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American Family Physician - December 15, 2002

Gluten-Sensitive Enteropathy (Celiac Disease): More Common Than You Think

DAVID A. NELSEN, JR., M.D., M.S., University of Arkansas for Medical Sciences, Little Rock, Arkansas

Gluten-sensitive enteropathy or, as it is more commonly called, celiac disease, is an autoimmune inflammatory disease of the small intestine that is precipitated by the ingestion of gluten, a component of wheat protein, in genetically susceptible persons. Exclusion of dietary gluten results in healing of the mucosa, resolution of the malabsorptive state, and reversal of most, if not all, effects of celiac disease. Recent studies in the United States suggest that the prevalence of celiac disease is approximately one case per 250 persons. Gluten-sensitive enteropathy commonly manifests as "silent" celiac disease (i.e., minimal or no symptoms). Serologic tests for antibodies against endomysium, transglutaminase, and gliadin identify most patients with the disease. Serologic testing should be considered in patients who are at increased genetic risk for gluten-sensitive enteropathy (i.e., family history of celiac disease or personal history of type I diabetes) and in patients who have chronic diarrhea, unexplained anemia, chronic fatigue, or unexplained weight loss. Early diagnosis and management are important to forestall serious consequences of malabsorption, such as osteoporosis and anemia. (Am Fam Physician 2002;66:2259-66,2269-70. Copyright� 2002 American Academy of Family Physicians.)

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 flat tening, 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 neuro logic 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 alpha-gliadin (a component of the gluten protein) and related peptides bind with tissue transglutaminase (a ubiquitous intracellular enzyme) in enterocytes. The alpha-gliadin is rich in glutamine; transglutaminase deamidates glutamine residues, forming glutamic acid. Deamidation enhances the immunogenicity of alpha-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 Sj�gren'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

FIGURE 2. Dermatitis herpetiformis, sometimes termed "celiac disease of the skin." Vesicular, crusted, intensely pruritic lesions develop on the back (top left and right), buttocks (lower left), and elbows (lower right). Secondary infection of the lesions is common.
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 disease13,14 (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 studies8-11 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.

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

The presence of IgA antiendomysial and antitransglutaminase antibodies correlates with intestinal damage. Tests for these antibodies are highly sensitive in patients with total and subtotal villous atrophy. IgA antiendomysial antibody testing has been reported to be 100 percent sensitive in patients with total villous atrophy. The combination of IgA antiendomysial antibody and IgG and IgA antigliadin antibodies detects 76 percent of patients with mucosal damage.

It is important to note that 2 to 3 percent of patients with gluten-sensitive enteropathy also have selective IgA deficiency. Because these patients may not produce the diagnostic IgA antibodies, a positive IgG antigliadin antibody test may be the only serologic evidence of the disease. If clinical suspicion is high, quantitative IgA measurements should be obtained in these patients.26 Endoscopy and biopsy should be strongly considered in patients with selective IgA deficiency.

Declining autoantibody titers correlate with resolution of the gastrointestinal lesion and may be used to document clinical improvement. In equivocal cases or when a patient has been on a gluten-free diet, a gluten challenge test may be used to provoke the gastrointestinal lesion and serologic response.

DISTAL DUODENAL BIOPSY

Distal duodenal biopsy is the gold standard for the diagnosis of celiac disease. Biopsy should be performed in most patients with suspected gluten-sensitive enteropathy. In determining the need for biopsy, family physicians should consult a gastroenterologist who is experienced in the diagnosis and management of celiac disease.1

Complications

OSTEOPOROSIS

Calcium and vitamin D malabsorption dramatically increases the risk of osteoporosis and osteomalacia in patients with gluten-sensitive enteropathy. Most patients with celiac disease have some degree of osteopenia or osteoporosis. Fortunately, calcium and vitamin D supplementation, coupled with a strict gluten-free diet, usually results in remineralization of the skeleton.27,28

Bone density should be assessed in all patients with newly diagnosed celiac disease. Postmenopausal women should be advised about the benefits of estrogen replacement. The use of antiresorptive agents (e.g., alendronate [Fosamax]) has not been extensively studied, but these drugs may be of benefit.

NEUROLOGIC MANIFESTATION

Cerebral calcifications and epilepsy have been associated with celiac disease29,30 and do not always resolve with the institution of a gluten-free diet. Peripheral neuropathy, postural instability, "gluten ataxia," and other vague neurologic complaints may be the sole manifestation of gluten-sensitive enteropathy.31 Autoantibodies associated with celiac disease have demonstrated a strong affinity for brain vasculature.32

REFRACTORY SPRUE

In patients with refractory sprue, gastrointestinal tract inflammation continues despite maintenance of a gluten-free diet. Dietary noncompliance is the most common reason for persistent inflammation; however, coexistent conditions such as hyperthyroidism and collagenous colitis should also be considered.

Patients who are truly refractory to dietary measures may have cryptic lymphoma of (bowel) intraepithelial lymphocytes. All diet-refractory patients should be evaluated by a gastroenterologist with expertise in the management of celiac disease. Corticosteroids and immunosuppressant drugs have been used to treat refractory sprue, but data on their effectiveness are sparse.

IgA antiendomysial antibody has been shown to be 85 to 100 percent sensitive and 96 to 100 specific for celiac disease.

Intestinal strictures and bowel obstruction may develop in patients with refractory sprue or celiac disease that has been untreated over a long period.

LYMPHOMA AND BOWEL ADENOCARCINOMA

Enteropathy-associated T-cell lymphoma has been associated with untreated gluten-sensitive enteropathy and refractory sprue.33 Lymphoma may develop in patients with celiac disease who also have dermatitis herpetiformis.

Studies34,35 have shown that maintenance of a long-term gluten-free state reduces the risk of lymphoma to the level in the general population. Thus, it is imperative that patients with celiac disease (and dermatitis herpetiformis) maintain a gluten-free diet for the rest of their lives.

Patients with celiac disease are also at risk for the development of bowel adenocarcinoma in all sites. The risk is especially high in patients with a long period of disease preceding institution of a gluten-free diet.

Management

Once the diagnosis of celiac disease has been made, patients should be evaluated for known manifestations and complications (Table 5). Iron deficiency should be treated with supplemental iron. Osteoporosis should be treated with calcium and vitamin D replacement. Depending on individual factors, patients with gluten-sensitive enteropathy may need to take a multivitamin, iron, calcium, magnesium, zinc, selenium, vitamin D, or other nutrients.

The primary treatment for celiac disease is the removal of gluten and related proteins from the diet. Complete exclusion of dietary gluten generally results in rapid and complete healing of small-bowel inflammation. Advice from a registered dietitian is essential to outline an appropriate diet.

Gluten, a prolamine, is the primary protein in wheat. Hence, wheat and products containing wheat must be avoided. Barley and rye contain similar proteins and must also be avoided. Oats are a subject of controversy.36,37 Although oats themselves may be nontoxic in limited quantities, commercial oat products are measurably contaminated with wheat. Rice, corn, maize, flax, quinoa, tapioca, potato, amaranth, and other grain substitutes, such as nuts and beans, are safe.

There are many commercial gluten-free products, including breads, cookies, chips, and cereals, that can be used to fashion a rich and interesting diet. Meats, vegetables, fruit, and most dairy products are free of gluten, as long as they have not been contaminated during production.

A number of food manufacturers maintain lists of gluten-free products. These lists can be obtained from the manufacturers' Web sites or by telephone request. Information on gluten-free foods is also available from local or national support groups such as the Celiac Sprue Association. Selected resources are provided in Table 6.

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.

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The Author

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.

REFERENCES

Ciclitira PJ, King AL, Fraser JS. AGA technical review on celiac sprue. American Gastroenterological Association. Gastroenterology 2001;120:1526-40.
Van De Wal Y, Kooy Y, Van Veelen P, Vader W, Koning F, Pena S. Coeliac disease: it takes three to tango! Gut 2000;46:734-7.
Marsh MN. The natural history of gluten sensitivity: defining, refining and re-defining. QJM 1995;88:9-13.
Sollid LM, Markussen G, Ek J, Gjerde H, Vartdal F, Thorsby E. Evidence for a primary association of celiac disease to a particular HLA-DQ alpha/beta heterodimer. J Exp Med 1989;169:345-50
Collin P, Salmi J, Hallstrom O, Reunala T, Pasternack A. Autoimmune thyroid disorders and coeliac disease. Eur J Endocrinol 1994; 130:137-40.
American Gastroenterological Association medical position statement: celiac sprue. Gastroenterology 2001;120:1522-25.
Catassi C, Ratsch IM, Fabiani E, Rossini M, Bordicchia F, Candela F, et al. Coeliac disease in the year 2000: exploring the iceberg. Lancet 1994;343:200-3.
Fasano A, Catassi C. Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum. Gastroenterology 2001;120:636-51.
Hin H, Bird G, Fisher P, Mahy N, Jewell D. Coeliac disease in primary care: case finding study. BMJ 1999;318:164-7.
Branski D, Troncone R. Celiac disease: a reappraisal. J Pediatr 1998;133:181-7.
Not T, Horvath K, Hill ID, Partanen J, Hammed A, Magazzu G, et al. Celiac disease risk in the USA: high prevalence of antiendomysium antibodies in healthy blood donors. Scand J Gastroenterol 1998;33:494-8.
Cronin CC, Shanahan F. Insulin-dependent diabetes mellitus and coeliac disease. Lancet 1997;349:1096-7.
Iovino P, Ciacci C, Sabbatini F, Acioli DM, D'Argenio G, Mazzacca G. Esophageal impairment in adult celiac disease with steatorrhea. Am J Gastroenterol 1998;93:1243-9.
Clemens, PC. Coeliac disease in adults with atypical symptoms [Letter]. Lancet 1996;347:1050.
Ciacci C, Cirillo M, Sollazzo R, Savino G, Sabbatini F, Mazzacca G. Gender and clinical presentation in adult celiac disease. Scand J Gastroenterol 1995;30:1077-81.
Trier JS. Celiac sprue and refractory sprue. In: Feldman M, Fordtran JS, Sleisenger MH, Scharschmidt BF, eds. Sleisenger & Fordtran's Gastrointestinal and liver disease: pathophysiology, diagnosis, management. 6th ed. Philadelphia: Saunders, 1998:1557-73.
Fine KD. The prevalence of occult gastrointestinal bleeding in celiac sprue. N Engl J Med 1996;334:1163-7.
Sher KS, Mayberry JF. Female fertility, obstetric and gynaecological history in coeliac disease. A case control study. Digestion 1994; 55:243-6.
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.
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.
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.
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.
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.
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.
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.
Cataldo F, Marino V, Bottaro G, Greco P, Ventura A. Celiac disease and selective immunoglobulin A deficiency. J Pediatr 1997;131: 306-8.
Valdimarsson T, Lofman O, Toss G, Strom M. Reversal of osteopenia with diet in adult coeliac disease. Gut 1996;38:322-7.
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.
Dickey W. Epilepsy, cerebral calcifications, and coeliac disease. Lancet 1994;344:1585-6.
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.
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.
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.
Pricolo VE, Mangi AA, Aswad B, Bland KI. Gastrointestinal malignancies in patients with celiac sprue. Am J Surg 1998;176:344-7.
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.
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.
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.
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.

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Copyright � 2002 by the American Academy of Family Physicians.

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Against the grain: The growing awareness of celiac sprue

The wide-ranging symptoms of the disease can disguise the intestinal disorder, but new tests are helping to make diagnosis easier.

By Susan J. Landers, AMNews staff. Aug. 18, 2003.

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True or false: Celiac disease is rarely seen in the United States. When Alessio Fasano, MD, born, raised and medically trained in Italy, first arrived on American shores, he would have said "true" without hesitation.

The intestinal disorder was common in his native country. One of his medical school mentors was an expert in the condition. And he already had treated celiac patients of all ages with a wide variety of symptoms ranging from diarrhea and abdominal pain to constipation, osteoporosis, anemia and even behavior changes.

But it also was widely accepted that Americans almost never harbor this illness, which is triggered in genetically susceptible people by gluten-containing foods. Dr. Fasano looked forward to the different experiences he thought would accompany his new position as professor of medicine, pediatrics and physiology at the University of Maryland School of Medicine in Baltimore.

Instead, he almost immediately began seeing patients who had the very familiar range of complaints.

Now, Dr. Fasano co-directs the University of Maryland's Center for Celiac Research and focuses on spreading a different truth among primary care physicians. Celiac disease actually is one of the most common lifelong disorders in the United States -- American doctors just had not been trained to look for it.

This task -- making physicians more aware about celiac disease -- runs counter to much of American conventional wisdom about the disorder's incidence. Thus, Dr. Fasano and colleagues decided that mounting a large-scale study was necessary to gather the evidence that celiac disease affected many patients.

One in 133 Americans is at risk for celiac disease.
They hypothesized that because the necessary components for the disease almost certainly were present in the United States -- both the genetic background and the gluten trigger -- there either was a third element at work that prevented the interplay of the components or the disorder was being overlooked.

After screening more than 13,000 people in 32 states, they found that the latter assertion proved true. One in 133 Americans is at risk for celiac disease.

Those figures, published in the Feb. 10 Archives of Internal Medicine, demonstrated a tremendous increase from the one in 4,700 Americans who had been diagnosed up until that point. Estimates of the prevalence of celiac disease, also called celiac sprue, now range from one in 100 to one in 300.

"Whichever way you look at it, it's a very large number of people," said Chaitan Khosla, PhD, a professor of chemistry at Stanford (Calif.) University, who started the Celiac Sprue Research Foundation after his son and wife were diagnosed with the disease.

The disorder also can be found in many of the world's populations, he said, "pretty much all the way from the Indian subcontinent to Eastern and Western Europe as well as Northern Africa."

The fact that it is not always recognized in the United States doesn't surprise Joseph Murray, MD, professor of medicine at the Mayo Clinic in Rochester, Minn. Originally from Ireland, where celiac disorder is considered a very common ailment, and trained in medicine at the University of Galway, he never expected to confront the disease again once he arrived in the New World. "I came to study another part of the digestive system, and celiac disease kind of came along and bit me on the leg."

Celiac disease is often overlooked in the U.S.
He attributes celiac's lack of American celebrity to the fact that there are a lot of diseases, and places in the medical school curriculum are reserved for those that are either very big, such as cancer or heart disease, or very noticeable.

"It has to be a classic something," he said. Celiac disease doesn't fit this description -- it often presents atypically, "so it's not what you're expecting."

Others would agree. "It falls into that category of squirrelly disorders that show themselves in many different ways," Dr. Khosla said. Dr. Fasano described it in the June 19 New England Journal of Medicine as a "clinical chameleon."

Despite this shifty nature, celiac disease can be suspected if a patient complains of chronic diarrhea that's been going on for several weeks; has other autoimmune diseases such as type 1 diabetes, thyroid disorders, some types of arthritis or lupus, or if they have a family history of those disorders; or is anemic and the condition cannot be easily explained, Dr. Murray said.

Dr. Fasano defined the disease even more broadly. "You can have vomiting, bloating or constipation, or you can have symptoms that have nothing to do with the gastrointestinal system, such as chronic fatigue syndrome, joint pain, osteoporosis, depression or miscarriage."

Many people with the disorder go undiagnosed for years. The typical time between the onset and diagnosis in the United States is 11 to 13 years. Sometimes the disease is triggered by severe emotional stress, surgery, pregnancy or viral infections.

The disease is split about 50/50 between being a disease of children and a disease of adults, Dr. Fasano said. In textbooks, it is likely to be described as a pediatric condition with the typical symptoms of diarrhea and big belly developing a few weeks after grains are introduced into a child's diet. If there is anything like a classic form of this condition, it is the one diagnosed in very young children.

"During the past two decades, however, the clinical picture of the disease has changed to include milder forms, thus resulting in an upward shift of the age at diagnosis," writes Maki Markku, MD, PhD, of the Pediatric Research Center in Tampere, Finland, also in the June 19 NEJM.

Testing one, two, three
The disease can be detected in patients via blood tests. And these readily available screens put the power to consider the disorder in the hands of the primary care physician.

That's a good thing, according to the experts. After all, it's the primary care physicians who are seeing most of the patients with celiac disorder, although they might not know it. "If a primary care doctor has 2,000 to 3,000 patients, then he or she is likely to have 10 or 15 patients with celiac disease. That's not a small number for a chronic disease," Dr. Murray said.

Celiac's only treatment is to avoid foods with gluten.
Negative blood test results can rule out the disease, while a positive finding indicates there's a good chance a patient has it.

But these outcomes are not entirely clear cut.

One problem with the blood test is that it will result in a negative finding if patients already have eliminated gluten from their diets.

A way to circumvent this problem is to order a DNA test, which doesn't require the presence of antibodies to gluten to confirm the presence of the disease. The diagnostic gold standard, however, is a biopsy of the intestine performed when a patient has eaten gluten-containing food and the resulting damage to the villi lining the intestine can be verified.

Dr. Khosla urges primary care physicians to consider sending patients for a blood test the day they present with symptoms and before they make dietary changes.

He would also like to see an even simpler pin-prick blood test developed as a diagnostic tool that could be on hand in every primary care physician's office. "But it is just not on the radar screen, because primary care physicians aren't saying they have a need for it."

Changes for life
Once diagnosed, the effective, albeit difficult, treatment is to avoid eating anything containing gluten. Foods that contain wheat, rye, oats and barley must be eliminated from the diet. There are also hidden sources of gluten in many foods and even in prescription medications. Labels sometimes identify them as "vegetable" or "plant" protein.

The good news is that avoiding gluten allows damaged intestinal villi to heal and an individual to fully recover. Advocates are lobbying Congress for passage of food labeling legislation that clearly indicates which foods are off limits. Europe has adopted a universal sign of wheat with a line through it to indicate safe products.

Dr. Khosla is very familiar with the implications of diet and the changes celiac disease has made necessary in his life. "We've learned to keep a gluten-free kitchen. I would say on average, if someone asked me the difference between my kitchen now and my kitchen seven years ago [before his son was born], the primary difference is higher grocery bills."

But these costs are nothing compared with the high price patients can pay if the disorder is not adequately diagnosed and treated. Quality of life is one thing. Stomachaches and gas make it hard for individuals to socialize. Additional consequences include short-term memory loss and depression.

Miscarriages and osteoporosis also are among the complications. Dr. Fasano recently spoke with a woman who was diagnosed with celiac disease at age 46. She had experienced nine miscarriages, and her diagnosis came too late to allow her to have children.

"I can't do anything for her now because she is in menopause and has lost the opportunity to have a baby," he said.

Lymphoma is the scariest complication of undiagnosed celiac disease, although it is extremely rare, Dr. Fasano said. "But the chances of developing other autoimmune diseases as a consequence of celiac disease, like type 1 diabetes, are well described," he said. "And that is a travesty."

There are efforts under way to find a cure other than dietary restrictions, and Dr. Khosla hopes to hasten its discovery through the work of his foundation. "If this was like GERD [gastroesophageal reflux disease] or any other gastrointestinal disorder for which there are good treatments, there wouldn't be any room for a nonprofit organization to do what is typically done by the pharmaceutical industry."

Others agree that an alternate treatment or even a cure is not impossible in the next five or 10 years. After all, celiac disorder is unique in that it is the only autoimmune disease for which all elements are known, Dr. Fasano said. The trigger, gluten, is well understood. And the genes involved, though there may be more, also are known, as is the part of the body that is attacked.

"For scientists, that is the blessing. I believe we will come up with a cure," he said.

That's what Dr. Khosla hopes is in store for his young son.

"I have a dream that when he goes to college in the fall of 2014, he takes with him a refillable prescription for a pill he can take whenever he finds himself in a situation where he cannot avoid, or does not wish to avoid, a gluten-containing meal."

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Symptoms:
Behavior change
Bone pain
Chronic diarrhea
Dermatitis herpetiformis
Joint pain
Muscle cramps
Pale sores inside mouth
Recurring abdominal bloating and pain
Seizures
Tooth discoloration
Unexplained anemia
Weight loss
Source: National Institute of Diabetes & Digestive & Kidney Diseases

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Diagnosis
Blood tests are available to measure levels of antibodies to gluten, which is found in wheat, rye and barley, as well as other foods and some pharmaceutical products.
If the blood tests suggest celiac disease, a biopsy of the intestine would confirm the disease.
Blood tests and biopsy should be completed before an individual begins a gluten-free diet.
Source: National Institute of Diabetes & Digestive & Kidney Diseases

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Weblink
Celiac Disease Foundation (www.celiac.org)

Celiac Sprue Assn. (www.csaceliacs.org)

University of Maryland Center for Celiac Research (www.celiaccenter.org)

Celiac Sprue Research Foundation (www.celiacsprue.org)

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Copyright 2003 American Medical Association. All rights reserved.

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Heather is the Administrator of the IBS Message Boards. She is the author of Eating for IBS and The First Year: IBS, and the CEO of Heather's Tummy Care. Join her IBS Newsletter. Meet Heather on Facebook!

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