Celiac Disease and Gluten Sensitivity

Celiac Disease and Gluten Sensitivity

By Carol E. Semrad, M. D.

Celiac disease, also referred to as celiac sprue, is an inflammatory condition of the small intestine precipitated by the ingestion of wheat in individuals with certain genetic makeups. The onset of illness most commonly occurs around age two, after wheat has been introduced into the diet, and in early adult life (third and fourth decades). However celiac disease can begin anytime in life. In susceptible individuals, the wheat protein gluten triggers an inflammatory reaction in the small bowel which results in a decrease in the amount of surface area available for nutrient and fluid and electrolyte absorption. The extent of loss of intestinal absorptive surface area generally dictates whether an individual with celiac disease will develop symptoms. Individuals with celiac disease may experience severe symptoms such as diarrhea, weakness, and weight loss indicating a marked decrease in intestinal absorptive surface area involving much of the small intestine. On the other hand, some individuals present with anemia related fatigue and have no symptoms referable to the gastrointestinal tract. Such individuals likely have disease limited to the proximal small bowel where iron is normally absorbed, with the remainder of bowel adequate for nutrient and fluid absorption. Other extraintestinal manifestations of celiac disease include osteopenic bone disease, tetany and rarely neurologic disorders. Gluten sensitivity can also manifest itself as a blistering, burning, itchy rash on the extensor surfaces of the body (dermatitis herpetiformis). Most of these individuals have intestinal biopsies characteristic of celiac disease regardless of gastrointestinal symptomatology. Recently, with the discovery of antibodies which are specific for celiac disease, screening of families of celiacs and select populations have identified a growing number of asymptomatic individuals who have circulating antibodies and changes on intestinal biopsies characteristic of celiac disease. These individuals clearly have a gluten sensitivity but it is unclear whether they will develop the clinical features of celiac disease over time. Removal of wheat (gluten) from the diet of individuals with celiac disease or gluten sensitivity results in regeneration of the intestinal mucosal absorptive surface area and resolution of symptoms in most patients.

Cause of celiac disease

There are two important factors that contribute to the development of celiac disease:

The ingestion of wheat: The "Coeliac Affection" was first reported by Gee in 1888, however it was not until 1950 that wheat was proposed to be the cause of celiac disease. The evidence was based on the observation of a Dutch physician named Dicke who noted during World War II, a time when wheat grains were scarce in Holland, that children with celiac disease who had otherwise failed to thrive improved on a wheat-poor diet. Since then the large water-insoluble protein, gluten, present in wheat has been identified as the offending substance. Extraction of gluten with alcohol has further narrowed activity to smaller proline-rich proteins called gliadins which are capable of precipitating disease in previously asymptomatic celiacs. Analogous proteins exist in other grains such as rye, barley and oats and therefore these grains are also capable of exacerbating celiac disease. The specific peptide sequence of the gliadins responsible for triggering intestinal inflammation has not yet been identified.
The genetic background of the individual: Celiac disease runs in families. First degree relatives of individuals with celiac disease may or may not manifest symptoms of the disease. Predisposition to gluten sensitivity has been mapped to the major histocompatibility (MHC) D region on chromosome 6. The most important HLA haplotype is DQw2 which is often in linkage with DR3. Other important HLA haplotypes identified are DR7 and DPB 1, 3, 4.1 and 4.2. The sites on these MHC class 2 expressed proteins responsible for interacting with gliadin and host T cell receptors thereby sensitizing the intestine to gluten have not been identified.

Intestinal response to inflammation

The main function of the small intestine is to absorb nutrients and fluid and electrolytes, a process dependent on adequate surface area. In this regard, the absorptive epithelium (villus) of the small intestine is pleated in the intestinal lumen to increase its surface area. Intestinal inflammation of any etiology, if severe enough, is associated with flattening of the villus epithelium which results in a decrease in intestinal absorptive surface area. How activated inflammatory cells in the lamina propria beneath the surface epithelium and interspersed between epithelial cells bring about villus flattening remains a mystery. Intestinal biopsies taken from individuals with celiac disease and gluten sensitivity show a spectrum of these mucosal abnormalities. Three distinct patterns have clinical relevance:

Infiltration of the villus epithelium with lymphocytes and a normal villus and crypt architecture: This pattern is found in 40% of individuals with Dermatitis Herpetiformis and a portion of first degree relatives of celiacs who have no gastrointestinal symptomatology.
A flat mucosa characterized by villus flattening and crypt elongation with inflammatory cells in the lamina propria: This pattern is classically found in individuals with celiac disease who have gastrointestinal symptoms, but has also been reported in asymptomatic celiac relatives and individuals with Dermatitis Herpetiformis. It is important to keep in mind that intestinal biopsies are most commonly obtained endoscopically from the duodenum and therefore do not provide information as to the extent of disease along the length of jejunum. Since the duodenum is the first segment of small intestine exposed to gluten, villus flattening might be most severe in this location while much of the jejunal villi remain relatively normal, accounting for an asymptomatic state. In most of these individuals, treatment with a gluten-free diet results in the return of villus and crypt architecture to normal or near normal.
A hypoplastic mucosa characterized by villus flattening and small crypts: This biopsy is found in the small group of patients with presumed severe celiac disease refractory to a gluten-free diet. These individuals have persistent ill-health due to intestinal malabsorption and sometimes require nutritional support parenterally. This intestinal lesion is irreversible.

Diagnosis of celiac disease

There is no test yet which is definitively diagnostic of celiac disease. Relief of symptoms or reversion of an abnormal intestinal biopsy to normal on a gluten-free diet is the most convincing evidence that an individual has celiac disease or gluten sensitivity. Intestinal biopsies as discussed above show characteristic findings compatible with celiac disease but are obtained just as often to exclude other intestinal conditions, most importantly infection, which can have a clinical presentation similar to celiac disease.

The first serologic marker reported to be of use in the diagnosis of celiac disease was the IgG class antigliadin antibody (AGA). Though sensitive, this antibody is also found in other diseases and is therefore not specific for celiac disease. IgA class AGA is more specific, however about 2 % of patients with celiac disease have selective IgA deficiency. A positive IgG and IgA AGA gives a reported sensitivity of 96 % to100 % and specificity of 96 % to 97 %. If only the IgG AGA is positive an evaluation for selective IgA deficiency should be undertaken. Antireticulin antibodies (ARA) have also been reported in individuals with celiac disease, but are nonspecific. IgG ARA is relatively useless, but IgA ARA has a high sensitivity and specificity in adults (97 % and 98 % respectively). In children these values are much lower. Recently two antibodies, IgA class antiendomysial antibody (EMA) and human jejunal antibody (JAB), have been identified which are highly sensitive and specific for active celiac disease (100 % sensitivity and specificity reported in one study). The one best characterized is the EMA, an antibody against endomysium reticulin fibers. In adult studies, EMA was only found in patients with active celiac disease and not other diseases. The test is less powerful in children as EMAs have been detected in other childhood diseases. The more important limitation of EMAs in children is the reported fall in sensitivity observed in children with celiac disease less than 2 years old. Even the EMA and JAB antibody tests in adults are not fool proof as they may not be positive in individuals with celiac disease and IgA deficiency.

A panel of these antibodies seems to be most useful in the diagnosis of celiac disease. A combination of IgG AGA, IgA AGA and EMA have a reported positive predictive value of 99.3 % when all were positive and a negative predictive value of 99.6 % when all were negative. These antibodies tend to lessen or disappear when individuals are maintained on a gluten-free diet. Antibody testing is important in screening individuals who are at risk for having celiac disease but have no symptomatology, in individuals with atypical symptoms or extraintestinal manifestations of celiac disease, and in individuals with presumed celiac disease who fail to respond to a gluten-free diet. Patients with postive antibody tests must undergo small intestinal biopsy to confirm the diagnosis and assess the degree of mucosal involvement.

Treatment of celiac disease

Unlike autoimmune diseases in which the precipitating antigen either is not identified or if identified can not be removed, the antigen precipitating celiac disease i.e. gluten can be removed from the diet. This sounds easier than done as wheat is used as a filler and thickener in a number of store bought and restaurant prepared foods. Avoidance of gluten in the diet requires careful scrutiny of food labels for the presence of wheat and other offending grains such as rye, oats and barley. Products labelled wheat-free are not necessarily gluten-free. Common food items that can not be eaten include breads, bagels, pastries, pasta and pizza. There are companies throughout the United States which produce gluten-free products made predominantly from rice flour. Most patients treated with a gluten-free diet will note a lessening of symptoms within 2 weeks and no follow up intestinal biopsy is required. A small group of patients have partial or no response to a gluten-free diet. One important cause of a poor dietary response is the continued ingestion of gluten in foods thought to be gluten-free or just plain dietary cheating. Antibody testing while such patients are on a "strict" gluten-free diet may be useful in this situation. A kit which utilizes the Elisa assay has been developed to test food products for the presence of the gluten antigen. In individuals who have a poor response to a gluten-free diet, a repeat intestinal biopsy is mandatory after 3 months treatment to assure that other intestinal lesions such as infection or intestinal lymphoma was not missed.

Why treat celiac disease?

In symptomatic patients the obvious answer is to relieve debilitating symptoms. What about individuals who have minimal symptoms or who are asymptomatic? There are two reasons to treat such individuals with a gluten-free diet: 1) a subgroup of these patients will progress to more severe disease and hence develop symptoms and 2) there is an increased incidence of small intestinal lymphomas and adenocarcinomas in individuals with celiac disease. The increased incidence of cancer seems to correlate with the degree of intestinal inflammation (activity) present, as individuals whose disease responded to a gluten-free diet and who remained compliant with the diet had a lower incidence of such cancers. Whether individuals who are found to have elevated antibodies specific for celiac disease but are asymptomatic and have normal intestinal biopsies should be treated with a gluten-free diet is unclear.

The following patient organizations provide information on celiac disease, gluten sensitivity and dietairy treatment:

American Celiac Society-Dietary Support Coalition
58 Musano Court
West Orange, NJ 07052
(201) 325-8837

Celiac Disease Foundation (CDF)
13251 Ventura Blvd. #3
Studio City, CA 91604
(818) 990-2354

Celiac Sprue Association/USA, Inc.
P.O. Box 31700
Omaha, NE 68131-0700
(402) 558-0600

Gluten Intolerance Group of North America
Cynthai Kupper, Exectutive Director
15110 10 Ave SW Suite A
Seattle WA 98166-1820
206-246-6652
FAX 206-246-6531
gig@accessone.com
www.gluten.net