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.

Genetics and What's New in Research

Martin Kagnoff, M.D., Professor of Medicine, Director of Laboratory of Mucosal

Immunology, University of California at San Diego, La Jolla, CA, Keynote Address at CSA/USA Conference in San Francisco, October 6, 1995
Lifeline, Winter 1996, Vol XIV, No 1, pp 4-5

Celiac Disease is typically regarded as associated with small bowel damage when eating "gluten"-containing foods. Consequently, nutrients are not absorbed normally because of damage in the small bowel, and a wide spectrum of different symptoms results. The disease in nontropical sprue can vary from very minimal to rather extensive. Nutrients are not absorbed normally because of the damage to the small bowel and that process can result in a wide spectrum of symptoms. The extent of small intestinal damage (minimal to extensive) depends on a number of factors including the amount of gliadin/gluten proteins taken in. Research is finding not only sensitivity in the small bowel area, but sensitivity also may extend to the rest of the small bowel and other parts of the intestine. Probably the whole intestine is sensitive to gliadin.

Also somewhat relevant is what you absorb and where. One of the things malabsorbed earliest in CS is iron. Sometimes all you see in some celiac patients is iron deficiency. Dr. Kagnoff has seen a number of undiagnosed celiac patients with mild iron deficiency for quite a number of years (10 - 30 years) with no apparent other symptoms until something else happens and either the iron deficiency anemia becomes a major problem or they start malabsorbing other nutrients. Iron deficiency related to very minimal malabsorption can go on for years in people and not be diagnosed. The reason is that iron is mainly absorbed very high up in the small bowel, the site of the most severe celiac damage. Similarly, a person with calcium malabsorption may manifest fractures or osteoporosis as the only symptom of Celiac Disease.

Some nutrients absorbed in the small bowel:

PATHOGENESIS OF CELIAC DISEASE

Why we get Celiac Disease:

Environmental Factors:

Certain dietary grain proteins that activate sprue:

Note that although these are correct terms for the "toxic" protein that causes CD, commonly we refer to all as gluten. The common feature of all these grains is that they have a very high content of alcohol soluble proteins called prolamins; the characteristic feature of the prolamins is a very high content of two amino acids, glutamine and proline.

Gliadins, like other proteins, are made up many different building blocks termed amino acids. It seems only a small part of gliadin is needed to activate the disease. These small parts are called peptides. There is much interest now in the celiac research community in discovering which particular sets of these building blacks/amino acids activates disease.

GENETIC FACTORS:

Yes, susceptibility to Celiac Disease is genetic. When you have certain genes, there is a higher occurrence of sprue. These genes increase Celiac Disease susceptibility. However, just to have those particular genes alone is not sufficient to get the disease. There are other factors involved as well, but we still do not totally understand the factors.

FAMILIES -

In 2 to 15% of families, multiple family members or siblings have CD. Conversely, in 85% to 98% of families there are not multiple members affected. What really points toward very strong association is that in monozygotic (identical) twins, approximately 70% develop sprue when one twin has the disease.

Susceptibility to CD is associated with HLA genes. HLA genes are a set of genes coded on the 6th chromosome that determine and govern why we are different and how our immune system reacts. Among hundreds of possibilities of HLA genes, those HLA genes that are associated with CD are commonly found among the Northern and Southern European Caucasian population. These celiac-associated genes are rare in Japan, Africa, etc. However, these genes are not rare in Northern and Southern Caucasians. However, only a small fraction of individuals with those genes get CD.

Approximately 25 to 30 percent of the populations of northern Europe individuals have the HLA DQ2 and/or DQ8 molecules associated with CD. However, almost everyone with CD has DQ2 or DQ8. These molecules bond peptides. Researches are looking at a model where these DQ molecules bind a particular piece of gliadin, and that process sets off immune response by activating T-cells.

You can inherit the genetic markers (DQ molecules) from either one parent or the other, or alternatively, inherit one particular gene from that mother and different one from the father. If a sibling in a family has the same HLA genes as his or her celiac sibling, there is as high as 30% - 40% risk of developing CD.

RESEARCH -

Studies are trying to find out what causes CD and induce similar changes in animals. Studies by Dr. Kagnoff's group (recently submitted for publication) are looking at how the DQ2 molecules associated with CD is regulated.

T-cells: T-cells are involved in CD. There are two types: Alpha beta T-cells and gamma delta T-cells. Celiac Disease has an unusual distribution of gamma delta T-cells. New studies are showing gamma delta T-cells make factors that are essential for growth and normal development of epithelial cells, rather than damaging the epithelial cells. A new concept is proposed that alpha/beta T-cells in the lamina propria are the ones that cause damage in Celiac Disease and gamma/delta T-cells help protect the epithelium.

DIAGNOSIS

We know that Celiac Disease presents with a broad range of symptoms. There is increased awareness on the part of physicians that the medical textbook picture of CD, including sudden onset, diarrhea, severe weight loss, etc., is only part of the disease. There are quite a number of other individuals who have been very delayed in diagnosis because they have much more subtle symptoms (growth retardation, iron deficiency, psychological symptoms, fatigue, etc.).

There is a range of abnormality of the mucosa which could be viewed as follows (read down):

Severe CD
Marked malabsorption
Extensive villus atrophy
Mark crypt hyperplasia

Eventually the subtle latent stage may develop into full-blown CD.

ANITBODY TESTS

The AntiEndomysial antibody test seems to be 95% sensitive; i.e., positive when there is fairly marked damage. The specificity is 90%, which means the test is quite specific for CD. However, these test are not as effective as were once thought. These test are good but not a substitute for the small bowel biopsy. They are good only as screening tests for active sprue and as a monitor for dietary compliance. These screening tests plus HLA typing might be used to show the risk for other siblings to get CD.

Question

1. Re Cancer. There is reasonable data evidence that increase is related to not being on a strict GF diet. How much gluten is ok? Even with a little gluten, there is ongoing inflammation of the bowel. We know from other malignancies, that ongoing inflammation is associated with increased risk of malignancy. On the other hand, the risk of lymphoma is still very low. The best route is to keep a strict GF diet and keep the inflammation minimal or absent as much as possible.

There is no evidence, that Dr. Kagnoff is aware of, that there is an increased risk of colon cancer with Celiac Disease. Increased risk of cancer for celiacs, which is minimal, is mainly Lymphoma, cancer of the mouth, esophagus, oropharynx, some of the small bowel and small intestine.