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Borderline Enteropathies

Craig, Robert M., M.D.

Journal of Clinical Gastroenterology: January 2003 - Volume 36 - Issue 1 - p 6-7

Northwestern University Medical School

Chicago, Illinois

There has been considerable progress in the understanding of gluten-sensitive enteropathy since the seminal observation by Dicke more than 50 years ago that the removal of grains containing gluten from the diet promotes resolution of symptoms and signs of celiac disease (CD). 1 Overwhelming data support the pathogenesis of CD to be immunologically mediated, probably autoimmune, induced by T-cell recognition of and activation by epitopes on gluten with subsequent, predominantly Th1-mediated autoreactivity against small intestinal enterocytes. 2,3 As in other autoimmune diseases, there is a susceptibility factor for CD, expressed by the strong genetic association with HLA-DQ2 alleles. 4,5 The putative gluten peptides bind to the HLA locus, allowing for T-cell activation. This binding may be enhanced by tissue transglutaminase, which can deamidate glutamine residues on the gluten peptide to the more negatively charged glutamic acid. 6 It is also noteworthy that the target of the antibody to endomysium, which is present in most patients with CD, is tissue transglutaminase. 7 Further refinements of the genetics and molecular immunology will be forthcoming.

Marsh has been instrumental in defining the histologic abnormalities that occur with gluten enteropathy and gluten sensitivity and has described some patients who have lamina propria lymphocytosis (Marsh 1 lesions) and crypt hyperplasia without villous atrophy (Marsh 2 lesions) and has considered these groups to be subclinical CD or pre CD. 8,9 Some have suggested that these lesions are not subclinical and do indeed produce symptoms. Further, it has been suggested that there are some patients who have symptoms secondary to gluten and who have normal small bowel biopsies, but who have other manifestations of gluten damage, such as those with dermatitis herpetiformis. 10 Others have discussed similarities between CD and irritable bowel syndrome and have concluded that symptoms are similar and that some patients with presumed irritable bowel have evidence of CD serologically and histologically. 11

In the current issue of the Journal, Tursi and Bandimarte 12 extend observations on a group of patients with symptoms suggestive of gluten enteropathy but with only minor histologic abnormalities on small bowel biopsy who respond clinically to a gluten-free diet. The response to a gluten-free diet characterizes these patients much better than laboratory tests, including the serologic test for the antiendomysial antigen, tissue-transglutaminase, and gliadin and sorbitol breath testing. The authors suggest that the Marsh 1 and Marsh 2 lesions might indeed be clinical disease and not subclinical and that a gluten-free diet should probably be advised in these patients in addition to those with the more classic Marsh 3 lesions, which show villous atrophy.

There remain a number of uncertainties regarding this borderline enteropathy syndrome. First, it is not clear why these patients should have such profound clinically symptomatic illness, whereas numbers of patients with full-blown CD have minimal symptoms and might present only with iron deficiency anemia or osteomalacia. Second, it is not known whether this borderline enteropathy poses the same risk for the development of malignancies (in particular lymphoma) as full-blown CD and whether this risk can be eliminated with a gluten-free diet.

This confusing picture is partially clarified by classifying the “gluten diseases” as follows: first, there are some patients with symptoms induced by gluten-containing products with no serologic, biochemical, or histologic evidence of CD. These may indeed be representatives of irritable bowel syndrome with idiosyncratic intolerance of these foods. Second, some patients present with borderline small intestinal histology (Marsh 1 or 2) and have negative serology (represented by the patients described by Tursi and Brandimarti). Third, some may have positive serology yet perfectly normal histology, as some patients display with dermatitis herpetiformis. Fourth are those with characteristic Marsh 3 lesions with subtotal villous atrophy yet negative serology. Finally, the fifth category is classic CD, both histologically and serologically.

In future descriptions of some of these groups, I urge a more standardized evaluation of these patients, including fecal fat excretion, D-xylose testing, and a Schilling test, to get a better understanding of the variable expressions of these illnesses.

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© 2003 Lippincott Williams & Wilkins, Inc.