CSA Library Series is a collection of articles that pertain to celiac disease and dermatitis herpetiformis. Most of these articles have appeared in CSA’s quarterly newsletter, Lifeline, which all CSA members receive. Historic articles included in these resources may or may not include updated notes. Updated information indicated in red type. Articles represent the work of the author.

Celiac Disease: Then and Now

Richard J. Grand, M.D., Pediatric Gastroenterologist, Chief, Division of Gastroenterology and Nutrition
The Floating Hospital for Children, New England Medical Center and Department of Pediatrics
Division of Gastroenterology, Tufts University School of Medicine
Excerpts from Keynote Address, 21st Annual CSA Conference, Warwick, RI, October 30, 1998
Lifeline, Winter 1999, Vol XV, No 1, pp 1-2

The challenge of living with celiac sprue is not trivial. A lot of people say, "Well, what's the big deal. You just get on the gluten-free diet, and you are cured." But eating gluten-free is not simple, so that is the challenge. The good news, of course, is that the complications of celiac disease can be avoided by careful adherence to a self-managed gluten-free diet.

History of Celiac Disease. Celiac disease is a very old disease, but it is not a very old recognized disease since it was only described a hundred years ago. The fact that the bowel showed a flat villus lesion, was recognized before Samuel Gee actually described the celiac affection in 1888. But it wasn't until his landmark paper that people recognized that all of the diseases that were associated with other clinical findings were the same thing. And it wasn't until 1960 when Margot Shiner and Cyrus Rubin separately invented a small bowel biopsy capsule that they could use to make a proper diagnosis.

The implication from a historical review is that differing conditions were actually due to gluten intolerance and were what we call today celiac sprue, celiac disease or gluten-induced enteropathy. The landmark observation by Dicke in 1953, occurred because in the Netherlands, the Dutch children who had celiac disease did remarkably well during the war when there was a famine and there was not wheat available. He made the intuitive leap that the absence of wheat must be associated with the healing and return to health - and then was able to demonstrate in fact that was the case. So the ability to make the diagnosis and to have the correct pathophysiology for celiac disease is very modern. Celiac disease is a disease of the small intestine due to permanent intolerance to gluten and complicated by malabsorption of nutrients and associated symptoms. Diagnosis depends upon an abnormal, small intestinal biopsy in the presence of appropriate clinical symptoms.

Pathophysiology. How the disease occurs depends on an intolerance to gluten, the major component of the endosperm in grains. The major constituents of gluten, which is a large carbohydrate-containing protein, are glutenins and gliadins. And gliadin is the fraction which contains the toxic product; it has many minor constituents as well, other proteins that have nutritional value: lipids and carbohydrates. But, it is a specific fraction of gliadin that is the problem. Gliadins as a family are alcohol soluble and glutamine and proline rich. glutamine and proline are important amino acids in the diet and they are constituents of both plant and virtually all animal cells.

Gliadin can have as many as forty or more components. Finding the toxic fractions has been about a 20-year job. Only alpha-gliadin has been implicated in celiac disease and the specific antigen, that is the actual problem, is a small peptide with a molecular weight of about 1500 which causes the disease. A peptide is just a string of amino acids, the building blocks of proteins, which are strung in a chain. So, 1500 is a very small molecular weight and finding the exact configuration of the protein might be helpful in learning how to block the immune system response to the toxic fractions in people who have celiac disease.

Epidemiology. The epidemiology of celiac disease is variable. In Galway, Ireland, for example, the prevalence of celiac disease is actually one in three hundred which is a very high incidence. In Austria, it is equally prevalent. But as one goes across Europe and to Australia, the prevalence changes markedly. The data are from studies in which screening has been verified by biopsy.

The problem challenging us is to identify the prevalence of celiac disease in populations where it is not common. It is very easy to do screening and tests. But for every screened patient who has a positive result, the only way to be absolutely certain whether they are affected or just happen to have antibodies is to do the small bowel biopsy. That procedure is both expensive and often rejected by the patient or potential patients. So ascertainment of prevalence in the U.S. is really a challenge. We really do think that there are missed celiacs in the population, but it is not yet clear to those who have this feeling exactly how to go about ascertaining who is missed.

Overall in the United States, the prevalence, where it has been determined, is much more close to that of Australia which is not really a surprise because the bulk of the Australian population has the same genetic pool that is found, for example, in most if the New England Caucasian population.

Immunology in Celiac Disease. There is no question that celiac disease is an autoimmune disease in which the immune system is altered. The immune system is probably altered as a genetic variant; that is, those persons who have celiac disease have something different about their immune system from those who do not have the disease. But how that variant triggers the noxious interaction with gluten is still a challenge for the future.

How do we know the immunology in celiac disease is deranged? The damage can occur within hours wither after gluten ingestion or even more rapidly if gluten is placed directly on the mucosa (the lining of the bowel). This experiment is done by actually putting gluten on the small bowel in a targeted place and then serially biopsying that site or adjacent tissues. You can show that there was a progression of injury where the gluten has been placed in the small bowel.

IgA is a protein that is generally secreted by the body to protect itself against bacterial injury. In celiac disease, IgA against gluten is deposited in the basement membrane of the intestinal epithelial cell, the lining on which the cells sit. It is the first alteration that occurs when the bowel is exposed to gluten. It is this immune response that occurs very rapidly after gluten is presented to the lining cells of the small bowel.

There are other findings such as elevated serum IgA levels and marked IgA production by the lymphocytes in the small intestine. There are alterations of the marker proteins, the DR-antigens on the cells of the small bowel, especially in the crypts. There is a hyperproliferative response, an increase in the turnover of cells. There is also the risk of lymphoma disappears with compulsive attention to the gluten-free diet.

Immunogenetics. There is clearly a genetic (gene) association for the individual with celiac disease. There is a common susceptibility locus on chromosome six. That means that scientists can screen families and find what is known as haplotypes, i.e., markers associated with chromosome six that identify the presence of a susceptibility to celiac disease. The marker is associated with changes in the HLA status of the patient; the HLA markers are proteins on cells which distinguish us from one another. While the markers do not identify every single case of celiac disease, there is clearly a stratification of these markers in people who have celiac disease compared to people who don't.

The other interesting observation in immunogenetics is the concordance of celiac disease in twins. That means that if one twin has the condition, the other is very likely to have it. For geneticists, concordance identifies the intensity of the genetic linkage. For other first degree blood relatives, about two or four percent are affected at a minimum.

Associated Conditions. There are also associated conditions which link celiac disease to an immune dysfunction of some kind.

Puzzle to Recognize Celiac Disease. The challenge, particularly for physicians, is to recognize celiac disease. Often parents know that something is wrong with their child before doctors are willing to believe it. Recognizing celiac disease is not a trivial issue. Celiac disease does occasionally present under age nine months, although it is certainly not common in this country. There may be vomiting, diarrhea, failure to thrive and abdominal distension. Or, some symptoms may not be presented or marked in some babies. It is not uncommon for pediatricians to feel that symptoms can be explained by merely a viral infection. The challenge is to get the correct differential diagnosis and to proceed with the appropriate testing.

At age nine to nineteen months, classic findings begin to appear: the pot belly; the anger or irritability; the change in body composition such as loss of muscle bulk, loss of body fat, thinness; and other findings. In older patients, older children as well as adults, a whole series of other symptoms or signs may be present. We might see short stature, often without any other complaints; patients may have a workup for endocrine disease and come out positive. These patients are then referred for small bowel biopsy for a conclusive diagnosis.

Other symptoms may include the following: unexplained anemia; rickets which effects a vitamin D deficiency; personality problems; depression and irritability; deteriorating school or work performance; amenorrhea, an abnormal absence of menstruation; arthralgia, which is often seen as rheumatoid arthritis; infertility; changes around the mouth that signify vitamin malabsorption; lymphopenia, a reduction in the percent of lymphocytes in the blood; confirmed abnormal platelet count and vitamin K status; clinical and laboratory markers of nutritional status, particularly measures of serum folate, B-12 and the fat soluble vitamins A, D and E; reduced levels of ferritin, the iron binding protein in blood; low levels of calcium, phosphorus and magnesium.

Finally, specific serological tests for celiac disease itself are done. Antigliadin antibodies (IgA and IgM) are measured. In some clinics, antireticulin antibodies are evaluated; in other clinics antiendomysial antibodies are screened. These are antibodies in the circulation of people who have celiac disease that react with smooth muscle fibers in monkey esophagus or human umbilical cord smooth muscle. Why this particular marker is so effective as a screening test is not yet completely understood. But it is a very useful test.

The serum IgG antigliadin antibody is neither sensitive nor specific. Sensitivity means that it will be highly associated with disease and specificity means it will be highly associated with normal. The best way to do the diagnostic test in celiac disease is to combine the IgG and IgA antigliadin antibody with an IgA antiendomysial antibody. Then one is as close to 100 percent of both sensitivity and specificity that when the tests are positive they have positive and negative predictive value as one can possibly get with a clinical test. But the problem always is to be ascertained using small bowel biopsy. We don't diagnose patients on the basis of screening tests. Remember that IgA deficiency will alter the results and tests may be normal when in fact they should be positive.

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