Porth's Essentials of Pathophysiology, 4e

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Disorders of Gastrointestinal Function

C h a p t e r 2 9

to be one of the most common genetic diseases, with a mean prevalence of 1% in the general population. The disease is recognized not only in Europe and in countries populated by persons of European ancestry, but also in the Middle East, Asia, South America, and North Africa. The disease results from an inappropriate T-cell– mediated immune response against the gliadin fraction of gluten contained in the diet. Almost all persons with the disorder share the major histocompatibility com- plex class II allele HLA-DQ2 or HLA-DQ8. Several non-HLA genes that may influence susceptibility to the disease have been identified, but their role has not been confirmed. Persons with the disease have increased levels of antibodies to a variety of antigens, including transglutaminase, endomysium, and gliadin. The resul- tant immune response produces an intense inflammatory reaction that results in loss of absorptive villi from the small intestine. When the resulting lesions are extensive, they may impair absorption of macronutrients (i.e., pro- teins, carbohydrates, fats) and micronutrients (i.e., vita- mins and minerals). Small-bowel involvement is most prominent in the proximal part of the small intestine, where the exposure to gluten is greatest. Populations at higher risk for celiac disease include persons with type 1 diabetes mellitus, those with other autoimmune endocrine disorders such as autoimmune thyroid disorders or Addison disease, first- and second- degree relatives of persons with celiac disease, and indi- viduals with Turner syndrome. Various malignancies also appear to be a direct result of celiac disease, in that the increased incidence seen in persons with celiac disease returns to that of the general population after several years of a gluten-free diet. These malignancies include head and neck squamous cell carcinoma, small intesti- nal adenocarcinoma, and non-Hodgkin lymphoma. The clinical manifestations of celiac disease vary greatly according to age group. 55,56 Infants and young children generally present with diarrhea, abdominal dis- tention, failure to thrive, and, occasionally, severe mal- nutrition. Beyond infancy, the manifestations tend to be less dramatic. Older children may present with anemia, constitutional short stature, dental enamel defects, and constipation. Among adults, women constitute about 75% of newly diagnosed cases of celiac disease. The classic presentation in adults is diarrhea, which may be accompanied by abdominal pain or discomfort. It has been observed that fewer persons with celiac disease are presenting with the so-called “classic manifestations” of the disease. While diarrhea is still the most frequent mode of presentation, others include iron deficiency, osteoporo- sis, and recognition of mucosal changes in persons under- going endoscopy for esophageal reflux or dyspepsia. 55 A prior diagnosis of irritable bowel syndrome is common. Celiac disease is also becoming increasing recog- nized in the elderly population. 57 Rather than symptoms related to severe malabsorption, this age group often presents with anemia, accelerated osteoporosis, and osteomalacia. Although abdominal symptoms are still common in elderly persons, these individuals tend to present with milder symptoms such as abdominal bloat- ing, flatulence, and abdominal discomfort, which make diagnosis difficult.

The diagnosis of celiac disease is based on clinical manifestations and confirmed by serologic tests and intestinal biopsy. Based on very high sensitivities, the best available tests are the immunoglobulin (Ig) A anti- human tissue transglutaminase (TTG) and IgA endo- mysial antibody (EMA) immunofluorescence tests. 56 Biopsies of the proximal small bowel are indicated in persons with a positive celiac disease antibody test. Usually, additional laboratory tests are done to deter- mine if the disorder has resulted in nutritional disorders such as iron-deficiency anemia. The primary treatment of celiac disease consists of removal of gluten and related proteins from the diet. Gluten is the primary protein in wheat, barley, and rye. Oat products, which are nontoxic, may be contaminated with wheat during processing. Many gluten-free types of bread, cereals, cookies, and other products are available. 56 Meats, vegetables, fruits, and dairy products are free of gluten as long as they are not contaminated during process- ing. Complete exclusion of dietary gluten generally results in rapid and complete healing of the intestinal mucosa. Adenomatous polyps (adenomas) are benign neoplasms that arise from the mucosal epithelium of the intestine. 6,7 They are composed of neoplastic cells that have prolifer- ated in excess of those needed to replace the cells that normally are shed from the mucosal surface. The most common and clinically important neoplastic polyps are colonic adenomas that are precursors in the majority of colorectal adenocarcinomas. Adenomas can range in size from a barely visible nodule to a large, sessile mass. They can be classified as tubular, villous, or tubulovillous adenomas. Tubular adenomas, which constitute approximately 65% of benign large bowel adenomas, typically are smooth-surfaced spheres, usually less than 2 cm in diameter, that are attached to the mucosal surface by a stalk. 7 Although most tubular adenomas display little epithelial dysplasia, approximately 20% show a range of dysplastic changes, from mild nuclear changes to frank invasive carcinoma. Villous adenomas constitute 10% of adenomas of the colon. 7 They typically are broad-based, elevated lesions with a shaggy, cauliflower-like surface and are found predominantly in the rectosigmoid colon. In contrast to tubular adenomas, villous adenomas are more likely to contain malignant cells. When invasive carcinoma develops, there is no stalk to isolate the tumor and inva- sion is directly into the wall of the colon. Tubulovillous adenomas manifest both tubular and villous architec- ture. They are intermediate between tubular and villous adenomas in terms of invasive carcinoma risk. The pathogenesis of adenoma formation involves neoplastic alterations in the replication of the colonic crypt cells (Fig. 29-13). There may be diminished apoptosis (see Chapter 2), persistence of cell replication, and failure of cell maturation and differentiation of the cells that migrate to the surface of the crypts. Normally, DNA synthesis ceases as the cells reach the upper two Colorectal Neoplasms Adenomatous Polyps