Is Celiac Disease (Gluten Sensitivity) a Premalignant Disorder?

That celiac disease (CD) is a premalignant condition is no longer open to doubt. In this respect, the contribution of the late Dr. Trevor Cooke of Birmingham must be acknowledged to have provided some of the best clinical evidence for this important association. This subject has been reviewed in my recent book (1) by some of his co-workers and successors, Dr. Holmes and Dr. Thompson. HISTORICAL PERSPECTIVE The coexistence of intestinal tumors and malabsorption was recognized in the earliest decades of this century. In those initial case reports, it was invariably assumed that the malabsorptive process was secondary to mucosal damage arising from the tumor itself, either from infiltration or lymphatic blockage. The reverse notion, that celiac malabsorption itself predisposes to malignancy, was first proposed in Bristol by Gough and colleagues in 1962 (2). I do not wish to dwell on the better-known aspects of this undoubted association. Instead, I wish to expand the terms of reference and to consider the question of malignancy, as well as its risks, within the wider context of what I prefer to regard as gluten sensitivity. The reasons for this are as follows. Thirty years ago, following the introduction of the peroral biopsy technique, the diagnosis of CD was made if there was evidence of an overt malabsorption syndrome accompanied by characteristic villous flattening of (upper) jejunal mucosa. Subsequent response to a gluten-free diet with evidence of mucosal regeneration and healing added another component to the diagnosis, as well as to popular contemporary definitions of the disease. GLUTEN SENSITIVITY Unfortunately, that simplistic notion of CD is no longer a viable proposition, because over the past few years it has become apparent that a large proportion (50% to 60%) of individuals with undoubted sensitization to gluten are asymptomatic or have latent disease. This concept of latency (existing but not manifest) implies that an individual who is genetically predisposed to be hyperreactive to gluten may remain undetected, unless unmasked by other environmental factors, such as infection, stress, or tumor, or identified through directed clinical investigation. We have also come to the realization that some adults and children may have atypical features that do not immediately suggest a gastroenterological problem, so that the condition, either through its latency or atypical manifestation, may be entirely missed in its more subtle guises, even by very experienced physicians (3). A further difficulty has arisen through recent immunopathologic studies, which likewise confound earlier definitions. This difficulty has come with the realization that there is a spectrum of intestinal responses to gluten exposure that is host-driven and highly suggestive of T-cell-mediated responses operating at the mucosal level. These varied intestinal reactions make up a pattern of interrelated forms of mucosal change or injury, arbitrarily designated infiltrative, infiltrative-hyperplastic, flat-destructive, and irreversibly hypoplastic-atrophic. This latter appearance is sometimes linked to unresponsive end-stage intestinal failure, often within the context of multifocal lymphoma. Such unresponsiveness, rather than contradicting earlier definitions, is clearly an important stage in the natural history of the condition, wherein undoubted earlier sensitization (as evidenced by HLA type, family history, previous response to diet, or evidence of splenic atrophy) is superseded by a relentless downhill phase for reasons that have still to be recognized and understood (4). Dermatitis Herpetiformis These new insights have also found parallels in studies of patients with dermatitis herpetiformis. Dermatitis herpetiformis is an extremely useful model of gluten-driven hypersensitivity, since the rash acts not only as an external mirror of that hypersensitivity but also as a reason for referral to a specialist. Thus it has afforded us a very valuable glimpse into the entire spectrum of mucosal changes to be expected in gluten sensitivity. While 50% of patients have classic signs of flat mucosa, a small proportion (≈5% overall) are without evident proximal histologic abnormality and the remainder have infiltrative lesions or infiltrative hyperplastic lesions. In the latter patients, high-titer antibody to gluten is elaborated (so-called preinfiltrative lesions), suggesting that antibody reactivity may, in a few cases, predate lymphocytic infiltration or flattening of mucosal architecture (5). Many patients with dermatitis herpetiformis do not have symptomatic gastrointestinal problems, thus again emphasizing the idea of a compensated latent state. Further corroboration of the latent phase of the condition has also been derived from studies of large families with CD. Of the 15% to 20% of relatives deemed to be affected in any kindred studied, it is apparent that 50% of such relatives, despite having a flat, destructive proximal lesion, are nevertheless asymptomatic or have latent disease (6). That even the most severe form of proximal mucosal damage does not necessarily have to be associated with symptomatic malabsorption or diarrhea emphasizes the principles established in 1964 by MacDonald and colleagues (7) that the clinical syndrome is dependent on the length of bowel involved and not merely on the appearance of the proximal lesion obtained at biopsy. The obvious corollary is that the proximal lesion, and its associated digestive-absorptive defect, is compensated by functional hypertrophy of the distal small bowel and proximal colon, from which derives the idea of a compensated latent state. Unmasking of this compensated latent stage requires the cooperative effect of nutritional deficiency, metabolic stress, tumor growth, or infection (8). Gastrointestinal infection is probably by far the most common factor that unmasks the latent state, usually through direct cytotoxicity or toxin impairment of enterocytes of distal bowel that were operative in maintaining the compensated state. The term gluten sensitivity, then, serves to embrace all symptomatic individuals who have either classic or atypical features, all patients with gluten-driven dermatitis herpetiformis, and the remaining large pool of predisposed individuals who are in a compensated latent stage of the condition (9). It is of critical importance to recognize that of all gluten-sensitized individuals, the majority will fall into the compensated latent-stage group and hence will invariably require active testing for their proper identification. THE QUESTION OF MALIGNANCY In terms of malignancy and potential for malignant change, active identification should be of critical concern for medical attendants, especially those with a specialized interest in the gastrointestinal tract. It is evident from the literature that gluten-sensitized individuals in the latent compensated phase of disease are, like symptomatic patients, still at risk of malignant complications. There is no doubt that chronic gluten exposure leads to gastrointestinal malignancy and that the risk is higher with a severe (proximal) lesion than with one that has healed on gluten restriction (2,10). We should therefore recall that 50% of the affected first-degree relatives (15% to 20%) are in a compensated latent phase, despite having severe proximal mucosal lesions. This is in agreement with another of Cooke's surveys of family relatives, which revealed a tenfold increase in deaths from malignancy, compared with age/sex-matched controls in Birmingham, England (11). Those risks were for the esophagus, bladder, and brain in males and the breast in females. It would be valuable if this study could be duplicated on a European scale, incorporating genotyping at the molecular level together with evidence of mucosal reactivity, either by duodenal/jejunal biopsy or rectal gluten challenge. Conversely, prospective studies with similar forms of investigation should be performed on large populations of individuals seen for the first time with typical carcinomas (esophagus, jejunum, bladder, brain, breast) and in whom the possibility of gluten sensitivity is rarely, if at all, entertained. Such field studies, as outlined here, would provide epidemiological evidence of the prevalence of malignancy in terms of the degree of proximal mucosal damage. That is a most important consideration, since it has been demonstrated that malignancy occurs in the presence of minimal mucosal pathology and a compensated latent clinical phase (12-15). There seems to be a cogent ethical requirement to seek out as many individuals with compensated latent disease as possible with the techniques currently available and to provide informed advice for strict dietary gluten avoidance in such individuals (3).