Gluten-sensitive enteropathy : more common than you think - celiac disease

Author: David A. Nelsen, Jr.
Date: Dec 15, 2002

Although celiac disease was formally described late in the 19th century, treatment remained empiric until the middle of the 20th century when patients were noted to improve dramatically after wheat was removed from their diet. With the development of small-bowel biopsy techniques, the small intestine was identified as the target organ. Disease causality was established when the characteristic features of villous flattening, crypt hyperplasia, and increased intraepithelial lymphocytes (Figure 1) were shown to normalize after the institution of a gluten-free diet. (1)

In the mid-1960s, an enteropathy strikingly similar to celiac disease was identified in patients with dermatitis herpetiformis. Subsequently, this skin disorder was shown to be a manifestation of gluten-sensitive enteropathy. In the mid-1960s, adult celiac disease was also noted to be associated with numerous neurologic disorders, including epilepsy, cerebral calcifications, and peripheral neuropathy. (1)

Recent population studies indicate that celiac disease is more common than was previously thought. Some patients with gluten-sensitive enteropathy have minimal or no symptoms and are unlikely to be referred to a gastroenterologist unless the disease is considered. Hence, family physicians need to be familiar with the diagnosis and management of gluten-sensitive enteropathy.

Pathophysiology

Ingested protein does not normally provoke an immune response. This phenomenon is termed "oral tolerance." Patients who exhibit true allergy to an ingested protein (e.g., milk or soy protein) have a typical IgE-mediated response consisting of urticaria, angioedema, and bronchoreactivity.

The autoimmunity in gluten-sensitive enteropathy involves plasma cells that produce IgA and IgG; there is little or no IgE involvement. Current theory suggests that ingested a-gliadin (a component of the gluten protein) and related peptides bind with tissue transglutaminase (a ubiquitous intracellular enzyme) in enterocytes. The a-gliadin is rich in glutamine; transglutaminase deamidates glutamine residues, forming glutamic acid. Deamidation enhances the immunogenicity of a-gliadin by creating epitopes that are recognized as foreign by host cell-mediated immunity. (2)

Plasma cells produce IgA and IgG that are directed against a variety of antigens, including transglutaminase, endomysium, gliadin, and reticulin. Locally elaborated lymphokines attract inflammatory cells. (3) This intense local inflammatory reaction produces the villous flattening characteristic of gluten-sensitive enteropathy. Malabsorption of micronutrients (e.g., vitamins and minerals) and macronutrients (e.g., protein, carbohydrate, fat) follows. Small-bowel involvement is most prominent proximally and may be "patchy," especially in patients with "silent" celiac disease (i.e., minimal or no symptoms) and those with dermatitis herpetiformis.

Approximately 95 percent of patients with celiac disease exhibit specific Human Leukocyte Antigen (HLA) class II alleles DQA1*0501 and DQB1*0201. (4) Patients with type 1 diabetes, autoimmune thyroid disease, (5) Sjogren's syndrome, primary biliary cirrhosis, Addison's disease, systemic lupus erythematosus, selective IgA deficiency, and alopecia areata may also exhibit similar genotypes and are at risk for gluten-sensitive enteropathy (Table 1). Because many persons have these genotypes and only a few develop gluten-sensitive enteropathy, investigators have hypothesized that other genes or cofactors may be involved. (1)

Epidemiology

Until recently, celiac disease was considered to be relatively uncommon. Previous U.S. figures suggested that it affected one in 6,000 persons. (6) However, population studies published in the past four years suggest a much higher prevalence, particularly in persons of European ancestry. (7) Studies conducted in Europe estimate the seroprevalence of celiac disease to be one case per 130 to 300 persons. (8-10)

In a recent U.S. study, (11) investigators tested sera from 2,000 healthy Red Cross blood donors and found eight samples that were positive for antibodies associated with gluten-sensitive enteropathy (seven samples from white persons, one sample from a black person). The seroprevalence rate in this study (one case per 250 persons tested) is consistent with the rates in European studies.

The likelihood of having gluten-sensitive enteropathy increases to 10 to 20 percent in persons who have a first-degree relative with celiac disease. (1) In addition, celiac disease is associated with other autoimmune syndromes. For example, as many as 7 percent of patients with type I diabetes also have gluten-sensitive enteropathy. (12)

Clinical Presentation

Untreated gluten-sensitive enteropathy is associated with a range of symptoms13,14 (Table 2). The "classic" form typically presents in infancy and manifests as failure to thrive, diarrhea, abdominal distention, developmental delay, and, occasionally, severe malnutrition. Failure to diagnose the disorder may lead to a true medical emergency.

Beyond infancy, the symptoms of celiac disease tend to be less dramatic. Older children may present with constitutional short stature or dental enamel defects.

Women comprise approximately 75 percent of newly diagnosed adult celiac disease cases. Women also tend to have more clinically conspicuous disease. (15) In adults of both sexes, gastrointestinal tract involvement may manifest as diarrhea, constipation, or other symptoms of malabsorption, such as bloating, flatus, or belching. Fatigue, depression, fibromyalgia-like symptoms, aphthous stomatitis, bone pain, dyspepsia, gastroesophageal reflux, and other nonspecific symptoms may be present and can make the diagnosis quite challenging. (14) A number of other autoimmune syndromes have been associated with celiac disease (Table 1).

DERMATITIS HERPETIFORMIS

Fewer than 10 percent of adults with gluten-sensitive enteropathy present with dermatitis herpetiformis. (16) This skin condition may be misdiagnosed as atypical psoriasis or nonspecific dermatitis.

The rash of dermatitis herpetiformis is intensely pruritic and typically occurs on the back, buttocks, knees, and elbows (Figure 2). Unexcoriated lesions (Figure 3) are remarkably like those of herpes simplex (thus, the term "herpetiformis"). Granular IgA deposition on immunofluorescence of a skin biopsy specimen is diagnostic (Figure 4).

ANEMIA

Anemia is the most common laboratory manifestation of celiac disease (13,14) (Table 3). One half of patients with newly diagnosed gluten-sensitive enteropathy are anemic. Iron is absorbed in the proximal small intestine, where celiac manifestations are most prominent; hence, iron malabsorption is common. In addition, occult blood loss related to intense small-bowel inflammation may occur in 50 percent of patients with gluten-sensitive enteropathy. (17) Less commonly, vitamin B12 deficiency, folate deficiency, or both may be present.

SILENT CELIAC DISEASE

A number of investigators believe that clinically apparent gluten-sensitive enteropathy represents the "tip of the iceberg" of the overall disease burden. (7) Patients who were detected in the seroprevalence studies (8-11) were asymptomatic or oligosymptomatic (so-called "silent" celiac disease).

Family physicians should consider serologic testing in patients with the following: family history of celiac disease, personal history of thyroid disease or type I diabetes, irritable bowel syndrome, anemia (especially iron deficiency), chronic diarrhea, chronic fatigue, unexplained weight loss, short stature, epilepsy, infertility, (18) or unexplained elevation of transaminase levels. Asymptomatic or oligosymptomatic patients are still at risk for complications of celiac disease.

Diagnosis

SEROLOGIC TESTS

When the diagnosis of gluten-sensitive enteropathy is suspected, serologic tests can identify many affected patients. (19) (Figure 5). IgA antiendomysial antibody has been shown to be 85 to 100 percent sensitive and 96 to 100 percent specific for celiac disease. IgA antiendomysial antibody is measured using direct immunofluorescence of monkey esophagus or umbilical cord tissue processed with suspect serum.

[FIGURE 5 OMITTED]

IgG and IgA antigliadin antibodies are also useful in diagnosing celiac disease. The antibody directed against endomysium has recently been identified as identical to the antibody directed against (tissue) transglutaminase. An enzyme-linked immunosorbent assay has been developed to measure IgA antitransglutaminase; this test will generally replace the more tedious direct fluorescent antibody test for IgA antiendomysial antibody. (20-22) In diagnosing celiac disease, antitransglutaminase antibody is considered to be approximately as sensitive and specific as antiendomysial antibody (Table 4). (21,23-25)

(19.) Fotoulaki M, Nousia-Arvanitakis S, Augoustidou-Savvopoulou P, Kanakoudi-Tsakalides F, Zaramboukas T, Vlachonikolis J. Clinical application of immunological markers as monitoring tests in celiac disease. Dig Dis Sci 1999;44:2133-8.

(20.) Troncone R, Maurano F, Rossi M, Micillo M, Greco L, Auricchio R, et al. IgA antibodies to tissue transglutaminase: an effective diagnostic test for celiac disease. J Pediatr 1999;134:166-71.

(21.) Vitoria JC, Arrieta A, Arranz C, Ayesta A, Sojo A, Maruri N, et al. Antibodies to gliadin, endomysium, and tissue transglutaminase for the diagnosis of celiac disease. J Pediatr Gastroenterol Nutr 1999;29:571-4.

(22.) Dieterich W, Ehnis T, Bauer M, Donner P, Volta U, Riecken EO, et al. Identification of tissue transglutaminase as the autoantigen of celiac disease. Nat Med 1997;3:797-801.

(23.) Biagi F, Ellis HJ, Yiannakou JY, Brusco G, Swift GL, Smith PM, et al. Tissue transglutaminase antibodies in celiac disease. Am J Gastroenterol 1999;94:2187-92.

(24.) Russo PA, Chartrand LJ, Seidman E. Comparative analysis of serologic screening tests for the initial diagnosis of celiac disease. Pediatrics 1999;104(1 pt 1):75-8.

(25.) Valdimarsson T, Franzen L, Grodzinsky E, Skogh T, Strom M. Is small bowel biopsy necessary in adults with suspected celiac disease and IgA anti-endomysium antibodies? 100% positive predictive value for celiac disease in adults. Dig Dis Sci 1996;41:83-7.

(26.) Cataldo F, Marino V, Bottaro G, Greco P, Ventura A. Celiac disease and selective immunoglobulin A deficiency. J Pediatr 1997;131: 306-8.

(27.) Valdimarsson T, Lofman O, Toss G, Strom M. Reversal of osteopenia with diet in adult coeliac disease. Gut 1996;38:322-7.

(28.) Sategna-Guidetti C, Grosso SB, Grosso S, Mengozzi G, Aimo G, Zaccaria T, et al. The effects of 1-year gluten withdrawal on bone mass, bone metabolism and nutritional status in newly-diagnosed adult coeliac disease patients. Aliment Pharmacol Ther 2000; 14:35-43.

(29.) Dickey W. Epilepsy, cerebral calcifications, and coeliac disease. Lancet 1994;344:1585-6.

(30.) Hadjivassiliou M, Chattopadhyay AK, Davies-Jones GA, Gibson A, Grunewald RA, Lobo AJ. Neuromuscular disorder as a presenting feature of coeliac disease. J Neurol Neurosurg Psychiatry 1997;63: 770-5.

(31.) Hadjivassiliou M, Grunewald RA, Chattopadhyay AK, Davies-Jones GA, Gibson A, Jarratt JA, et al. Clinical, radiological, neurophysiological, and neuropathological characteristics of gluten ataxia. Lancet 1998;352:1582-5.

(32.) Pratesi R, Gandolfi L, Friedman H, Farage L, de Castro CA, Catassi C. Serum IgA antibodies from patients with coeliac disease react strongly with human brain blood-vessel structures. Scand J Gastroenterol 1998;33:817-21.

(33.) Pricolo VE, Mangi AA, Aswad B, Bland KI. Gastrointestinal malignancies in patients with celiac sprue. Am J Surg 1998;176:344-7.

(34.) Lewis HM, Renaula TL, Garioch JJ, Leonard JN, Fry JS, Collin P, et al. Protective effect of gluten-free diet against development of lymphoma in dermatitis herpetiformis. Br J Dermatol 1996; 135:363-7.

(35.) Holmes GK, Prior P, Lane MR, Pope D, Allan RN. Malignancy in coeliac disease--effect of a gluten free diet. Gut 1989;30:333-8.

(36.) Hoffenberg EJ, Haas J, Drescher A, Barnhurst R, Osberg I, Bao F, et al. A trial of oats in children with newly diagnosed celiac disease. J Pediatr 2000;137:361-6.

(37.) Janatuinen EK, Pikkarainen PH, Kemppainen TA, Kosma VM, Jarvinen RM, Uusitupa MI, et al. A comparison of diets with and without oats in adults with celiac disease. N Engl J Med 1995;333: 1033-7.

The author indicates that he does not have any conflicts of interest. Sources of funding: none reported.

Figure 1 provided by Laura Lamps, M.D., assistant professor of pathology, University of Arkansas for Medical Sciences (UAMS), Little Rock. Figure 4 provided by Bruce Smoller, M.D., professor of pathology and dermatology, UAMS.

DAVID A. NELSEN, JR., M.D., M.S., is associate professor in the Department of Family and Community Medicine at the University of Arkansas for Medical Sciences, Little Rock, where he earned his medical degree and completed a family medicine residency. He completed a faculty development and clinical investigation fellowship at the University of Minnesota Medical School, Minneapolis, where he also earned a master's degree in family and community medicine. Dr. Nelsen has published and presented in the area of medical informatics and speech recognition. He serves on the technical panel of the American Academy of Family Physicians.

Address correspondence to David A. Nelsen Jr., M.D., M.S., University of Arkansas for Medical Sciences, Department of Family and Community Medicine, Mail Slot #530, 4301 W. Markham, Little Rock, AR 72205 (e-mail: nelsendavida@uams.edu). Reprints are not available from the author.

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