Detecting celiac disease in adult patients

Your differential diagnosis should include celiac disease if the patient has symptoms as diverse as diarrhea, constipation, malabsorption, indigestion, pain, fatigue, and anemia.

Pamela Early, PA-C

The author works in trauma surgery at Prince George’s Hospital Center, Cheverly, Md. She has indicated no relationships to disclose relating to the content of this article.

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Only a few years ago, researchers believed the prevalence of celiac disease (CD) in the United States to be approximately 1 in 6,000 people—much lower than in Europe, where it was 1 in 300.¹ However, the most recent data show that this number is sorely underestimated, largely because screening is uncommon in the United States and CD is difficult to recognize, especially in adults. Newer serologic tests have improved the diagnostic process worldwide and, as a result, the disease is being diagnosed more and more often in adults. Currently, an estimated 1 in 120 to 300 people in North America and Europe have CD (also called celiac sprue). Unfortunately, primary care providers diagnose only 6% of cases.²    

History

Although accounts of CD date back to the first century, no one linked the symptoms to gluten ingestion until the 1940s. At that time, Willem Karel Dicke, a Dutch pediatrician, observed that the condition of children with CD improved during the food shortages of World War II, only to relapse after cereal supplies were restored.¹ Most primary care providers still regard CD as a disease of malnutrition and chronic diarrhea, although these manifestations are rare with modern diets. CD exists in people of all ages, can involve practically any organ system, and manifests with signs and symptoms ranging from severe to mild to none at all. 

Testing is crucial

Testing adults for CD should be done in a primary care setting because patients who go untreated are at risk for various complications, including malabsorption, vitamin or mineral deficiency, infertility, osteoporosis, autoimmune diseases, and small bowel lymphoma.³ A delay of more than 10 years in diagnosis and treatment can increase mortality nearly fourfold compared to that in age-matched controls.⁴ If PAs begin to consider CD in their differential diagnoses, they can improve quality of life and decrease mortality in their patients with CD (see Table 1).

Pathophysiology

CD is a genetic autoimmune enteropathy that causes malabsorption. Affected persons are sensitive to gluten, the protein that gives wheat, rye, and barley their elastic substance. Since a wide variety of beverages, medicines, and foods—including potato chips, cookies, soups, and breads—contain gluten in some form, avoiding it is a challenge. CD is caused by a delayed-type cellular hypersensitivity to the proteins in these grains, specifically the gliadin portion of wheat protein. This causes a CD4+ cell response that results in inflammation of the small bowel.⁴ These physiologic effects tend to improve dramatically when gluten is removed from the diet. 

Genetics

The concordance rate for CD in monozygotic twins is estimated to be 75%, and approximately 10% to 15% of first-degree relatives of persons with CD also have the disease.⁴ Eighty percent of affected persons express the human leukocyte antigen (HLA) alleles DQ2 and DQ8 (compared to 20% of the general population), though for reasons not yet understood, not all HLA-DQ2/8-positive persons develop CD.⁵ CD is more common in people of Celtic descent and uncommon in those of African or Asian descent. 

Clinical presentation

Age CD has a bimodal distribution, manifesting both in young children and in adults in the fourth or fifth decades. Symptoms can occur early in life, subside for many years, and then reappear in adulthood. Researchers do not know what causes discernible disease to develop in adulthood after existing subclinically for years, although studies suggest that signs and symptoms may become noticeable after physically or emotionally stressful events. In the United States, CD is most often diagnosed in adults, which is probably a result of the lack of a specific screening protocol in children and the limited knowledge of CD and underestimation of its prevalence among clinicians.⁶

Signs and symptoms Clinical manifestations of CD vary noticeably with the duration and extent of the disease and the age of the patient (see Table 2). Most patients receive a diagnosis after presenting with symptomatic CD, which may include a diarrheal syndrome, malabsorption, or other GI symptoms such as indigestion, constipation, abdominal pain, and reflux.⁷

Some studies show that the most common presenting signs and symptoms of CD in adults are abdominal pain, fatigue, bloating or gas, and iron deficiency anemia. In one study, 32% of affected adults were underweight, and 50% complained of frequent diarrhea and weight loss.⁶ In another study, 17% of patients with CD fulfilled the Rome II criteria for irritable bowel syndrome (IBS) (12 or more weeks of abdominal discomfort or pain that has two of the following three features: it is relieved by defecation, onset is associated with a change in the frequency of stool, and onset is associated with a change in the appearance of stool). Thirty-seven percent of these respondents reported an initial diagnosis of IBS. Other frequent diagnoses were anxiety, depression, stress, and fibromyalgia.⁸

Women, who comprise 75% of all patients with CD, often present differently than do men and at a younger age. Their symptoms are more diverse, severe, and rapid, whereas men are more likely to present with low body mass index and weight loss.⁹

Patients with CD also commonly present with hematologic abnormalities, such as iron or folate deficiency and, very rarely, vitamin B₁₂ deficiency. Blood chemistry results, including decreased levels of serum albumin, carotene, and HDL and LDL cholesterol, provide clues to more advanced CD. Depletion of minerals and ions, such as zinc, magnesium, and potassium, may occur as well (see Table 3).⁹

Endocrine-related problems, including osteomalacia, osteoporosis, vitamin D insufficiency, secondary hyperparathyroidism, autoimmune thyroiditis, hypocalcemia, and hypocalciuria are also important features of CD. Furthermore, because of decreased intestinal absorption of levothyroxine, CD may manifest with excessive levothyroxine requirements in hypothyroid patients.³

Less common manifestations of CD include neurologic conditions such as ataxia, polyneuropathy, dementia, and epilepsy. Hair loss, vitamin and mineral deficiencies, aphthous ulcers, and angular cheilitis are other possible indicators, as are primary biliary cirrhosis, idiopathic chronic hepatitis, and isolated hypertransaminasemia.¹⁰ Approximately 10% of patients exhibit dermatitis herpetiformis, a rash specific to CD consisting of intensely pruritic papulovesicular lesions along the extensor surfaces.⁹  

Screening and diagnosis

The diagnosis of CD remains difficult in the primary care setting, but many screening strategies can be used before referring the patient to a gastroenterologist.

Serologic tests serve as an excellent screening tool for CD and should be considered in patients at high risk for the disease, including those with a family history, chronic diarrhea, unexplained anemia, chronic fatigue, and unexplained weight loss.⁹ Patients with certain autoimmune diseases are also more likely to have CD. Although CD satisfies the World Health Organization criteria for general screening, sufficient research has yet to be performed justifying its use in the general population rather than in groups at increased risk.⁷ Because 10% to 15% of first-degree relatives of people with CD have the disease as well, experts recommend that these relatives be screened. Screening is also advised for patients with the following conditions:

• Type 1 diabetes (~10% prevalence of CD)
• Down syndrome (~10% prevalence)
• Sjögren’s syndrome (~10% prevalence)
• Autoimmune thyroiditis³
• Unexplained metabolic bone disease or hypocalcemia
• Addison’s disease (~8%)¹¹
• IBS (Rome II criteria with referral to a secondary care center)⁸
• Chronic liver disease of unknown origin.³

Cells producing IgA, IgG, and IgM are increased in patients with CD, and genetic studies demonstrate antibodies in the serum to gliadin, reticulin, or endomysium. To screen for CD, some practices use the IgA endomysium antibody (EMA) tests, which are 75% to 90% sensitive and 82% to 95% specific. However, the newest and most accurate way to screen for CD is to test serum for antitissue transglutaminase (anti-tTG) antibodies. Transglutaminase is a normal intestinal enzyme released during injury; it links with gliadin, becoming the target of antibody response. Elimination of gliadin stops direct mucosal injury. The anti-tTG test is inexpensive, 95% to 98% sensitive, and more than 95% specific. After diagnosis and abstinence from gluten for about 1 year, the titer should return to the normal range, which means that this test can also be used to monitor adherence to recommended therapy.¹

Intestinal biopsy while the patient is on a wheat-containing diet is the gold standard for diagnosis. It is performed when there is a moderate to high index of suspicion for CD. The biopsy, which can be obtained endoscopically from the distal duodenum, may show flat duodenal mucosa and inflammation; nevertheless, results can range from mild to severe. Classic histologic signs are increased intraepithelial lymphocytes, increased cellularity in the lamina propria, enterocyte damage, villous atrophy, lengthened crypts, and an increase in plasma cells. Biopsy results are nonspecific, so to confirm a diagnosis of CD, the clinician must first confirm that the patient improves clinically after following a gluten-free diet.¹²

The carbohydrate tolerance test has shown that two thirds of patients with CD exhibit inhibited D-xylose absorption. Soon after ingestion, poor absorption of D-xylose will be evident by serum concentration, showing small bowel disease or luminal bacterial overgrowth. This test is nonspecific, however, and no longer recommended for screening.¹

Ultrasonography can reveal several nonspecific signs of CD and may help to avoid a delay in diagnosis. Signs include an abnormal fluid-filled small intestine; flaccid, moderately dilated small bowel loops; increased peristalsis; enlarged mesenteric lymph nodes; and slight, diffuse thickening of the small bowel wall.¹³  

Referral

Clinicians must remember that CD is not rare. PAs should maintain a high index of suspicion and refer to a gastroenterologist early in the workup, especially if the patient has anemia, symptoms of IBS, and general lassitude.¹⁴ Blood screening tests and endoscopy should be performed while the patient is still eating gluten-containing food; therefore, patients should not abstain from these foods until after tests are performed. 

Treatment

The only known treatment for CD is a strict gluten-free diet. Since gluten is a component of many foods and no federal regulations require foods and drugs to be labeled for gluten content, avoidance is difficult. However, with the help of a knowledgeable provider, nutritionist, and support groups, adherence to the required diet is achievable. Various Web sites provide gluten-free recipes and lists of foods and medications (see “Resources for patients and providers.” 

Follow-up care

Living with CD requires that providers and nutritionists who are knowledgeable about gluten-free products educate the patient on an ongoing basis. The primary care provider should monitor the patient’s serology to evaluate progress, assess status, and detect changes in the condition that may require additional treatment.¹⁴

Patients with a new diagnosis of CD need bone density scans, as many will have osteoporosis or osteomalacia. If patients are osteoporotic, vitamin D and parathyroid hormone concentrations should be monitored.¹⁵ Providers should pay special attention to weight changes and neurologic status, and laboratory tests should be used to monitor blood counts, prothrombin time, liver function, electrolytes, thyroid function, and levels of vitamin B₁₂, folate, glucose, calcium, serum ferritin, and urea.¹⁶ Hyposplenism is common. Patients with CD should receive the pneumococcal vaccine.¹⁴    

Patient education will be crucial to successful treatment. Providers should encourage patients to avoid hidden pitfalls, such as taking medications that contain gluten. They should also provide counseling regarding the testing of first-degree relatives for CD.¹⁵

Patients should follow up with their gastroenterologists every 6 to 12 months, as well as during exacerbation of symptoms, pregnancy, or times of physical or emotional stress. Lifelong follow-up with a specialist is strongly recommended.¹⁴  

Complications and prognosis

CD predisposes patients to small bowel lymphoma, which may manifest as refractory sprue, a clinical and histologic lack of response to a gluten-free diet followed for 6 months or longer. There may be a return of symptoms, including diarrhea, fatigue, and weight loss. Nevertheless, the main cause of refractory sprue is failure to adhere to a gluten-free diet.¹⁴

Recent studies show that CD also increases the risk for squamous cell esophageal cancer, primary small bowel adenocarcinoma, non-Hodgkin’s lymphoma, lymphocytic gastritis, and lymphocytic colitis. Indeed, the risk of these cancers seems to be eliminated in patients who remain gluten-free for more than 5 years.¹²

Additionally, the rate of autoimmune diseases in patients with CD is increased and is related to the duration of exposure to gluten.¹⁷ Type 1 diabetes, psoriasis, Addison’s disease, thyroid disease, hypopituitarism, Sjögren’s syndrome, collagen disorders, rheumatoid arthritis, liver disease, and selective IgA deficiency exist with higher prevalence in patients with CD.¹⁸ Results of some studies suggest that autoimmune diseases might be prevented by early diagnosis and treatment of CD.¹⁵ The natural history of undiagnosed CD remains unknown because research has involved patients who receive a diagnosis.⁷ It is clear, however, that symptoms resolve in most patients who receive a diagnosis and appropriate treatment.  

Conclusion

CD is common, often remains undiagnosed for years, and can manifest in various different ways. Providers should maintain a low threshold for serologic screening of patients with celiac-associated symptoms or conditions. At some time in their careers, PAs will likely encounter this illness and should keep it in mind in order to improve quality of life, prevent complications, and alleviate suffering in their patients with CD.  

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