gut obstruction. For patients in whom more definitive therapy is not feasible, a gastrostomy tube for decompression with a jejunal extension available for feeding appears to be a reasonable and safe treatment option. Duodenojejunostomy is considered the procedure of choice in severe cases.

CASE CONCLUDED

Fortunately, our patient responded well to conservative management. She was treated with intravenous hydration and correction of electrolytes and 10 days later was able to tolerate a soft diet. She was discharged in stable condition. At a follow-up visit 2 weeks later, she reported minimal abdominal discomfort, was able to tolerate meals, and had gained a few pounds. She continues to do well.

A 20-year-old woman presents to the emergency department with postprandial epigastric and right-upper-quadrant pain, sometimes associated with nausea. She has been having six to eight loose bowel movements every day, with no blood or mucus, and she has lost about 20 lb despite a good appetite. The diarrhea did not improve when she tried omitting milk products and carbohydrates.

Her symptoms began several months ago, but she says that 3 days ago the pain worsened steadily, radiating to the middle of her back, with associated episodes of nonbloody, nonbilious emesis. She cannot keep down liquids or solids. She says she has never had such episodes in the past.

She reports no oral ulcers, urinary symptoms, skin rashes, musculoskeletal pain, or neurologic symptoms, and she denies being anxious or depressed.

She has no history of serious illness, surgery, or hospitalization. She smokes a half pack of cigarettes a day, drinks alcohol occasionally, and smokes marijuana occasionally. She is employed as a certified nursing assistant.

She is taking ethinyl estradiol-levonorgestrel pills for birth control and takes calcium carbonate as needed for abdominal discomfort. She is taking no other medications, including nonsteroidal anti-inflammatory drugs (NSAIDs).

Her maternal uncle died of colon cancer at age 32, and her mother had colon polyps on colonoscopy. There is no family history of inflammatory bowel disease or celiac sprue. Her father committed suicide.

Her laboratory values

• White blood cell count 10.2 × 10⁹/L (normal range 4–11)
• Red blood cell count 4.71 × 10¹²/L (3.9–5.5)
• Hemoglobin 14.4 g/dL (12–16)
• Hematocrit 42.4% (37%–47%)
• Mean corpuscular volume 90 fL (83–99)
• Mean corpuscular hemoglobin 30.6 pg (27–33)
• Platelet count 230 × 10⁹/L (150–400)
• Red cell distribution width 13.3% (11.5%–14.5%)
• Sodium 140 mmol/L (132–148)
• Potassium 3.3 mmol/L (3.5–5.0)
• Chloride 104 mmol/L (98–111)
• Bicarbonate 28 mmol/L (23–32)
• Blood urea nitrogen 9 mg/dL (8–25)
• Creatinine 0.8 mg/dL (0.7–1.4)
• Glucose 87 mg/dL (65–100)
• Alanine aminotransferase 26 U/L (0–45)
• Aspartate aminotransferase 21 U/L (7–40)
• Alkaline phosphatase 101 U/L (40–150)
• Total bilirubin 0.8 mg/dL (0–1.5)
• Albumin 3.5 g/dL (3.5–5)
• Pregnancy screen negative
• Urine toxicology screen negative.

Physical examination

The patient is very thin and appears quite uncomfortable. Her temperature is 99.7°F (37.6°C), pulse rate 101, respiratory rate 18, blood pressure 111/67 mm Hg, and oxygen saturation 96% on room air. Her skin is warm and dry. Her height is 66 inches, weight 116 lb, and body mass index 18.7.

Examination of the head and neck shows normal dentition, dry mucus membranes, and no oral exudates. The thyroid is normal, and no masses or lymphadenopathy are noted.

Heart sounds and rhythm are normal, and the lungs are clear with no crackles or rubs. The abdomen is scaphoid and soft, with no distention. She has epigastric tenderness but no rebound, guarding, rigidity, palpable mass, or costovertebral angle tenderness. Bowel sounds are normal. The neurologic examination is normal.

NARROWING THE DIAGNOSIS

1. Given the history and findings so far, which is the least likely cause of her symptoms?

• Lactose intolerance
• Celiac disease
• Crohn disease
• Duodenal ulcer
• Eating disorder

This young woman’s presentation has some features found in all of these conditions. However, the least likely is lactose intolerance.

Lactose intolerance results from a shortage of the enzyme lactase, which is normally produced by the cells that line the small intestine. Close to 50 million American adults have lactose intolerance. Common symptoms include nausea, cramps, bloating, gas, and diarrhea, which begin about 30 minutes to 2 hours after eating or drinking foods containing lactose.

Since the patient’s symptoms did not improve when she tried omitting milk products, and since lactose intolerance is rarely associated with pain radiating to the back and with severe vomiting, this is the least likely cause of her symptoms.

Celiac disease presents with a myriad of symptoms—sometimes without gastrointestinal (GI) symptoms. Anemia is the most common laboratory finding, due most often to iron deficiency, but also due to deficiencies of vitamin B₁₂ and folate as a result of malabsorption.¹

Our patient’s laboratory values—especially her red cell indices—do not confirm this finding. One must also remember, however, that hemoglobin tends to be falsely elevated in patients who are dehydrated.

Crohn disease often presents with occult blood loss, low-grade fever, weight loss, and anemia. Though the condition is most often ileocolic, it can affect any part of the gastrointestinal tract. Nevertheless, most patients with gastroduodenal involvement have previously been diagnosed with ileocolic disease, and gastroduodenal involvement manifests later. Nonradiating epigastric pain is very common. Obstructive symptoms due to gastroduodenal strictures (eg, postprandial vomiting, epigastric pain, weight loss, bloating) are also common. ²

Duodenal ulcer. The most important factors responsible for duodenal ulcers are NSAID use and Helicobacter pylori infection.³ Duodenal ulcers have a variety of clinical presentations, ranging from no symptoms to severe pain. Epigastric pain can be sharp, dull, burning, or penetrating. Many patients complain of a feeling of hunger and weight gain—as opposed to gastric ulcer, in which patients experience anorexia and weight loss. Abdominal pain generally occurs several hours after meals and often awakens the patient at night. Pain is often relieved by food, but this phenomenon is present in only 20% to 60% of patients and probably is not specific for duodenal ulcer.

Our patient does not use NSAIDs, but some of her symptoms, such as postprandial pain, epigastric pain radiating to the back, and nausea and vomiting are seen with duodenal ulcer.

Eating disorders. The two main types of eating disorders—anorexia nervosa and bulimia nervosa—have a significant diagnostic overlap,⁴ and a third type, binge-eating disorder, is currently being investigated and defined. Girls and women are 10 times as likely as boys and men to develop an eating disorder.

People with anorexia have a distorted view of their bodies. Even when they are extremely thin, they see themselves as too fat.

Bulimia is characterized by binge-eating, purging, and overexercising to compensate for the excess calories. Patients are often close to normal weight.

Binge-eating disorder involves the consumption of very large amounts of food in a short period of time. About 2% of all young adults in the United States struggle with bingeeating. They are either overweight or obese.

These disorders tend to be associated with other psychiatric disorders such as depression or obsessive-compulsive disorder. Our patient sought medical attention and was appropriately concerned about her weight loss, which make an eating disorder unlikely.

CASE CONTINUED: SHE UNDERGOES CT

2. Which of the following is the most likely diagnosis at this point?

• SMA syndrome
• Chronic mesenteric ischemia involving the SMA
• Megaduodenum due to a connective tissue disorder

SMA syndrome is the most likely diagnosis. Despite its name, this syndrome is not a vascular condition. It is an uncommon cause of proximal intestinal obstruction in which the duodenum is compressed between the SMA and the aorta. First described in 1861, it has also been known as cast syndrome, Wilkie syndrome, and arteriomesenteric duodenal obstruction.⁵

To date, more than 400 cases of this syndrome have been reported, twice as many in women as in men. Most patients are between 20 and 40 years of age at the time of diagnosis. Common presenting symptoms include postprandial abdominal pain, nausea, vomiting, and weight loss, which may further reduce the angle between the SMA and the aorta. Diarrhea is not generally associated with this syndrome, and in our patient’s case the diarrhea was thought to be unrelated to the SMA syndrome, since it subsided spontaneously.

Conditions and events that cause, contribute to, or worsen SMA syndrome include:

• Rapid weight loss (as in cancer or burns) or lean body habitus
• Prolonged bed rest
• Use of a body cast
• Malabsorption
• Spinal disease, deformity, or trauma
• Scoliosis surgery
• Rapid linear growth without compensatory weight gain
• Abnormally high and fixed position of the ligament of Treitz
• Abdominal surgery
• Cardiac cachexia
• Unusually low origin of the SMA.⁷

More common causes of mechanical smallbowel obstruction are adhesions, hernias, and tumors.⁸ Hyperactive, high-pitched peristalsis with rushes coinciding with cramps is typical. Abdominal cramps are centered around the umbilicus or in the epigastrium and are associated with vomiting; obstipation develops in patients with complete obstruction. Patients with partial obstruction may develop diarrhea. Paralytic ileus secondary to hypokalemia is an important consideration in partial obstruction. However, abdominal radiography and CT did not confirm an obstruction, and her symptoms persisted despite correction of the potassium level.

Chronic mesenteric ischemia can be caused by vasculitis, nonocclusive conditions that cause prolonged vasoconstriction (eg, cocaine ingestion), or reduced cardiac output.⁹ Symptoms are due to the gradual reduction in blood flow to the intestine that occurs during eating. Our patient’s toxicology report did not suggest cocaine abuse, and her history and the workup thus far do not suggest heart failure. A workup for vasculitis was negative.

Megaduodenum, SMA-like syndrome. In rare cases, dilation of the duodenum at the level of the SMA may be part of a generalized duodenal dilation caused by something other than obstruction due to mechanical compression. There are conditions, as described below, that cause an SMA-like syndrome.

A compression defect of the duodenum at the site where the SMA crossed the duodenum was found in a series of 11 cases of systemic sclerosis.¹⁰ These patients had definite dilation of the duodenum, but it was a result of atrophy of the muscle layers and replacement by collagenous tissue, changes that result in diminished peristalsis, loss of muscle tone, and dilation. The duodenum yields to pressure in its third portion under the SMA.

Several pathologic conditions, particularly connective tissue disorders, may predispose to the development of a megaduodenum that may result in an imprint on the duodenum at the level of the SMA. The most noteworthy of these conditions is scleroderma. Other conditions that can cause reduced duodenal peristalsis include diabetes, pancreatitis, dermatomyositis, lupus erythematosus, myxedema, and amyloidosis.¹¹

It is important to distinguish SMA syndrome from SMA-like syndromes for several reasons.¹² SMA-like syndromes result in loss of normal peristalsis. Further, the conditions have different outcomes, even though they are managed similarly initially, ie, with rehydration and parenteral nutrition. Surgery is to be avoided if possible in conditions that affect widespread areas of the intestine, such as scleroderma or diabetic neuropathy.

3. Which of the following is helpful in confirming SMA syndrome?

• CT of the abdomen
• Upper GI radiography series
• Upper GI endoscopy

All three can help confirm the diagnosis.

CT of the abdomen is a convenient, safe, rapid, readily available, and relatively noninvasive way to evaluate the aortomesenteric angle and to view retroperitoneal and mesenteric fat.¹³ Rehydration before injecting intravenous dye is important to avoid precipitating renal failure. In this patient, CT findings that helped make the diagnosis included a narrow aortomesenteric angle, compression of the duodenum, and a paucity of fat around the SMA.

An upper GI series can reveal dilation of the first and second portions of the duodenum and abrupt compression of the duodenal mucosal folds. Other findings can include a delay of 4 to 6 hours in gastroduodenal transit and relief of the obstruction when the patient is in the left lateral decubitus position. The Hayes maneuver refers to the disappearance of these radiologic features in the knee-chest position on cinefluoroscopy.¹⁴ The findings mentioned above are best noted in the supine position on both radiography and CT.

Endoscopy is necessary to rule out mechanical causes of duodenal obstruction. A pulsatile extrinsic compression suggests this condition but is found only occasionally.

Other imaging studies, such as ultrasonography, arteriography, and hypotonic duodenography, are used less often.

4. At this time, which of the following would be the most appropriate initial treatment in this patient?

• Conservative treatment
• Narcotics
• Duodenojejunostomy

Conservative treatment is indicated initially in all cases of SMA syndrome.¹⁵ This involves reversing precipitating factors and replacing fluid, electrolytes, and nutrition via total parenteral nutrition and nasogastric decompression.

To avoid keeping the patient on intravenous therapy for a prolonged time, it is important to start enteral feeding once the pain has subsided and the patient can tolerate it. A double-lumen nasojejunal tube is passed distal to the obstruction under fluoroscopic guidance. During feedings, the patient should be in the modified knee-chest, prone, or leftside-down position, all of which increase the aortomesenteric angle.

Delaying the treatment of SMA syndrome can increase the risk of morbidity and mortality by progressive malnutrition, dehydration, oliguria, electrolyte abnormalities (eg, hypokalemia), or intestinal perforation from prolonged ischemia.^16,17

Narcotics and other drugs known to slow gut motility should be avoided.

Symptoms typically improve after restoration of normal body weight. If conservative treatment fails, or if the case is severe or chronic, surgery is required.¹⁸ Fortunately, this is not required often.

Duodenojejunostomy is the most common surgical treatment and involves creation of an alternate route between the duodenum and the jejunum, bypassing the compression between the aorta and the SMA. Other procedures include gastrojejunostomy, laparoscopic duodenojejunostomy, ¹⁹ a Roux-en-Y procedure, robotically assisted duodenojejunostomy, and anterior transposition of the third portion of the duodenum. Cleavage of the ligament of Treitz is another option, enabling the duodenum to drop away from the apex of the sharpened aortomesenteric angle.

WHEN TO CONSIDER SMA SYNDROME

The SMA syndrome is an uncommon cause of a very common presenting symptom, ie, abdominal pain. Nevertheless, it should be considered in the differential diagnosis of abdominal pain, especially in patients who have conditions that cause significant weight loss, such as anorexia nervosa, malabsorption, or hypercatabolic states such as burns, major surgery, severe injuries, or malignancies. The diagnosis is based on a thorough history and on supportive findings from CT and endoscopy.

In our patient, weight loss began with nonspecific diarrhea but perpetuated itself as SMA syndrome occurred.

Appropriate management consists of interrupting the cycle of weight loss and secondary upper gut obstruction. For patients in whom more definitive therapy is not feasible, a gastrostomy tube for decompression with a jejunal extension available for feeding appears to be a reasonable and safe treatment option. Duodenojejunostomy is considered the procedure of choice in severe cases.

CASE CONCLUDED

Fortunately, our patient responded well to conservative management. She was treated with intravenous hydration and correction of electrolytes and 10 days later was able to tolerate a soft diet. She was discharged in stable condition. At a follow-up visit 2 weeks later, she reported minimal abdominal discomfort, was able to tolerate meals, and had gained a few pounds. She continues to do well.

Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders of blood cell production in the bone marrow that can transform into acute myeloid leukemia (AML).^1,2 They are diagnosed most often in the elderly.

Primary care physicians and geriatricians tend to be the first to identify the problem, as they recognize that cytopenias are not simply a normal consequence of aging.

MDS are considered to be cancers, akin to chronic leukemia or acute leukemia, with epidemiologic data tracked by national cancer registries and the US Centers for Disease Control and Prevention, under the auspices of the Surveillance, Epidemiology, and End Results (SEER) program.³

In this article, we briefly review the classification of MDS, current epidemiologic data, key diagnostic features, and current management options.

WHEN TO SUSPECT MDS

In many patients, MDS are asymptomatic and appear as an abnormality on a routine complete blood cell count (CBC) or as part of a workup for anemia. Symptoms develop as the bone marrow’s ability to produce normal-functioning blood cells is more and more compromised. The range of symptoms depends on the bone marrow cell type affected.

Patients with MDS typically have some degree of anemia, often detected incidentally on a routine CBC, or they have symptoms stemming from anemia or thrombocytopenia, or have recurrent infections.

Subtypes of MDS have different pathologic and clinical presentations and different prognoses. They are often categorized as lower-risk or higher-risk, depending on the likelihood of transforming to AML. Patients with lower-risk MDS survive a median of 3 to 7 years. Higher-risk types are pathobiologically similar to AML in older adults, and patients either develop AML or die of complications of MDS, on average within 1.5 years.

Several classification schemes and prognostic models guide the selection of the most appropriate therapy.

Older age and comorbidities such as coronary artery disease, chronic obstructive pulmonary disease, and chronic kidney disease make MDS more difficult to manage and worsen the prognosis.⁴

MOST PATIENTS ARE OLDER

Only since 2001, when MDS became reportable to SEER,^3,5 has the epidemiology of MDS been reported in the United States.

MDS are currently diagnosed in an estimated 3.4 per 100,000 US citizens yearly.

The incidence rate increased from 3.28 per 100,000 per year in 2001 to 3.56 per 100,000 in 2004.⁵ The increase has been attributed to enhanced awareness of the disease and to the aging of the population, with the number of people age 65 or older in the United States expected to double from the year 2000 to 2030. Another factor is that effective therapies are now available, possibly making hematologists and oncologists more likely to pursue the diagnosis.

These numbers translate to 10,000 to 15,000 new cases annually, and given the life expectancy of patients affected by this disease (and the life-extending treatments for it), an estimated 30,000 to 60,000 Americans living with MDS.^6,7

Even though MDS can occur at any age, most patients are older. The median age at diagnosis is 71 years,^3,5,8 and 72% of patients are age 70 or older.³ The prevalence increases with age, to a rate of 36 per 100,000 in those age 80 and older.⁹ However, in areas of East Asia, it occurs at ages almost 2 decades younger than in the rest of the world.⁵

MDS are more common in men than in women and in whites than in blacks. Smoking appears to increase the risk, but alcohol consumption does not.¹⁰

About 10% of cases of MDS are secondary, most often due to radiation treatment or chemotherapy (particularly with alkylating agents and topoisomerase inhibitors) for cancer. The time from treatment of a primary malignancy (most often prostate, breast, bladder, lung, or non-Hodgkin lymphoma) to the development of MDS is about 5 years.⁵ A small number of cases are due to occupational exposure to radiation or benzene or other organic solvents, as might occur in the rubber industry (see below). Secondary MDS have a worse prognosis than primary (de novo) MDS.

GENETIC AND ENVIRONMENTAL FACTORS

The cause of de novo MDS is not known. Genetic and environmental factors probably both play a role. The lower median age at diagnosis in Eastern countries such as Japan than in the United States suggests that environmental factors¹¹ such as smoking, ionizing radiation, and benzene exposure play a role.^12,13 Some epidemiologic evidence suggests a higher incidence of MDS after exposure to solvents, hair dyes, and pesticides.¹³

Congenital conditions such as Down syndrome, Fanconi anemia, and Bloom syndrome are associated with MDS. Those affected usually present at an earlier age,¹³ suggesting a “multiple-hit” mechanism of cancer development with genetic and environmental factors. MDS rarely run in families.

SYMPTOMS ARE OFTEN NONSPECIFIC

Symptoms of MDS are often vague and nonspecific, and the diagnosis is often made during a workup for anemia, thrombocytopenia, or neutropenia discovered on a CBC. If present, signs and symptoms depend on the blood and bone marrow cell types that are affected.

When erythrocytes are affected (the most common situation), patients present with signs of anemia, including pallor, pale conjunctiva, tachycardia, hypotension, fatigue, headache, and exercise intolerance, or with signs and symptoms of a worsening underlying condition such as angina pectoris, heart failure, or emphysema.

When platelets or neutrophils are affected. Fewer than 20% of patients present with symptoms of isolated thrombocytopenia such as minor bleeding (eg, mucosal bleeding, petechiae, easy bruising, epistaxis) or major bleeding (eg, gastrointestinal bleeding, intracranial hemorrhage) or of isolated neutropenia (eg, fatigue, frequent bacterial infections of different organs systems).

Splenomegaly and lymphadenopathy are uncommon in MDS and, if detected, should raise suspicion of a myeloproliferative or lymphoproliferative neoplasm.

LABORATORY TESTS NEEDED

Complete blood cell count

Once the common causes of patient’s symptoms are evaluated, a CBC is needed to look for a hematologic cause. If a patient is ultimately determined to have MDS, anemia is the most common finding on the CBC: about 80% of patients with MDS are anemic at presentation. ⁶

Anemia associated with MDS can be microcytic, normocytic, or, most commonly, macrocytic. ¹⁴ Thrombocytopenia and neutropenia can be solitary or associated with anemia, and they are seen in about 40% of patients at the time of diagnosis.⁶ As the disease progresses, the degree of cytopenia worsens and, in most cases, preserved cell lineages are eventually affected.

Once cytopenia is discovered, a workup for the cause is needed. We emphasize a workup first for anemia, as it is the most common form of cytopenia in MDS. A workup for isolated thrombocytopenia or neutropenia usually requires a bone marrow examination earlier in the course, and we will discuss it only briefly here. Multilineage cytopenia almost always suggests abnormal bone marrow function and can be the basis for referral to a hematologist or oncologist.

Evaluation of anemia

If anemia is detected, it is reasonable to look for nonhematologic causes such as gastrointestinal bleeding, a cardiac cause, or a nutritional deficiency.

Anemia has a variety of possible hematologic causes, as shown in a study in the United States.¹⁵ When blood samples were collected from more than 2,000 people age 65 and older, 10.6% were found to have anemia, categorized as follows:

• Nutrient-deficiency anemia, related to low levels of vitamin B₁₂, folate, or more commonly iron
• Anemia of chronic inflammation (formerly anemia of chronic disease, associated with a major medical disorder)
• Unexplained anemia (of those with unexplained anemia, 17.4% had blood findings compatible with MDS).¹⁵

• Tests for nutrient deficiencies such as iron, vitamin B₁₂, and folate levels. Subsequent tests can include assessment for copper deficiencies. Vitamin B₁₂ and copper deficiency can mimic MDS.
• Fecal occult blood testing, and, if positive, further evaluation for a source of gastrointestinal bleeding.
• Liver function tests, renal function tests, and tests for endocrine disorders, such as thyroid function tests.
• Review of drugs that can cause megaloblastoid erythropoiesis, such as methotrexate (Trexall), valproic acid (Depakote), phenytoin (Dilantin), phenobarbital (Luminal), sulfasalazine (Sulfazine), and zidovudine (Retrovir).
• Assesment of the responsiveness of the bone marrow to anemia, via a reticulocyte count or an erythropoietin level, or both, prior to any blood transfusion.
• Screening for relevant infections, including human immunodeficiency virus (HIV), hepatitis, or, in rare cases, parvovirus.
• Screening for lifestyle factors that may result in bone marrow suppression, such as excessive alcohol intake.

Evaluation of other cytopenias

In cases of isolated thrombocytopenia or combined bicytopenia (eg, anemia and thrombocytopenia), abdominal ultrasonography should be done to evaluate for splenomegaly.

Blood tests to evaluate for immune-mediated cytopenias, including idiopathic thrombocytopenic purpura and hemolytic anemia, include the direct and indirect Coombs antiglobulin tests, the lactate dehydrogenase level, the reticulocyte count, and the haptoglobin level. Other immune-mediated causes of cytopenia include connective tissue disorders and vasculitides, and an antinuclear antibody titer and rheumatoid factor level can also be considered.

Referral if tests are negative

If all these tests are negative, the next step is referral to a hematologist-oncologist for further workup, which may include a review of the peripheral blood smear; bone marrow aspiration and biopsy for evaluation of iron stores and bone marrow cellularity; and specialized tests such as assessment of antiplatelet antibodies, protein electrophoresis, or fluorescence in situ hybridization to evaluate for specific clonal disorders. The purpose of bone marrow aspiration and biopsy in MDS is to evaluate the morphology of the bone marrow and the patient’s cytogenetic profile. Each has its prognostic and therapeutic implications.

SCORING SYSTEMS FOR MDS, RATHER THAN STAGING SYSTEMS

The purpose of classification systems for any medical condition is to uniformly evaluate and group patients with a disease subtype to compare patient populations similarly throughout the world, to predict prognosis, and to dictate therapeutic directions.

MDS have two main classification systems, the FAB (French-American-British) and the WHO (World Health Organization). Revised in 2008,¹⁶ the WHO classification (Table 2, not available online)¹⁷ is widely accepted because it incorporates morphologic and cytogenetic factors and correlates with prognosis.¹⁸ The categories are distinguished by specific characteristics of peripheral blood and bone marrow.

Unlike many other cancers, MDS are not “staged.” Rather, prognostic systems have been devised to predict the risk of transformation to AML and to predict overall survival. These systems are based on:

• The number of myeloblasts in the bone marrow (the higher the count, the worse the prognosis)
• The number or degree of cytopenias
• Cytogenetic abnormalities (acquired genetic abnormalities in the neoplastic clone), found in about half of patients with MDS.¹⁹

The most widely used prognostic systems are the International Prognostic Scoring System (Table 3, not available online)² and the WPSS (WHO Classification-based Prognostic Scoring System¹). The latter system encorporates transfusion burden.

 

 

SUPPORTIVE CARE

Supportive care includes transfusion of blood products to minimize complications of cytopenias and to improve quality of life, as well as antibiotics to treat active infections.

Transfusions

Almost all patients with MDS need red cell transfusions at some point, while fewer need platelets. The frequency of transfusion depends on the extent of the disease and on comorbidities.

Red blood cells typically are given when the hemoglobin level falls below 8.5 g/dL, and platelets are given when the platelet count is below 100 × 10⁹/L, in the absence of symptoms. Patients with symptomatic anemia should receive transfusion to relieve their symptoms. Some patients need transfusions occasionally, while others are transfusion-dependent.

Iron chelation

Blood product transfusions can lead to iron overload, particularly with a lifetime administration of more than 20 units, or with a year of continuous transfusions, and this is associated with diminished survival.²⁰

However, considering the short survival of patients with MDS, the benefit of iron chelation is debatable. This intervention should be reserved for patients with lower-risk disease who are expected to survive more than 1 year and who have received more than 25 units of packed red blood cells.²¹

Antibiotics

Neutropenia is defined as an absolute neutrophil count less than 1.5 × 10⁹/L. The risk of infection, particularly bacterial infection, is significantly increased when the neutrophil count is below 0.5 × 10⁹/L. Fever (temperature > 100.4°F or 38.0°C) in neutropenic patients is an emergency, requiring hospitalization and immediate initiation of broad-spectrum antibiotics along with a workup for the cause of the fever.²² Prophylactic antibiotics have no proven role in MDS patients with neutropenia.

TREATMENT OF LOWER-RISK DISEASE

Erythropoiesis-stimulating agents

Once a patient starts to require red blood cell transfusions, an erythropoiesis-stimulating agent (EPA) can be considered.^23,24 These include recombinant agents such as erythropoietin (Procrit) and darbepoetin alfa (Aranesp).

Response is measured as an improvement in hemoglobin or as independence from transfusions in those previously dependent on them. Patients most likely to respond are those whose pretransfusion erythropoietin level is below 100 IU/L and who have minimal transfusion needs.^25,26 Addition of a colony-stimulating factor can be considered for patients with neutropenia. On average, about 40% of patients ultimately respond to an EPA, but those who respond eventually develop resistance to the agent. Retrospective data indicate that use of EPAs may improve survival in MDS.^23,24

The recommended threshold hemoglobin level for starting an EPA is less than 10 g/dL. Patients need to be monitored with a CBC every time they receive treatment. The agent should be stopped once the hemoglobin level reaches 12 g/dL. A number of studies have shown lower survival rates when ESAs are used in nonhematologic malignancies, particularly if the malignancy is advanced and when the ESA is used to achieve a goal hemoglobin above 12 g/dL. There are no data to suggest a higher death rate in patients with hematologic malignancies who take ESAs. The use of ESAs in MDS patients should be judicious, however, and titrated to a goal hemoglobin level no higher than 12 g/dL.²⁷

Other treatments

If ESA treatment is ineffective, other treatments may be considered, usually initiated by a hematologist or medical oncologist.

Immunosuppressive therapy with antithymocyte globulin (Thymoglobulin)²⁸ is an option for patients with hypocellular or immune-mediated MDS. This treatment may decrease the need for transfusion and may improve the blood count.

Lenalidomide (Revlimid) for MDS with isolated chromosome 5q deletion²⁹ can decrease the need for blood transfusion in approximately two-thirds of these patients.

Azacitidine (Vidaza) or decitabine (Dacogen), in patients with more advanced subtypes of MDS (eg, those with excess blasts) or with pancytopenia unresponsive to other therapies, can induce hematologic improvement and decrease transfusion dependence, as well as prolong survival.

Stem cell transplantation, for patients with more advanced subtypes of MDS and who have an appropriately matched donor, has the potential of being curative.

Experimental treatments are available in clinical trials.

TREATMENT OF HIGHER-RISK DISEASE

About 25% of patients with newly diagnosed MDS and 15% to 20% of patients with established MDS have higher-risk disease.³⁰ These patients should almost always be followed by a hematologist or medical oncologist, with therapy initiated immediately, regardless of blood counts, given the high likelihood of transformation to AML or death within 1.5 years.

The treatment options for higher-risk disease include:

• Methyltransferase inhibitors such as azacitidine and decitabine^31–34
• Cytotoxic chemotherapy (similar to treatment of acute myeloid leukemia)
• Bone marrow-hematopoeitic stem cell transplantation^35,36
• Experimental treatments in clinical trials.

As mentioned earlier, outside of transplantation, only azacitidine has been shown to improve overall survival (with a doubling of survival at 2 years, to 50%), and no drug therapy is curative. Managing patient expectations for treatment outcome is thus crucial in higher-risk disease, and ongoing assessments of quality of life, both on or off therapy, should be considered obligatory.

Stem cell transplantation cures MDS

MDS are complex and heterogeneous, so treatment options range from supportive care to chemotherapy and allogeneic stem cell transplantation.⁶ The choice depends on the severity of disease, ie, lower-risk or higherrisk (Table 3, not available online), as well as on the prognosis, the availability of therapeutic options, and the patient’s expectations.

Hematopoietic stem cell transplantation is the only curative treatment for MDS. However, it is performed in fewer than 5% of patients,³⁰ usually younger patients with few comorbidities, because the rate of transplantrelated death is high. Therefore, most treatments are palliative, aimed at improving the quality of life and prolonging survival.

The balance between risks and benefits of these treatments must be justifiable.³⁰ Further, patients who have no symptoms or who have lower-risk disease need no treatment and may not for years. However, they do need close follow-up, because their symptoms will worsen and will eventually require treatment.

TAKE-HOME POINTS

• Myelodysplastic syndromes are more prevalent than previously realized. Mainly a disease of older adults, they should be suspected in any patient with unexplained cytopenia.
• Life expectancy at the time of diagnosis depends on the types of cells affected.
• Supportive and disease-altering options are available.
• Prompt referral to a hematologist or oncologist is important for confirmation of the diagnosis and initiation of an appropriate treatment plan. Patients with lower-risk disease can continue follow-up with their primary care provider once treatment goals and plans are established.

ACKNOWLEDGMENT

We thank Dr. Karl Theil of the Cleveland Clinic Department of Clinical Pathology for the photomicrographs used on the cover.

Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders of blood cell production in the bone marrow that can transform into acute myeloid leukemia (AML).^1,2 They are diagnosed most often in the elderly.

Primary care physicians and geriatricians tend to be the first to identify the problem, as they recognize that cytopenias are not simply a normal consequence of aging.

MDS are considered to be cancers, akin to chronic leukemia or acute leukemia, with epidemiologic data tracked by national cancer registries and the US Centers for Disease Control and Prevention, under the auspices of the Surveillance, Epidemiology, and End Results (SEER) program.³

In this article, we briefly review the classification of MDS, current epidemiologic data, key diagnostic features, and current management options.

WHEN TO SUSPECT MDS

In many patients, MDS are asymptomatic and appear as an abnormality on a routine complete blood cell count (CBC) or as part of a workup for anemia. Symptoms develop as the bone marrow’s ability to produce normal-functioning blood cells is more and more compromised. The range of symptoms depends on the bone marrow cell type affected.

Patients with MDS typically have some degree of anemia, often detected incidentally on a routine CBC, or they have symptoms stemming from anemia or thrombocytopenia, or have recurrent infections.

Subtypes of MDS have different pathologic and clinical presentations and different prognoses. They are often categorized as lower-risk or higher-risk, depending on the likelihood of transforming to AML. Patients with lower-risk MDS survive a median of 3 to 7 years. Higher-risk types are pathobiologically similar to AML in older adults, and patients either develop AML or die of complications of MDS, on average within 1.5 years.

Several classification schemes and prognostic models guide the selection of the most appropriate therapy.

Older age and comorbidities such as coronary artery disease, chronic obstructive pulmonary disease, and chronic kidney disease make MDS more difficult to manage and worsen the prognosis.⁴

MOST PATIENTS ARE OLDER

Only since 2001, when MDS became reportable to SEER,^3,5 has the epidemiology of MDS been reported in the United States.

MDS are currently diagnosed in an estimated 3.4 per 100,000 US citizens yearly.

The incidence rate increased from 3.28 per 100,000 per year in 2001 to 3.56 per 100,000 in 2004.⁵ The increase has been attributed to enhanced awareness of the disease and to the aging of the population, with the number of people age 65 or older in the United States expected to double from the year 2000 to 2030. Another factor is that effective therapies are now available, possibly making hematologists and oncologists more likely to pursue the diagnosis.

These numbers translate to 10,000 to 15,000 new cases annually, and given the life expectancy of patients affected by this disease (and the life-extending treatments for it), an estimated 30,000 to 60,000 Americans living with MDS.^6,7

Even though MDS can occur at any age, most patients are older. The median age at diagnosis is 71 years,^3,5,8 and 72% of patients are age 70 or older.³ The prevalence increases with age, to a rate of 36 per 100,000 in those age 80 and older.⁹ However, in areas of East Asia, it occurs at ages almost 2 decades younger than in the rest of the world.⁵

MDS are more common in men than in women and in whites than in blacks. Smoking appears to increase the risk, but alcohol consumption does not.¹⁰

About 10% of cases of MDS are secondary, most often due to radiation treatment or chemotherapy (particularly with alkylating agents and topoisomerase inhibitors) for cancer. The time from treatment of a primary malignancy (most often prostate, breast, bladder, lung, or non-Hodgkin lymphoma) to the development of MDS is about 5 years.⁵ A small number of cases are due to occupational exposure to radiation or benzene or other organic solvents, as might occur in the rubber industry (see below). Secondary MDS have a worse prognosis than primary (de novo) MDS.

GENETIC AND ENVIRONMENTAL FACTORS

The cause of de novo MDS is not known. Genetic and environmental factors probably both play a role. The lower median age at diagnosis in Eastern countries such as Japan than in the United States suggests that environmental factors¹¹ such as smoking, ionizing radiation, and benzene exposure play a role.^12,13 Some epidemiologic evidence suggests a higher incidence of MDS after exposure to solvents, hair dyes, and pesticides.¹³

Congenital conditions such as Down syndrome, Fanconi anemia, and Bloom syndrome are associated with MDS. Those affected usually present at an earlier age,¹³ suggesting a “multiple-hit” mechanism of cancer development with genetic and environmental factors. MDS rarely run in families.

SYMPTOMS ARE OFTEN NONSPECIFIC

Symptoms of MDS are often vague and nonspecific, and the diagnosis is often made during a workup for anemia, thrombocytopenia, or neutropenia discovered on a CBC. If present, signs and symptoms depend on the blood and bone marrow cell types that are affected.

When erythrocytes are affected (the most common situation), patients present with signs of anemia, including pallor, pale conjunctiva, tachycardia, hypotension, fatigue, headache, and exercise intolerance, or with signs and symptoms of a worsening underlying condition such as angina pectoris, heart failure, or emphysema.

When platelets or neutrophils are affected. Fewer than 20% of patients present with symptoms of isolated thrombocytopenia such as minor bleeding (eg, mucosal bleeding, petechiae, easy bruising, epistaxis) or major bleeding (eg, gastrointestinal bleeding, intracranial hemorrhage) or of isolated neutropenia (eg, fatigue, frequent bacterial infections of different organs systems).

Splenomegaly and lymphadenopathy are uncommon in MDS and, if detected, should raise suspicion of a myeloproliferative or lymphoproliferative neoplasm.

LABORATORY TESTS NEEDED

Complete blood cell count

Once the common causes of patient’s symptoms are evaluated, a CBC is needed to look for a hematologic cause. If a patient is ultimately determined to have MDS, anemia is the most common finding on the CBC: about 80% of patients with MDS are anemic at presentation. ⁶

Anemia associated with MDS can be microcytic, normocytic, or, most commonly, macrocytic. ¹⁴ Thrombocytopenia and neutropenia can be solitary or associated with anemia, and they are seen in about 40% of patients at the time of diagnosis.⁶ As the disease progresses, the degree of cytopenia worsens and, in most cases, preserved cell lineages are eventually affected.

Once cytopenia is discovered, a workup for the cause is needed. We emphasize a workup first for anemia, as it is the most common form of cytopenia in MDS. A workup for isolated thrombocytopenia or neutropenia usually requires a bone marrow examination earlier in the course, and we will discuss it only briefly here. Multilineage cytopenia almost always suggests abnormal bone marrow function and can be the basis for referral to a hematologist or oncologist.

Evaluation of anemia

If anemia is detected, it is reasonable to look for nonhematologic causes such as gastrointestinal bleeding, a cardiac cause, or a nutritional deficiency.

Anemia has a variety of possible hematologic causes, as shown in a study in the United States.¹⁵ When blood samples were collected from more than 2,000 people age 65 and older, 10.6% were found to have anemia, categorized as follows:

• Nutrient-deficiency anemia, related to low levels of vitamin B₁₂, folate, or more commonly iron
• Anemia of chronic inflammation (formerly anemia of chronic disease, associated with a major medical disorder)
• Unexplained anemia (of those with unexplained anemia, 17.4% had blood findings compatible with MDS).¹⁵

• Tests for nutrient deficiencies such as iron, vitamin B₁₂, and folate levels. Subsequent tests can include assessment for copper deficiencies. Vitamin B₁₂ and copper deficiency can mimic MDS.
• Fecal occult blood testing, and, if positive, further evaluation for a source of gastrointestinal bleeding.
• Liver function tests, renal function tests, and tests for endocrine disorders, such as thyroid function tests.
• Review of drugs that can cause megaloblastoid erythropoiesis, such as methotrexate (Trexall), valproic acid (Depakote), phenytoin (Dilantin), phenobarbital (Luminal), sulfasalazine (Sulfazine), and zidovudine (Retrovir).
• Assesment of the responsiveness of the bone marrow to anemia, via a reticulocyte count or an erythropoietin level, or both, prior to any blood transfusion.
• Screening for relevant infections, including human immunodeficiency virus (HIV), hepatitis, or, in rare cases, parvovirus.
• Screening for lifestyle factors that may result in bone marrow suppression, such as excessive alcohol intake.

Evaluation of other cytopenias

In cases of isolated thrombocytopenia or combined bicytopenia (eg, anemia and thrombocytopenia), abdominal ultrasonography should be done to evaluate for splenomegaly.

Blood tests to evaluate for immune-mediated cytopenias, including idiopathic thrombocytopenic purpura and hemolytic anemia, include the direct and indirect Coombs antiglobulin tests, the lactate dehydrogenase level, the reticulocyte count, and the haptoglobin level. Other immune-mediated causes of cytopenia include connective tissue disorders and vasculitides, and an antinuclear antibody titer and rheumatoid factor level can also be considered.

Referral if tests are negative

If all these tests are negative, the next step is referral to a hematologist-oncologist for further workup, which may include a review of the peripheral blood smear; bone marrow aspiration and biopsy for evaluation of iron stores and bone marrow cellularity; and specialized tests such as assessment of antiplatelet antibodies, protein electrophoresis, or fluorescence in situ hybridization to evaluate for specific clonal disorders. The purpose of bone marrow aspiration and biopsy in MDS is to evaluate the morphology of the bone marrow and the patient’s cytogenetic profile. Each has its prognostic and therapeutic implications.

SCORING SYSTEMS FOR MDS, RATHER THAN STAGING SYSTEMS

The purpose of classification systems for any medical condition is to uniformly evaluate and group patients with a disease subtype to compare patient populations similarly throughout the world, to predict prognosis, and to dictate therapeutic directions.

MDS have two main classification systems, the FAB (French-American-British) and the WHO (World Health Organization). Revised in 2008,¹⁶ the WHO classification (Table 2, not available online)¹⁷ is widely accepted because it incorporates morphologic and cytogenetic factors and correlates with prognosis.¹⁸ The categories are distinguished by specific characteristics of peripheral blood and bone marrow.

Unlike many other cancers, MDS are not “staged.” Rather, prognostic systems have been devised to predict the risk of transformation to AML and to predict overall survival. These systems are based on:

• The number of myeloblasts in the bone marrow (the higher the count, the worse the prognosis)
• The number or degree of cytopenias
• Cytogenetic abnormalities (acquired genetic abnormalities in the neoplastic clone), found in about half of patients with MDS.¹⁹

The most widely used prognostic systems are the International Prognostic Scoring System (Table 3, not available online)² and the WPSS (WHO Classification-based Prognostic Scoring System¹). The latter system encorporates transfusion burden.

 

 

SUPPORTIVE CARE

Supportive care includes transfusion of blood products to minimize complications of cytopenias and to improve quality of life, as well as antibiotics to treat active infections.

Transfusions

Almost all patients with MDS need red cell transfusions at some point, while fewer need platelets. The frequency of transfusion depends on the extent of the disease and on comorbidities.

Red blood cells typically are given when the hemoglobin level falls below 8.5 g/dL, and platelets are given when the platelet count is below 100 × 10⁹/L, in the absence of symptoms. Patients with symptomatic anemia should receive transfusion to relieve their symptoms. Some patients need transfusions occasionally, while others are transfusion-dependent.

Iron chelation

Blood product transfusions can lead to iron overload, particularly with a lifetime administration of more than 20 units, or with a year of continuous transfusions, and this is associated with diminished survival.²⁰

However, considering the short survival of patients with MDS, the benefit of iron chelation is debatable. This intervention should be reserved for patients with lower-risk disease who are expected to survive more than 1 year and who have received more than 25 units of packed red blood cells.²¹

Antibiotics

Neutropenia is defined as an absolute neutrophil count less than 1.5 × 10⁹/L. The risk of infection, particularly bacterial infection, is significantly increased when the neutrophil count is below 0.5 × 10⁹/L. Fever (temperature > 100.4°F or 38.0°C) in neutropenic patients is an emergency, requiring hospitalization and immediate initiation of broad-spectrum antibiotics along with a workup for the cause of the fever.²² Prophylactic antibiotics have no proven role in MDS patients with neutropenia.

TREATMENT OF LOWER-RISK DISEASE

Erythropoiesis-stimulating agents

Once a patient starts to require red blood cell transfusions, an erythropoiesis-stimulating agent (EPA) can be considered.^23,24 These include recombinant agents such as erythropoietin (Procrit) and darbepoetin alfa (Aranesp).

Response is measured as an improvement in hemoglobin or as independence from transfusions in those previously dependent on them. Patients most likely to respond are those whose pretransfusion erythropoietin level is below 100 IU/L and who have minimal transfusion needs.^25,26 Addition of a colony-stimulating factor can be considered for patients with neutropenia. On average, about 40% of patients ultimately respond to an EPA, but those who respond eventually develop resistance to the agent. Retrospective data indicate that use of EPAs may improve survival in MDS.^23,24

The recommended threshold hemoglobin level for starting an EPA is less than 10 g/dL. Patients need to be monitored with a CBC every time they receive treatment. The agent should be stopped once the hemoglobin level reaches 12 g/dL. A number of studies have shown lower survival rates when ESAs are used in nonhematologic malignancies, particularly if the malignancy is advanced and when the ESA is used to achieve a goal hemoglobin above 12 g/dL. There are no data to suggest a higher death rate in patients with hematologic malignancies who take ESAs. The use of ESAs in MDS patients should be judicious, however, and titrated to a goal hemoglobin level no higher than 12 g/dL.²⁷

Other treatments

If ESA treatment is ineffective, other treatments may be considered, usually initiated by a hematologist or medical oncologist.

Immunosuppressive therapy with antithymocyte globulin (Thymoglobulin)²⁸ is an option for patients with hypocellular or immune-mediated MDS. This treatment may decrease the need for transfusion and may improve the blood count.

Lenalidomide (Revlimid) for MDS with isolated chromosome 5q deletion²⁹ can decrease the need for blood transfusion in approximately two-thirds of these patients.

Azacitidine (Vidaza) or decitabine (Dacogen), in patients with more advanced subtypes of MDS (eg, those with excess blasts) or with pancytopenia unresponsive to other therapies, can induce hematologic improvement and decrease transfusion dependence, as well as prolong survival.

Stem cell transplantation, for patients with more advanced subtypes of MDS and who have an appropriately matched donor, has the potential of being curative.

Experimental treatments are available in clinical trials.

TREATMENT OF HIGHER-RISK DISEASE

About 25% of patients with newly diagnosed MDS and 15% to 20% of patients with established MDS have higher-risk disease.³⁰ These patients should almost always be followed by a hematologist or medical oncologist, with therapy initiated immediately, regardless of blood counts, given the high likelihood of transformation to AML or death within 1.5 years.

The treatment options for higher-risk disease include:

• Methyltransferase inhibitors such as azacitidine and decitabine^31–34
• Cytotoxic chemotherapy (similar to treatment of acute myeloid leukemia)
• Bone marrow-hematopoeitic stem cell transplantation^35,36
• Experimental treatments in clinical trials.

As mentioned earlier, outside of transplantation, only azacitidine has been shown to improve overall survival (with a doubling of survival at 2 years, to 50%), and no drug therapy is curative. Managing patient expectations for treatment outcome is thus crucial in higher-risk disease, and ongoing assessments of quality of life, both on or off therapy, should be considered obligatory.

Stem cell transplantation cures MDS

MDS are complex and heterogeneous, so treatment options range from supportive care to chemotherapy and allogeneic stem cell transplantation.⁶ The choice depends on the severity of disease, ie, lower-risk or higherrisk (Table 3, not available online), as well as on the prognosis, the availability of therapeutic options, and the patient’s expectations.

Hematopoietic stem cell transplantation is the only curative treatment for MDS. However, it is performed in fewer than 5% of patients,³⁰ usually younger patients with few comorbidities, because the rate of transplantrelated death is high. Therefore, most treatments are palliative, aimed at improving the quality of life and prolonging survival.

The balance between risks and benefits of these treatments must be justifiable.³⁰ Further, patients who have no symptoms or who have lower-risk disease need no treatment and may not for years. However, they do need close follow-up, because their symptoms will worsen and will eventually require treatment.

TAKE-HOME POINTS

• Myelodysplastic syndromes are more prevalent than previously realized. Mainly a disease of older adults, they should be suspected in any patient with unexplained cytopenia.
• Life expectancy at the time of diagnosis depends on the types of cells affected.
• Supportive and disease-altering options are available.
• Prompt referral to a hematologist or oncologist is important for confirmation of the diagnosis and initiation of an appropriate treatment plan. Patients with lower-risk disease can continue follow-up with their primary care provider once treatment goals and plans are established.

ACKNOWLEDGMENT

We thank Dr. Karl Theil of the Cleveland Clinic Department of Clinical Pathology for the photomicrographs used on the cover.

Myelodysplastic syndromes (MDS) are a heterogeneous group of disorders of blood cell production in the bone marrow that can transform into acute myeloid leukemia (AML).^1,2 They are diagnosed most often in the elderly.

Primary care physicians and geriatricians tend to be the first to identify the problem, as they recognize that cytopenias are not simply a normal consequence of aging.

MDS are considered to be cancers, akin to chronic leukemia or acute leukemia, with epidemiologic data tracked by national cancer registries and the US Centers for Disease Control and Prevention, under the auspices of the Surveillance, Epidemiology, and End Results (SEER) program.³

In this article, we briefly review the classification of MDS, current epidemiologic data, key diagnostic features, and current management options.

WHEN TO SUSPECT MDS

In many patients, MDS are asymptomatic and appear as an abnormality on a routine complete blood cell count (CBC) or as part of a workup for anemia. Symptoms develop as the bone marrow’s ability to produce normal-functioning blood cells is more and more compromised. The range of symptoms depends on the bone marrow cell type affected.

Patients with MDS typically have some degree of anemia, often detected incidentally on a routine CBC, or they have symptoms stemming from anemia or thrombocytopenia, or have recurrent infections.

Subtypes of MDS have different pathologic and clinical presentations and different prognoses. They are often categorized as lower-risk or higher-risk, depending on the likelihood of transforming to AML. Patients with lower-risk MDS survive a median of 3 to 7 years. Higher-risk types are pathobiologically similar to AML in older adults, and patients either develop AML or die of complications of MDS, on average within 1.5 years.

Several classification schemes and prognostic models guide the selection of the most appropriate therapy.

Older age and comorbidities such as coronary artery disease, chronic obstructive pulmonary disease, and chronic kidney disease make MDS more difficult to manage and worsen the prognosis.⁴

MOST PATIENTS ARE OLDER

Only since 2001, when MDS became reportable to SEER,^3,5 has the epidemiology of MDS been reported in the United States.

MDS are currently diagnosed in an estimated 3.4 per 100,000 US citizens yearly.

The incidence rate increased from 3.28 per 100,000 per year in 2001 to 3.56 per 100,000 in 2004.⁵ The increase has been attributed to enhanced awareness of the disease and to the aging of the population, with the number of people age 65 or older in the United States expected to double from the year 2000 to 2030. Another factor is that effective therapies are now available, possibly making hematologists and oncologists more likely to pursue the diagnosis.

These numbers translate to 10,000 to 15,000 new cases annually, and given the life expectancy of patients affected by this disease (and the life-extending treatments for it), an estimated 30,000 to 60,000 Americans living with MDS.^6,7

Even though MDS can occur at any age, most patients are older. The median age at diagnosis is 71 years,^3,5,8 and 72% of patients are age 70 or older.³ The prevalence increases with age, to a rate of 36 per 100,000 in those age 80 and older.⁹ However, in areas of East Asia, it occurs at ages almost 2 decades younger than in the rest of the world.⁵

MDS are more common in men than in women and in whites than in blacks. Smoking appears to increase the risk, but alcohol consumption does not.¹⁰

About 10% of cases of MDS are secondary, most often due to radiation treatment or chemotherapy (particularly with alkylating agents and topoisomerase inhibitors) for cancer. The time from treatment of a primary malignancy (most often prostate, breast, bladder, lung, or non-Hodgkin lymphoma) to the development of MDS is about 5 years.⁵ A small number of cases are due to occupational exposure to radiation or benzene or other organic solvents, as might occur in the rubber industry (see below). Secondary MDS have a worse prognosis than primary (de novo) MDS.

GENETIC AND ENVIRONMENTAL FACTORS

The cause of de novo MDS is not known. Genetic and environmental factors probably both play a role. The lower median age at diagnosis in Eastern countries such as Japan than in the United States suggests that environmental factors¹¹ such as smoking, ionizing radiation, and benzene exposure play a role.^12,13 Some epidemiologic evidence suggests a higher incidence of MDS after exposure to solvents, hair dyes, and pesticides.¹³

Congenital conditions such as Down syndrome, Fanconi anemia, and Bloom syndrome are associated with MDS. Those affected usually present at an earlier age,¹³ suggesting a “multiple-hit” mechanism of cancer development with genetic and environmental factors. MDS rarely run in families.

SYMPTOMS ARE OFTEN NONSPECIFIC

Symptoms of MDS are often vague and nonspecific, and the diagnosis is often made during a workup for anemia, thrombocytopenia, or neutropenia discovered on a CBC. If present, signs and symptoms depend on the blood and bone marrow cell types that are affected.

When erythrocytes are affected (the most common situation), patients present with signs of anemia, including pallor, pale conjunctiva, tachycardia, hypotension, fatigue, headache, and exercise intolerance, or with signs and symptoms of a worsening underlying condition such as angina pectoris, heart failure, or emphysema.

When platelets or neutrophils are affected. Fewer than 20% of patients present with symptoms of isolated thrombocytopenia such as minor bleeding (eg, mucosal bleeding, petechiae, easy bruising, epistaxis) or major bleeding (eg, gastrointestinal bleeding, intracranial hemorrhage) or of isolated neutropenia (eg, fatigue, frequent bacterial infections of different organs systems).

Splenomegaly and lymphadenopathy are uncommon in MDS and, if detected, should raise suspicion of a myeloproliferative or lymphoproliferative neoplasm.

LABORATORY TESTS NEEDED

Complete blood cell count

Once the common causes of patient’s symptoms are evaluated, a CBC is needed to look for a hematologic cause. If a patient is ultimately determined to have MDS, anemia is the most common finding on the CBC: about 80% of patients with MDS are anemic at presentation. ⁶

Anemia associated with MDS can be microcytic, normocytic, or, most commonly, macrocytic. ¹⁴ Thrombocytopenia and neutropenia can be solitary or associated with anemia, and they are seen in about 40% of patients at the time of diagnosis.⁶ As the disease progresses, the degree of cytopenia worsens and, in most cases, preserved cell lineages are eventually affected.

Once cytopenia is discovered, a workup for the cause is needed. We emphasize a workup first for anemia, as it is the most common form of cytopenia in MDS. A workup for isolated thrombocytopenia or neutropenia usually requires a bone marrow examination earlier in the course, and we will discuss it only briefly here. Multilineage cytopenia almost always suggests abnormal bone marrow function and can be the basis for referral to a hematologist or oncologist.

Evaluation of anemia

If anemia is detected, it is reasonable to look for nonhematologic causes such as gastrointestinal bleeding, a cardiac cause, or a nutritional deficiency.

Anemia has a variety of possible hematologic causes, as shown in a study in the United States.¹⁵ When blood samples were collected from more than 2,000 people age 65 and older, 10.6% were found to have anemia, categorized as follows:

• Nutrient-deficiency anemia, related to low levels of vitamin B₁₂, folate, or more commonly iron
• Anemia of chronic inflammation (formerly anemia of chronic disease, associated with a major medical disorder)
• Unexplained anemia (of those with unexplained anemia, 17.4% had blood findings compatible with MDS).¹⁵

• Tests for nutrient deficiencies such as iron, vitamin B₁₂, and folate levels. Subsequent tests can include assessment for copper deficiencies. Vitamin B₁₂ and copper deficiency can mimic MDS.
• Fecal occult blood testing, and, if positive, further evaluation for a source of gastrointestinal bleeding.
• Liver function tests, renal function tests, and tests for endocrine disorders, such as thyroid function tests.
• Review of drugs that can cause megaloblastoid erythropoiesis, such as methotrexate (Trexall), valproic acid (Depakote), phenytoin (Dilantin), phenobarbital (Luminal), sulfasalazine (Sulfazine), and zidovudine (Retrovir).
• Assesment of the responsiveness of the bone marrow to anemia, via a reticulocyte count or an erythropoietin level, or both, prior to any blood transfusion.
• Screening for relevant infections, including human immunodeficiency virus (HIV), hepatitis, or, in rare cases, parvovirus.
• Screening for lifestyle factors that may result in bone marrow suppression, such as excessive alcohol intake.

Evaluation of other cytopenias

In cases of isolated thrombocytopenia or combined bicytopenia (eg, anemia and thrombocytopenia), abdominal ultrasonography should be done to evaluate for splenomegaly.

Blood tests to evaluate for immune-mediated cytopenias, including idiopathic thrombocytopenic purpura and hemolytic anemia, include the direct and indirect Coombs antiglobulin tests, the lactate dehydrogenase level, the reticulocyte count, and the haptoglobin level. Other immune-mediated causes of cytopenia include connective tissue disorders and vasculitides, and an antinuclear antibody titer and rheumatoid factor level can also be considered.

Referral if tests are negative

If all these tests are negative, the next step is referral to a hematologist-oncologist for further workup, which may include a review of the peripheral blood smear; bone marrow aspiration and biopsy for evaluation of iron stores and bone marrow cellularity; and specialized tests such as assessment of antiplatelet antibodies, protein electrophoresis, or fluorescence in situ hybridization to evaluate for specific clonal disorders. The purpose of bone marrow aspiration and biopsy in MDS is to evaluate the morphology of the bone marrow and the patient’s cytogenetic profile. Each has its prognostic and therapeutic implications.

SCORING SYSTEMS FOR MDS, RATHER THAN STAGING SYSTEMS

The purpose of classification systems for any medical condition is to uniformly evaluate and group patients with a disease subtype to compare patient populations similarly throughout the world, to predict prognosis, and to dictate therapeutic directions.

MDS have two main classification systems, the FAB (French-American-British) and the WHO (World Health Organization). Revised in 2008,¹⁶ the WHO classification (Table 2, not available online)¹⁷ is widely accepted because it incorporates morphologic and cytogenetic factors and correlates with prognosis.¹⁸ The categories are distinguished by specific characteristics of peripheral blood and bone marrow.

Unlike many other cancers, MDS are not “staged.” Rather, prognostic systems have been devised to predict the risk of transformation to AML and to predict overall survival. These systems are based on:

• The number of myeloblasts in the bone marrow (the higher the count, the worse the prognosis)
• The number or degree of cytopenias
• Cytogenetic abnormalities (acquired genetic abnormalities in the neoplastic clone), found in about half of patients with MDS.¹⁹

The most widely used prognostic systems are the International Prognostic Scoring System (Table 3, not available online)² and the WPSS (WHO Classification-based Prognostic Scoring System¹). The latter system encorporates transfusion burden.

 

 

SUPPORTIVE CARE

Supportive care includes transfusion of blood products to minimize complications of cytopenias and to improve quality of life, as well as antibiotics to treat active infections.

Transfusions

Almost all patients with MDS need red cell transfusions at some point, while fewer need platelets. The frequency of transfusion depends on the extent of the disease and on comorbidities.

Red blood cells typically are given when the hemoglobin level falls below 8.5 g/dL, and platelets are given when the platelet count is below 100 × 10⁹/L, in the absence of symptoms. Patients with symptomatic anemia should receive transfusion to relieve their symptoms. Some patients need transfusions occasionally, while others are transfusion-dependent.

Iron chelation

Blood product transfusions can lead to iron overload, particularly with a lifetime administration of more than 20 units, or with a year of continuous transfusions, and this is associated with diminished survival.²⁰

However, considering the short survival of patients with MDS, the benefit of iron chelation is debatable. This intervention should be reserved for patients with lower-risk disease who are expected to survive more than 1 year and who have received more than 25 units of packed red blood cells.²¹

Antibiotics

Neutropenia is defined as an absolute neutrophil count less than 1.5 × 10⁹/L. The risk of infection, particularly bacterial infection, is significantly increased when the neutrophil count is below 0.5 × 10⁹/L. Fever (temperature > 100.4°F or 38.0°C) in neutropenic patients is an emergency, requiring hospitalization and immediate initiation of broad-spectrum antibiotics along with a workup for the cause of the fever.²² Prophylactic antibiotics have no proven role in MDS patients with neutropenia.

TREATMENT OF LOWER-RISK DISEASE

Erythropoiesis-stimulating agents

Once a patient starts to require red blood cell transfusions, an erythropoiesis-stimulating agent (EPA) can be considered.^23,24 These include recombinant agents such as erythropoietin (Procrit) and darbepoetin alfa (Aranesp).

Response is measured as an improvement in hemoglobin or as independence from transfusions in those previously dependent on them. Patients most likely to respond are those whose pretransfusion erythropoietin level is below 100 IU/L and who have minimal transfusion needs.^25,26 Addition of a colony-stimulating factor can be considered for patients with neutropenia. On average, about 40% of patients ultimately respond to an EPA, but those who respond eventually develop resistance to the agent. Retrospective data indicate that use of EPAs may improve survival in MDS.^23,24

The recommended threshold hemoglobin level for starting an EPA is less than 10 g/dL. Patients need to be monitored with a CBC every time they receive treatment. The agent should be stopped once the hemoglobin level reaches 12 g/dL. A number of studies have shown lower survival rates when ESAs are used in nonhematologic malignancies, particularly if the malignancy is advanced and when the ESA is used to achieve a goal hemoglobin above 12 g/dL. There are no data to suggest a higher death rate in patients with hematologic malignancies who take ESAs. The use of ESAs in MDS patients should be judicious, however, and titrated to a goal hemoglobin level no higher than 12 g/dL.²⁷

Other treatments

If ESA treatment is ineffective, other treatments may be considered, usually initiated by a hematologist or medical oncologist.

Immunosuppressive therapy with antithymocyte globulin (Thymoglobulin)²⁸ is an option for patients with hypocellular or immune-mediated MDS. This treatment may decrease the need for transfusion and may improve the blood count.

Lenalidomide (Revlimid) for MDS with isolated chromosome 5q deletion²⁹ can decrease the need for blood transfusion in approximately two-thirds of these patients.

Azacitidine (Vidaza) or decitabine (Dacogen), in patients with more advanced subtypes of MDS (eg, those with excess blasts) or with pancytopenia unresponsive to other therapies, can induce hematologic improvement and decrease transfusion dependence, as well as prolong survival.

Stem cell transplantation, for patients with more advanced subtypes of MDS and who have an appropriately matched donor, has the potential of being curative.

Experimental treatments are available in clinical trials.

TREATMENT OF HIGHER-RISK DISEASE

About 25% of patients with newly diagnosed MDS and 15% to 20% of patients with established MDS have higher-risk disease.³⁰ These patients should almost always be followed by a hematologist or medical oncologist, with therapy initiated immediately, regardless of blood counts, given the high likelihood of transformation to AML or death within 1.5 years.

The treatment options for higher-risk disease include:

• Methyltransferase inhibitors such as azacitidine and decitabine^31–34
• Cytotoxic chemotherapy (similar to treatment of acute myeloid leukemia)
• Bone marrow-hematopoeitic stem cell transplantation^35,36
• Experimental treatments in clinical trials.

As mentioned earlier, outside of transplantation, only azacitidine has been shown to improve overall survival (with a doubling of survival at 2 years, to 50%), and no drug therapy is curative. Managing patient expectations for treatment outcome is thus crucial in higher-risk disease, and ongoing assessments of quality of life, both on or off therapy, should be considered obligatory.

Stem cell transplantation cures MDS

MDS are complex and heterogeneous, so treatment options range from supportive care to chemotherapy and allogeneic stem cell transplantation.⁶ The choice depends on the severity of disease, ie, lower-risk or higherrisk (Table 3, not available online), as well as on the prognosis, the availability of therapeutic options, and the patient’s expectations.

Hematopoietic stem cell transplantation is the only curative treatment for MDS. However, it is performed in fewer than 5% of patients,³⁰ usually younger patients with few comorbidities, because the rate of transplantrelated death is high. Therefore, most treatments are palliative, aimed at improving the quality of life and prolonging survival.

The balance between risks and benefits of these treatments must be justifiable.³⁰ Further, patients who have no symptoms or who have lower-risk disease need no treatment and may not for years. However, they do need close follow-up, because their symptoms will worsen and will eventually require treatment.

TAKE-HOME POINTS

• Myelodysplastic syndromes are more prevalent than previously realized. Mainly a disease of older adults, they should be suspected in any patient with unexplained cytopenia.
• Life expectancy at the time of diagnosis depends on the types of cells affected.
• Supportive and disease-altering options are available.
• Prompt referral to a hematologist or oncologist is important for confirmation of the diagnosis and initiation of an appropriate treatment plan. Patients with lower-risk disease can continue follow-up with their primary care provider once treatment goals and plans are established.

ACKNOWLEDGMENT

We thank Dr. Karl Theil of the Cleveland Clinic Department of Clinical Pathology for the photomicrographs used on the cover.

Q: Which is the most likely diagnosis?

• Addison disease
• Lupus erythematosus
• Polymorphous light eruption
• Porphyria cutanea tarda
• Bullous pemphigoid

A: Urine testing, including examination under ultraviolet light with a Wood lamp, indicates porphyria cutanea tarda. This is the most common porphyria, occurring mainly in men. Its true prevalence is not known but is estimated to be from 1:5,000 to 1:25,000.¹

There are three types of porphyria cutanea tarda. About 80% of cases are type I, also referred to as “sporadic.” In type I, levels of uroporphyrinogen decarboxylase (UROD) in red blood cells are normal, but are low in the liver during episodes of the disease. In type II, UROD levels are about 50% below normal in all tissues. Type III is similar to type I, except that it occurs in more than one family member.

The genetic mutation that produces a deficiency of UROD leads to an excess of uroporphyrins and porphyrins that are partially decarboxylated and that irreversibly oxidize. When they are deposited in the skin and the skin is exposed to the sun, they cause the classic cutaneous manifestations.¹

Risk factors² for porphyria cutanea tarda can be extrinsic (eg, high iron blood levels,^2,3 excessive ethanol intake, hepatitis C,^2,4 human immunodeficiency virus, estrogen use,⁵ dialysis for end-stage renal disease) or intrinsic (altered iron metabolism or cytochrome P450 function²).

CLINICAL PRESENTATION

The cardinal symptom of porphyria cutanea tarda is photosensitivity, with the development of chronic blistering lesions on sun-exposed areas such as the hands, face, and forearms. Fluid-filled vesicles develop and rupture easily, and the denuded areas become crusted and heal slowly.⁵ Secondary infections can occur. Previous areas of blisters may appear atrophic, brownish, or violaceous. Small white plaques (milia) are also common and may precede or follow vesicle formation. These cutaneous lesions, however, are not specific to porphyria cutanea tarda and can appear in variegated porphyria and coproporphyria. Hypertrichosis⁵ and hyperpigmentation are usually present, mainly over the cheekbones and around the eyes. Patches of alopecia and hypopigmented sclerodermiform lesions may also be observed.

Porphyria cutanea tarda is usually accompanied by alterations in liver metabolism, affecting mainly aminotransferases and gammaglutamyltransferase. The absence of hepatitis C infection does not rule out porphyria cutanea tarda. About 50% of patients have pathologic structural changes in the liver such as lobular necrosis or fibrotic tracts, and 15% of patients have cirrhosis at presentation.⁶ The risk of hepatocellular carcinoma is clearly increased.⁶ Hepatitis C virus infection, iron overload, and excessive ethanol intake lead to a more severe liver disease.

DIAGNOSIS

The diagnosis of porphyria cutanea tarda is strongly suggested by the characteristic skin lesions in sun-exposed areas, but confirmation requires demonstration of high levels of uroporphyrins or coproporphyrins, or both.

Porphyrins accumulate in the liver, plasma, urine, and feces. Plasma porphyrin levels in porphyria cutanea tarda are usually above 10 μg/dL (normal < 1.4 μg/dL), and plasma fluorescence scanning usually shows a maximum fluorescence emission at an excitation wavelength of 619 nm. In this patient, however, the definitive diagnosis was made by chromatographic separation and the quantification of porphyrins in the urine and feces, which showed a predominance of uroporphyrins and heptacarboxyporphyrins in the urine and an excess of isocoproporphyrins in the feces.¹

Analysis of UROD activity in erythrocytes can help determine the type of porphyria cutanea tarda. Type I and type III and porphyria cutanea tarda secondary to hepatotoxin exposure have normal levels, whereas type II and the hepatoerythropoietic form have abnormally low levels. Examination of the urine with a Wood lamp reveals coral pink fluorescence due to elimination of porphyrins, and this is another diagnostic clue.

Conditions that need to be ruled out include viral infection with hepatitis B or C or human immunodeficiency virus, iron overload, and hereditary hemochromatosis. Serum alpha fetoprotein level assessment, liver ultrasonography, or even biopsy may be indicated to exclude hepatocellular carcinoma.

TREATMENT

Once secondary causes of porphyria are excluded or treated (eg, advising the patient to avoid alcohol, discontinuing estrogens or iron intake), the next step in management is to reduce the patient’s porphyrin and iron loads. Phlebotomy is the standard way to reduce stores of iron throughout the body and particularly in the liver. It works by interrupting iron-mediated oxidative inhibition of hepatic UROD and the oxidation of hepatic porphyrinogens to porphyrinogens.

This adjustment must be gradual, with about 450 mL of blood removed at intervals of 1 to 2 weeks.⁷ This improves the cutaneous symptoms progressively, with resolution of vesicles in 2 to 3 months, improvement of skin fragility in 6 to 9 months, and normalization of porphyrin levels in 13 months. The scleroderma, atrophy, hyperpigmentation, and hypertrichosis respond more slowly and may take years to resolve.

Porphyria cutanea tarda can recur, usually with new exposure to risk factors. Treatment by phlebotomy may be stopped when the serum ferritin level has reached low-normal levels; the porphyrin levels may not yet be normal at that point but may continue to decline without additional phlebotomy sessions.

If phlebotomy is contraindicated, alternatives include iron chelation with deferoxamine (Desferal),⁷ or a low dose of chloroquine (Aralen) (125–250 mg orally twice a week) or hydroxychloroquine (Plaquenil) (100 mg orally twice a week) to avoid acute hepatic damage that may be caused by the release of large amounts of porphyrins that accompany standard dosing levels.

Q: Which is the most likely diagnosis?

• Addison disease
• Lupus erythematosus
• Polymorphous light eruption
• Porphyria cutanea tarda
• Bullous pemphigoid

A: Urine testing, including examination under ultraviolet light with a Wood lamp, indicates porphyria cutanea tarda. This is the most common porphyria, occurring mainly in men. Its true prevalence is not known but is estimated to be from 1:5,000 to 1:25,000.¹

There are three types of porphyria cutanea tarda. About 80% of cases are type I, also referred to as “sporadic.” In type I, levels of uroporphyrinogen decarboxylase (UROD) in red blood cells are normal, but are low in the liver during episodes of the disease. In type II, UROD levels are about 50% below normal in all tissues. Type III is similar to type I, except that it occurs in more than one family member.

The genetic mutation that produces a deficiency of UROD leads to an excess of uroporphyrins and porphyrins that are partially decarboxylated and that irreversibly oxidize. When they are deposited in the skin and the skin is exposed to the sun, they cause the classic cutaneous manifestations.¹

Risk factors² for porphyria cutanea tarda can be extrinsic (eg, high iron blood levels,^2,3 excessive ethanol intake, hepatitis C,^2,4 human immunodeficiency virus, estrogen use,⁵ dialysis for end-stage renal disease) or intrinsic (altered iron metabolism or cytochrome P450 function²).

CLINICAL PRESENTATION

The cardinal symptom of porphyria cutanea tarda is photosensitivity, with the development of chronic blistering lesions on sun-exposed areas such as the hands, face, and forearms. Fluid-filled vesicles develop and rupture easily, and the denuded areas become crusted and heal slowly.⁵ Secondary infections can occur. Previous areas of blisters may appear atrophic, brownish, or violaceous. Small white plaques (milia) are also common and may precede or follow vesicle formation. These cutaneous lesions, however, are not specific to porphyria cutanea tarda and can appear in variegated porphyria and coproporphyria. Hypertrichosis⁵ and hyperpigmentation are usually present, mainly over the cheekbones and around the eyes. Patches of alopecia and hypopigmented sclerodermiform lesions may also be observed.

Porphyria cutanea tarda is usually accompanied by alterations in liver metabolism, affecting mainly aminotransferases and gammaglutamyltransferase. The absence of hepatitis C infection does not rule out porphyria cutanea tarda. About 50% of patients have pathologic structural changes in the liver such as lobular necrosis or fibrotic tracts, and 15% of patients have cirrhosis at presentation.⁶ The risk of hepatocellular carcinoma is clearly increased.⁶ Hepatitis C virus infection, iron overload, and excessive ethanol intake lead to a more severe liver disease.

DIAGNOSIS

The diagnosis of porphyria cutanea tarda is strongly suggested by the characteristic skin lesions in sun-exposed areas, but confirmation requires demonstration of high levels of uroporphyrins or coproporphyrins, or both.

Porphyrins accumulate in the liver, plasma, urine, and feces. Plasma porphyrin levels in porphyria cutanea tarda are usually above 10 μg/dL (normal < 1.4 μg/dL), and plasma fluorescence scanning usually shows a maximum fluorescence emission at an excitation wavelength of 619 nm. In this patient, however, the definitive diagnosis was made by chromatographic separation and the quantification of porphyrins in the urine and feces, which showed a predominance of uroporphyrins and heptacarboxyporphyrins in the urine and an excess of isocoproporphyrins in the feces.¹

Analysis of UROD activity in erythrocytes can help determine the type of porphyria cutanea tarda. Type I and type III and porphyria cutanea tarda secondary to hepatotoxin exposure have normal levels, whereas type II and the hepatoerythropoietic form have abnormally low levels. Examination of the urine with a Wood lamp reveals coral pink fluorescence due to elimination of porphyrins, and this is another diagnostic clue.

Conditions that need to be ruled out include viral infection with hepatitis B or C or human immunodeficiency virus, iron overload, and hereditary hemochromatosis. Serum alpha fetoprotein level assessment, liver ultrasonography, or even biopsy may be indicated to exclude hepatocellular carcinoma.

TREATMENT

Once secondary causes of porphyria are excluded or treated (eg, advising the patient to avoid alcohol, discontinuing estrogens or iron intake), the next step in management is to reduce the patient’s porphyrin and iron loads. Phlebotomy is the standard way to reduce stores of iron throughout the body and particularly in the liver. It works by interrupting iron-mediated oxidative inhibition of hepatic UROD and the oxidation of hepatic porphyrinogens to porphyrinogens.

This adjustment must be gradual, with about 450 mL of blood removed at intervals of 1 to 2 weeks.⁷ This improves the cutaneous symptoms progressively, with resolution of vesicles in 2 to 3 months, improvement of skin fragility in 6 to 9 months, and normalization of porphyrin levels in 13 months. The scleroderma, atrophy, hyperpigmentation, and hypertrichosis respond more slowly and may take years to resolve.

Porphyria cutanea tarda can recur, usually with new exposure to risk factors. Treatment by phlebotomy may be stopped when the serum ferritin level has reached low-normal levels; the porphyrin levels may not yet be normal at that point but may continue to decline without additional phlebotomy sessions.

If phlebotomy is contraindicated, alternatives include iron chelation with deferoxamine (Desferal),⁷ or a low dose of chloroquine (Aralen) (125–250 mg orally twice a week) or hydroxychloroquine (Plaquenil) (100 mg orally twice a week) to avoid acute hepatic damage that may be caused by the release of large amounts of porphyrins that accompany standard dosing levels.

Q: Which is the most likely diagnosis?

• Addison disease
• Lupus erythematosus
• Polymorphous light eruption
• Porphyria cutanea tarda
• Bullous pemphigoid

A: Urine testing, including examination under ultraviolet light with a Wood lamp, indicates porphyria cutanea tarda. This is the most common porphyria, occurring mainly in men. Its true prevalence is not known but is estimated to be from 1:5,000 to 1:25,000.¹

There are three types of porphyria cutanea tarda. About 80% of cases are type I, also referred to as “sporadic.” In type I, levels of uroporphyrinogen decarboxylase (UROD) in red blood cells are normal, but are low in the liver during episodes of the disease. In type II, UROD levels are about 50% below normal in all tissues. Type III is similar to type I, except that it occurs in more than one family member.

The genetic mutation that produces a deficiency of UROD leads to an excess of uroporphyrins and porphyrins that are partially decarboxylated and that irreversibly oxidize. When they are deposited in the skin and the skin is exposed to the sun, they cause the classic cutaneous manifestations.¹

Risk factors² for porphyria cutanea tarda can be extrinsic (eg, high iron blood levels,^2,3 excessive ethanol intake, hepatitis C,^2,4 human immunodeficiency virus, estrogen use,⁵ dialysis for end-stage renal disease) or intrinsic (altered iron metabolism or cytochrome P450 function²).

CLINICAL PRESENTATION

The cardinal symptom of porphyria cutanea tarda is photosensitivity, with the development of chronic blistering lesions on sun-exposed areas such as the hands, face, and forearms. Fluid-filled vesicles develop and rupture easily, and the denuded areas become crusted and heal slowly.⁵ Secondary infections can occur. Previous areas of blisters may appear atrophic, brownish, or violaceous. Small white plaques (milia) are also common and may precede or follow vesicle formation. These cutaneous lesions, however, are not specific to porphyria cutanea tarda and can appear in variegated porphyria and coproporphyria. Hypertrichosis⁵ and hyperpigmentation are usually present, mainly over the cheekbones and around the eyes. Patches of alopecia and hypopigmented sclerodermiform lesions may also be observed.

Porphyria cutanea tarda is usually accompanied by alterations in liver metabolism, affecting mainly aminotransferases and gammaglutamyltransferase. The absence of hepatitis C infection does not rule out porphyria cutanea tarda. About 50% of patients have pathologic structural changes in the liver such as lobular necrosis or fibrotic tracts, and 15% of patients have cirrhosis at presentation.⁶ The risk of hepatocellular carcinoma is clearly increased.⁶ Hepatitis C virus infection, iron overload, and excessive ethanol intake lead to a more severe liver disease.

DIAGNOSIS

The diagnosis of porphyria cutanea tarda is strongly suggested by the characteristic skin lesions in sun-exposed areas, but confirmation requires demonstration of high levels of uroporphyrins or coproporphyrins, or both.

Porphyrins accumulate in the liver, plasma, urine, and feces. Plasma porphyrin levels in porphyria cutanea tarda are usually above 10 μg/dL (normal < 1.4 μg/dL), and plasma fluorescence scanning usually shows a maximum fluorescence emission at an excitation wavelength of 619 nm. In this patient, however, the definitive diagnosis was made by chromatographic separation and the quantification of porphyrins in the urine and feces, which showed a predominance of uroporphyrins and heptacarboxyporphyrins in the urine and an excess of isocoproporphyrins in the feces.¹

Analysis of UROD activity in erythrocytes can help determine the type of porphyria cutanea tarda. Type I and type III and porphyria cutanea tarda secondary to hepatotoxin exposure have normal levels, whereas type II and the hepatoerythropoietic form have abnormally low levels. Examination of the urine with a Wood lamp reveals coral pink fluorescence due to elimination of porphyrins, and this is another diagnostic clue.

Conditions that need to be ruled out include viral infection with hepatitis B or C or human immunodeficiency virus, iron overload, and hereditary hemochromatosis. Serum alpha fetoprotein level assessment, liver ultrasonography, or even biopsy may be indicated to exclude hepatocellular carcinoma.

TREATMENT

Once secondary causes of porphyria are excluded or treated (eg, advising the patient to avoid alcohol, discontinuing estrogens or iron intake), the next step in management is to reduce the patient’s porphyrin and iron loads. Phlebotomy is the standard way to reduce stores of iron throughout the body and particularly in the liver. It works by interrupting iron-mediated oxidative inhibition of hepatic UROD and the oxidation of hepatic porphyrinogens to porphyrinogens.

This adjustment must be gradual, with about 450 mL of blood removed at intervals of 1 to 2 weeks.⁷ This improves the cutaneous symptoms progressively, with resolution of vesicles in 2 to 3 months, improvement of skin fragility in 6 to 9 months, and normalization of porphyrin levels in 13 months. The scleroderma, atrophy, hyperpigmentation, and hypertrichosis respond more slowly and may take years to resolve.

Porphyria cutanea tarda can recur, usually with new exposure to risk factors. Treatment by phlebotomy may be stopped when the serum ferritin level has reached low-normal levels; the porphyrin levels may not yet be normal at that point but may continue to decline without additional phlebotomy sessions.

If phlebotomy is contraindicated, alternatives include iron chelation with deferoxamine (Desferal),⁷ or a low dose of chloroquine (Aralen) (125–250 mg orally twice a week) or hydroxychloroquine (Plaquenil) (100 mg orally twice a week) to avoid acute hepatic damage that may be caused by the release of large amounts of porphyrins that accompany standard dosing levels.

Editor’s note: Portions of this article are based on an article previously published in an internal Cleveland Clinic publication, Pharmacotherapy Update. The version here has been revised, updated, and peer-reviewed.

This drug is generally considered safe, but high doses can be toxic. The number of overdoses is worrisome. In 2006 alone, the American Association of Poison Control Centers implicated acetaminophen in nearly 140,000 poisoning cases, in which more than 100 patients died.² It is responsible for more emergency room visits than any other drug on the market.

According to a position statement from the American Association for the Study of Liver Diseases (AASLD),³ the incidence of acetaminophen-related liver toxicity has been steadily increasing over the past decade, and this drug is now the most common cause of acute liver failure.

MANY OVERDOSES ARE UNINTENTIONAL

Cases of acetaminophen-related liver toxicity can be categorized as either intentional (ie, due to a suicide attempt) or unintentional (ie, due to multiple therapeutic but excessive doses over a period of time, usually more than 3 days).

Up to 50% of cases are unintentional. Bower et al⁴ reviewed cases of acute liver failure that occurred in the Atlanta, GA, area between November 2000 and October 2004. Acetaminophen was the most common cause in adult patients. Of greater concern is that 61% of the acetaminophen-related cases were due to unintentional overdose. According to the Institute for Safe Medication Practices,⁵ one hospital (not named) reported that an average of one patient per day was given more than the recommended maximum daily acetaminophen dose of 4 g while in the hospital.

Many patients take more than one acetaminophen product

Unintentional overdoses or “therapeutic misadventures” are most often due to taking multiple products that contain acetaminophen, taking acetaminophen-narcotic combinations, and impulsive behavior involving a lack of understanding of possible injury in consuming multiple acetaminophen-containing products.³

In the US Food and Drug Administration (FDA) Medwatch Database, in 307 cases of unintentional acetaminophen overdose between 1998 and 2001, 25% of patients had been taking more than one acetaminophencontaining product.⁵

Larson et al⁶ found that one-third of patients who had had an unintentional acetaminophen overdose were taking an acetaminophen-narcotic combination in addition to another acetaminophen-containing product.

Many consumers don’t know they are taking acetaminophen

Many consumers don’t know that some of the drugs they take contain acetaminophen. This may be because many drug labels contain abbreviations for acetaminophen such as “APAP” or have inconsistent formatting that makes it difficult to determine if the product contains acetaminophen.

Others may not be aware of the total maximum recommended daily dose or may not be able to calculate the total daily intake from the information on the label. The problem is not only with over-the-counter products. For example, if a physician prescribes one or two tablets of hydrocodone/acetaminophen (Vicodin) 5 mg/500 mg every 4 to 6 hours, a patient could easily exceed the recommended maximum daily dose of 4 g of acetaminophen.

Toxicity can occur even at therapeutic doses

Acetaminophen hepatotoxicity can also occur even with therapeutic doses in certain conditions. Risk factors:

• Chronic alcohol use (ie, more than three drinks per day)
• Malnutrition
• Concurrent use of drugs that induce cytochrome P450 (CYP450) enzymes (more on this below).⁶

FIRST USED IN 1893

Acetaminophen was first used in medicine in 1893, and it became widely used after 1949, when it was found to be a less-toxic metabolite of two parent compounds, acetanilide and phenacetin.¹

Acetaminophen is an effective antipyretic and analgesic, but its anti-inflammatory properties are minimal, especially compared with nonsteroidal anti-inflammatory drugs (NSAIDs). Nevertheless, acetaminophen is preferred over NSAIDs in some patients because it carries a lower risk of gastrointestinal toxicity (eg, ulceration, bleeding) and so may be better tolerated.¹

INDICATIONS AND DOSAGE

Acetaminophen is indicated for mild to moderate pain or fever, including the pain of osteoarthritis. It is not recommended for chronic inflammatory conditions such as rheumatoid arthritis, since it lacks anti-inflammatory properties.

In adults and in children over age 12, the usual dosage is 325 to 650 mg orally or rectally every 4 to 6 hours, or 1,000 mg three to four times daily.

The current package label recommends that the total daily dose not exceed 4 g in most adults. Lower maximum daily doses (eg, 2 g) are recommended in patients who may be at higher risk of hepatotoxicity, such as those who drink heavily, are malnourished, or take enzyme-inducing drugs. Tylenol products currently include an alcohol warning, advising those who consume three or more alcoholic drinks a day to ask their doctor if they should take acetaminophen.

In children up to 12 years of age, the recommended dosage is 10 to 15 mg/kg orally or rectally every 4 to 6 hours. The maximum dosing for children in this age group should not exceed five doses (or 50 to 75 mg/kg) in 24 hours.⁷ In children under age 2 or weighing less than 11 kg, acetaminophen should only be used under the direction of a physician.

MOST ACETAMINOPHEN IS CONJUGATED AND THEN EXCRETED IN THE URINE

Acetaminophen usually has excellent bioavailability (up to 98%), but the exact amount absorbed varies, depending on the dosage form and concomitant use of other drugs.⁸

At therapeutic doses, the elimination halflife is about 2 hours. Peak plasma concentrations are reached 30 to 60 minutes after the dose is taken,¹ but taking acetaminophen with opioids, anticholinergic drugs, or even food may delay the time to peak concentration by delaying gastric emptying.⁸

NAPQI is a toxic metabolite

Under normal circumstances, a small amount of acetaminophen undergoes hepatic metabolism by a different pathway, ie, by CYP450 enzymes, primarily CYP2E1 and to a lesser extent CYP1A2, CYP2A6, and CYP3A4, forming a toxic metabolite, N-acetyl-p-benzoquinone imine (NAPQI). Then, the sulfhydryl groups of glutathione convert NAPQI into harmless metabolites that are excreted in the urine.^1,7

Well tolerated and relatively safe

At recommended doses, acetaminophen is well tolerated, and it is considered relatively safe when used according to labeling instructions.

Rarely, patients experience an erythematous or urticarial rash or other allergic complications.¹

However, acetaminophen is a dose-dependent hepatotoxin, and excessive doses (intentional or unintentional) may lead to acute liver failure. In addition, even in therapeutic doses, acetaminophen may still cause transient liver enzyme elevations and possibly hepatotoxicity, particularly in people who are malnourished or alcoholic or are taking certain CYP450-inducing drugs.^3,6,10

HOW ACETAMINOPHEN CAN INJURE THE LIVER

Glucuronidation and sulfation, the major metabolic pathways, become saturated after an acetaminophen overdose.⁷ When this happens, more of the toxic metabolite NAPQI is formed by CYP450-mediated N-hydroxylation. When glutathione is depleted after large doses of acetaminophen or in malnourished people, the toxic metabolite accumulates, resulting in liver damage (Figure 1).⁶

The liver is damaged by two mechanisms. In one, NAPQI binds to hepatic cell macromolecules, causing dysfunction of the enzymatic systems, structural and metabolic disarray, and eventually necrotic cell death. The other mechanism is oxidative stress due to depletion of glutathione.

In children, single acetaminophen doses of 120 to 150 mg/kg of body weight have been associated with hepatotoxicity,¹¹ as have single doses of more than 150 mg/kg or a total dose of greater than 7.5 g in adults. However, the minimal dose associated with liver injury has ranged from 4 to 10 g, and in healthy volunteers even therapeutic doses of 1 g orally every 6 hours resulted in mild liver injury.¹²

Patients who are malnourished or fasting are thought to be at greater risk of acetaminophen hepatotoxicity because they may be deficient in glutathione at baseline. In addition, even at lower-than-therapeutic doses, induction of CYP450 enzymes by drugs or chronic alcohol consumption may lead to an increase in the formation of NAPQI, increasing the risk of hepatotoxicity. Examples of drugs that induce CYP450 enzymes to produce more NAPQI include the anticonvuslants phenytoin (Dilantin) and phenobarbital.

CLINICAL PRESENTATION OF ACETAMINOPHEN OVERDOSE

The diagnosis of acetaminophen overdose is often established by a thorough history. The pertinent information may be difficult to obtain, however, because the patient may be confused or stuporous at presentation, may not know that the overthe-counter products he or she has been taking contain acetaminophen, or may be embarrassed about taking too much acetaminophen.¹³

In acute intentional overdose, signs may not be apparent immediately

The symptoms of toxicity may not be apparent immediately after ingestion of an acute overdose of acetaminophen, but early recognition and treatment can prevent more severe liver damage, decreasing morbidity and the risk of death.⁹

Phase 1 of an acetaminophen overdose begins shortly after ingestion and can last for 12 to 24 hours. Patients may have signs of gastrointestinal upset, nausea, vomiting, anorexia, diaphoresis, and pallor. Although the signs and symptoms show a consistent pattern and are more pronounced after larger acute overdoses, they are not diagnostic or specific.

Phase 2 (up to 48 hours after ingestion). Patients may begin to feel better during this phase. However, the hepatic enzyme levels, the prothrombin time (PT), and the international normalized ratio (INR) may continue to rise, and right upper quadrant pain may develop. Additionally, other laboratory results may be abnormal, and renal insufficiency can occur due to acetaminophen-induced renal tubular necrosis.⁶ Most patients receive the antidote, acetylcysteine (Mycomyst, Acetadote) before or during this phase, and consequently, liver function gradually returns to normal.

Phase 3, if reached, may be marked by severe hepatic necrosis, typically 3 to 5 days after ingestion. Symptoms during this phase range from less severe (eg, nausea and general malaise) to more severe (eg, confusion and stupor). Also, at this time, liver enzyme levels can be as high as 10,000 IU/L or even higher, and lactic acidosis and coagulopathy may worsen. If death should occur, it is most likely from complications associated with fulminant hepatic failure, including cerebral edema, multiorgan-system failure, or sepsis.⁶

Phase 4. Patients who recover generally have complete recovery of liver function with no long-term sequelae..

In unintentional overdoses, patients may have low drug levels

Many patients who present with unintentional acetaminophen toxicity have been taking the drug or products that contain the drug over several days to treat an acute or chronic medical condition. They often have low or undetectable serum acetaminophen levels after 2 to 3 days of nonspecific symptoms.¹²

MANAGING ACETAMINOPHENHEN OVERDOSE

Unintentional overdoses occur over a more prolonged period, and therefore the nomogram is not useful in this situation.

Acetylcysteine is the antidote

Acetylcysteine is the antidote for acetaminophen toxicity and should be given within 8 hours of ingestion for maximal protection against hepatic injury in patients whose serum acetaminophen levels are above the “possible” toxicity line on the nomogram.¹⁵ If acetaminophen overdose is suspected but the time elapsed since ingestion cannot be determined, acetylcysteine should be given immediately regardless of the quantity of acetaminophen ingested. ¹⁶ In cases of unintentional overdose, it is often given at the discretion of the physician.

Acetylcysteine limits the toxicity of acetaminophen by increasing glutathione stores, binding with NAPQI as a substitute for glutathione, and enhancing sulfate conjugation.⁶ It may further limit acetaminophen toxicity by nonspecific mechanisms including anti-inflammatory, antioxidant, inotropic, and vasodilating effects.⁶ In addition, it may prevent further hepatic damage in any patient thought to have acetaminophen-related liver toxicity even beyond the first 12 hours of an overdose.¹

Acetylcysteine is available in an oral (Mucomyst) and an intravenous (Acetadote) formulation, which are similar in efficacy. Because many patients find the taste of the oral solution unpleasant and difficult to tolerate, it should be diluted in a 1:3 ratio with cola, orange juice, or other drink to mask its flavor. This mixture should be used within 1 hour of preparation.

Anaphylactoid reactions have occurred in patients receiving intravenous acetylcysteine for acetaminophen overdose soon after the infusion was started, most commonly during the loading dose. The frequency of infusion-related reactions has been reported to be 0.2% to 20.8%.¹⁵

The recommended dosage for intravenous acetylcysteine is a loading dose of 150 mg/kg given over 60 minutes, followed by a second dose of 50 mg/kg given over 4 hours, and finally a third dose of 100 mg/kg given over 16 hours.¹⁵ For oral acetylcysteine, the loading dose is 140 mg/kg followed by 70 mg/kg every 4 hours for 17 additional doses.¹⁷

Other measures

Activated charcoal can be used if the patient presents within 1 to 2 hours after taking acetaminophen. However, the rapid gastrointestinal absorption of acetaminophen makes this treatment ineffective in most cases.⁹