Celiac Disease This session introduces you to the intestinal malady known as celiac disease or celiac sprue. There are three reasons for looking at this disease at this stage of your career: 1. Youll learn something about an often undiagnosed intestinal disease which can compromise the overall health of a patient that has a pronounced morphological component. 2. Youll see the havoc the (enteric) immune system can wreak when it receives inappropriate signals. 3. Youll be able to observe the almost unbelievable regenerative capacity of the gut (and youll realize you do understand normal intestinal histology.)

Facts about Celiac Disease The most under diagnosed disease in the U.S.A., afflicts ~1:250, over a million individuals. Underdiagnosed by ~25%. Patients often experience symptoms for years before being diagnosed, average time to diagnosis is 8 years. Undiagnosed, untreated disease predisposes patients to osteoporosis, anemia, chronic gastrointestinal upset, developmental and learning disabilities in children, and certain forms of aggressive cancers especially lymphatic cancers. Its proper descriptive name is gluten sensitive enteropathy which indicates that it occurs as a consequence of ingesting grain products that contain gluten, such as wheat, as explained on the next page. Source:

Pathogenesis: 1 A component of gluten, gliaden, interacts with a specific genetic form of HLA receptor on an antigen presenting cell. 2. Tissue transglutaminase converts glutamine residues to glutamic acid residues making an even more potent antigen. 3. T helper cells are activated and, in turn, activate B and killer T cells. 4. Plasma cell antibodies bind to gliadin bound to enterocytes, tissue transglutaminase and reticular fibers surrounding gut smooth muscle (endomysial abs). 5. T cells release (inappropriate) inflammatory cytokines as well as inflict tissue damage. Source:NEJM 346:180, 2002

Biopsy of the intestine in a patient with no active disease following challenge with gluten (~ 1 week). What is particularly notable is the infiltration of the epithelium by lymphocytes (you can see the increased number of nuclei but its hard to determine specific cell types!) Enterocytes also show damage. (Source:same as slide 11) Progress of the disease is shown on the next slide.

Normal intestinal biopsy Small intestinal biopsy in a patient with active celiac disease Source:NEJM

Normal intestinal surgical specimen with distinct villi Celiac disease specimen with total loss of villi, the arrows indicate crypt openings Source: Pathology of the Gastrointestinal Tract, 2nd Ed., 1998, Ed. by Ming and Goldman,

Arrows indicate intraepithelial lymphocytes which, in this disease, are destructive. Arrowheads indicate plasma cells which are secreting abs against gliaden bound to enterocytes as well against reticulin and tissue transglutaminase resulting in tissue destruction. Source:NEJM

Biopsy from which the previous high power micrograph was taken. Villous atrophy, crypt hyperplasia (it almost looks like the colon) are evident. From what region of the small intestine was this biopsy taken? Duodenum, see Brunners glands? Source:NEJM

Treatment There is only one treatment, strict adherence to a gluten- free diet. Gluten-free foods are limited, and frequently unavailable. Gluten-free foods cost 2-3X that of normal foods. Unfortunately, purchase of gluten-free products is rarely covered by health insurance. The good news is that strict adherence to a gluten-free diet can have an extraordinary outcome as seen on the next slide. Source:

When the patient adheres to a strict gluten-free diet, the damaged intestinal mucosa (often but not always ) completely regenerates including reformation of normal villi. This is a normal biopsy; see screen 11 for a complete biopsy series. Source:NEJM

SprueNormal As the damage recedes, the ragged, lymphocyte infiltrated-enterocytes are replaced by normal columnar ones, thus assuring normal transport from the lumen into the body. Source:NEJM

This series takes you through active disease, repair (better cell and crypt morphology, decreased cell infiltration) and repair (reformation of villi and normal crypt:villus ratio -- difficult to see) in this micrograph. Source: Gastrointestinal Mucosal Biopsy by Harvey Goldman; Churchill Livingston

Study of this disease reveals that the genes that regulate the differentiation of the four main cell types found in the epithelium: 1. enterocyte, 2. goblet, 3. Paneth, and 4. enteroendocrine can restore the normal populations of these cells as the disease recedes. Beyond that, the genes that regulated villus and crypt formation (complicated processes) during embryonic histogenesis can be reactivated in the adult to restore tissue architecture. Its learning how to harness these genes to restore normal tissue architecture that remains a major challenge in medicine.

The Course of Celiac Disease The role of the physician is that of diagnosis. Treatment is almost entirely dependent on the patient. Cure is almost entirely dependent on the innate ability of the body to restore normal cell populations and tissue architecture (recapitulating, to a great degree, embryonic histogenesis.)