NIH CONSENSUS PANEL FINDS CELIAC DISEASE

IS UNDER-DIAGNOSED:

Panel Recommends Six Key Strategies for Disease Management

I attended the National Institutes of Health (NIH) Consensus Development Conference on Celiac Disease in Bethesda, MD, on June 28-30. 2004.

The full text of the panel's draft consensus statement is now available at http://consensus.nih.gov/cons/118/118cdc_intro.htm . The archived videocast of the conference sessions is available at http://consensus.nih.gov/ .

SUMMARY OF HIGHLIGHTS

Celiac Disease has many names: celiac sprue, gluten-sensitive enteropathy, non-tropical sprue, gluten intolerance, in addition to a host of other names. It is thought to result from activation of both a cell-mediated (T-cell) and humoral (B-cell) immune response upon exposure to gluten (prolamins and glutenins) of wheat, barley and rye. Celiac disease is considerably under diagnosed, according to an independent consensus panel convened in June 2004 by the National Institutes of Health (NIH).

The panel, charged with assessing all of the available scientific evidence on celiac disease announced its recommendations for the appropriate diagnosis and management of this disease, which was previously believed to be rare. Celiac disease may affect 3 million Americans. The disease is present in 0.5 to I % of the U.S. population, ten times higher than previous estimates.

"We know that celiac disease is caused by an immune response to the gluten in certain common grains, so we have a very effective treatment - a gluten-free diet - but if physicians don't recognize when to test for the disease, patients are going to suffer needlessly", said Charles Elson, M.D. of the University of Alabama at Birmingham, and chair of the consensus panel. He added, "Because the disease has been thought to be rare, testing for it may not occur to many physicians. We hope that this conference will help to increase physician awareness."

The panel found that increasing physician awareness of the various manifestations of celiac disease and appropriate use of available testing strategies may lead to earlier diagnosis and better outcomes for celiac patients.

How Is Celiac Disease Diagnosed?

All diagnostic tests need to be performed while the patient is on a gluten-containing diet. The first step in pursuing a diagnosis of celiac disease is a serologic test. Based on very high sensitivities and specificities, the best available attests are the IgA antihuman tissue transglutaminase (tTG) and IgA

endomysial antibody immunoflourescence (EMA) tests that appear to have equivalent diagnostic accuracy.

Biopsies of the proximal small bowel are indicated in individuals with a positive celiac disease antibody test, except those with biopsy-proven dermatitis herpetiformis. Multiple biopsies should be obtained because the histologic changes may be focal. Biopsies should be obtained from the second portion of the duodenum or beyond. The pathology report should specify the degree of crypt hyperplasia and villous atrophy as well as assess the number of intraepithelial lymphocytes. Some degree of villous atrophy is considered necessary to confirm a diagnosis of celiac disease. Standardization of the pathology reports in celiac disease is desirable, using published criteria such as modified Marsh criteria (1999). Communication between the pathologist and the individual’s physician is encouraged to help correlate the biopsy findings with laboratory results and clinical features. With concordant positive serology and biopsy results, a presumptive diagnosis of CD can be made. Definitive diagnosis is confirmed when symptoms resolve subsequently with a gluten-free diet. A

demonstration of normalized histology following a GF diet is no longer required for a definitive diagnosis of CD.

How Prevalent is Celiac Disease?

Population-based studies in the U.S. suggest that the prevalence of CD is in the range 0.5 to 1.0 percent, similar to estimates in Europe. These prevalence figures include both symptomatic and asymptomatic individuals.

Certain populations have an increased prevalence of CD. First-degree relatives of individuals with biopsy-proven celiac disease have a prevalence between 4 and 12 percent of villous atrophy on biopsy. Second-degree relatives also appear to have an increased prevalence. Among more groups with increased risk are those with diabetes mellitus, Down syndrome, Turner syndrome, Williams syndrome, selective IgA deficiency, and autoimmune disorders.

What are the Manifestations and Long-term Consequences of Celiac Disease?

Celiac disease traditionally has been defined as a gastrointestinal malabsorptive disorder that can present early in childhood after the introduction of gluten. It is now recognized, however, that the clinical manifestations are highly variable, may present at any age and involve multiple organ systems. Prolonged delays in diagnosis are common.

Typical gastrointestinal manifestations may include diarrhea, weight loss, failure to grow, vomiting, abdominal pain, bloating and distension, anorexia, and constipation. The presence of obesity does not exclude the diagnosis. It is very common for CD to present with extraintestinal manifestations, sometimes with little or no gastrointestinal symptoms. A distinctive example is dermatitis herpetiformis, an intensely pruritic rash on the extensor surfaces of the extremities. Iron deficiency anemia is common and may be the only presenting sign. Other extraintestinal presentations are unexplained short stature, delayed puberty, infertility, recurrent fetal loss, osteoporosis, vitamin deficiencies, fatigue, protein calorie malnutrition, recurrent aphthous stomatitis, elevated transaminases, and dental enamel hypoplasia. CD may also be associated with autoimmune conditions such as thyroiditis, diabetes type 1, Addition’s disease, Sjogren’s syndrome, Rheumatoid arthritis, etc. In addition, a variety of neurophychiatric conditions such as depression, anxiety, peripheral neuropathy, ataxia, epilepsy with or without cerebral calcifications, and migraine headaches have been reported in individuals with CD.

Based on the research presented it seems that CD represents a spectrum of clinical features and presentations. Although Classical CD (villous atrophy and intestinal malabsorption) is most commonly described, it appears that most patients have atypical CD which is fully developed gluten-induced villous atrophy found in the setting of another presentation such as iron deficiency, Osteoporosis, short stature, or infertility. The silent CD in asymptomatic patients is found either by serologic screening or perhaps an endoscopy for another reason. Another form is the latent CD, which is characterized by a previous diagnosis that responded to a GF diet and retained a normal mucosal histology upon a later introduction of gluten, or can represent patients with normal mucosa but develop gluten sensitive enteropathy.

Complications of Celiac Disease

Complications of CD typically occur after many years of disease and usually are observed in adults. Refractory CD refers to persistence of symptoms and intestinal inflammation despite a gluten-free diet. This may occur in the context of ulcerative jejunity, or it may be an early manifestation of intestinal lymphoma. Some evidence suggests that a GF diet may reduce lymphoma risk.

Who Should Be Tested for CD?

Individuals with GI symptoms, including chronic diarrhea, malabsorption, weight loss, and abdominal distension, should be tested for CD. Because CD is a multisystem disorder, physicians should be aware of other conditions for which CD testing should be considered. People with the conditions mentioned in the paragraph ”Manifestations and Long-Term Consequences” above are more at risk to develop CD. In addition, other conditions for which CD testing may be considered include irritable bowel syndrome, osteopenia/osteoporosis, etc. At this time, there are insufficient data to recommend screening of the general population for celiac disease.

What is the Management of Celiac Disease?

Treatment for CD should begin only after a complete diagnostic evaluation including serology and biopsy. The management of celiac disease is a gluten-free diet for life, excluding wheat, barley and rye. The practical inclusion of oats in a GF diet is limited by potential contamination with gluten during processing.

Based on its assessment of an extensive collection of medical literature and expert presentations, the panel identified six elements essential to treating celiac disease once it is diagnosed:

C - Consultation with a skilled dietitian,

E - Education about the disease,

L - Lifelong adherence to a gluten-free diet,

I - Identification and treatment of nutritional deficiencies,

A - Access to an advocacy group, and

C - Continuous long-term follow-up.

What Are the Recommendations For Future Research on Celiac Disease and Related Conditions? See list of research studies recommended in the NIH Draft site.

Conclusions and Recommendations

Celiac disease is an immune-mediated intestinal disorder with protean manifestations. CD is common, affecting 0.5 to 1.0 percent of the general population of the U.S., but is greatly under diagnosed. There are now specific and sensitive serologic tests available to aid in diagnosis that need to be more widely applied The treatment of CD remains a lifelong gluten-free diet, which results in remission for most individuals. The classic presentation of diarrhea and malabsorption is less common, and atypical and silent presentations are increasing. Most individuals are being seen by primary care providers and a broad range of specialists. Therefore, heightened awareness of this disease is imperative. Education of physicians, registered dietitians, and other health providers is needed.

The Panel recommended the following:

# Education of physicians, dietitians, nurses, and the public about CD by a trans-NIH initiative, to be led by the NIDDK in association with the Centers for Disease Control and Prevention.

# Standardization of serologic tests and pathologic criteria for the diagnosis of CD.

# Adoption of a standard definition of a gluten-free diet based on objective evidence such as that being developed by the American Dietetic Association.

# Development of an adequate testing procedure for gluten in foods and definition of standards for GF foods in the U.S. to lay the foundation for national food labeling.

# Formation of one federation of CD societies, CD interest groups, individuals with CD and their families, physicians, dietitians, and other health care providers for the advancement of education, research, and advocacy for individuals with celiac disease.

More information can be obtained by visiting the website listed at the beginning of this summary.

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