Drugs associated with malabsorption include arsenic, biguanides, methotrexate, methyldopa, azathioprine, and neomycin (253,254). Neomycin induces villous clubbing, brush border fragmentation, microvillous loss, lamina propria inflammation, and ballooning degeneration. Micelle disruption and decreased pancreatic lipase leads to malabsorption. Some progestational agents cause crypt atrophy of the hypoplastic type, resulting in an immaturity of the intestinal epithelium and giving rise to secondary malabsorption. Alcohol causes both mucosal and microvascular injury (255). It directly damages the crypts and villi, leading to malabsorption. Cyclamates cause reversible malabsorption. Histologically, the bowel is inflamed and shows crypt hypoplasia and slight villous atrophy and goblet cell depletion. Erythromycin produces diarrhea, increases GI motor activity, and inhibits intestinal absorption. Colchicine given regularly causes steatorrhea, megaloblastic anemia, and abnormal xylose absorption (256). Chemotherapeutic agents may induce lactose intolerance (257).

The eosinophilia-myalgia syndrome (EMS) usually follows ingestion of L-tryptophan. Patients present with profound eosinophilia, an abnormal hepatic profile, and myalgia. Some patients develop a connective tissue disease that resembles scleroderma (258) with dysmotility and diarrhea. GI involvement leads to significant malabsorption with steatorrhea, hypoalbuminemia, and weight loss. Diffuse eosinophilic infiltrates occur in the small bowel, stomach, and colon (259). The differential diagnosis of the GI eosinophilia usually includes parasitic infection, lymphomas, polyarteritis nodosa, allergic gastroenteritis, eosinophilic gastroenteritis, systemic mastocytosis, and Crohn disease.

Cyclosporine therapy following renal transplantation causes generalized microvascular small intestinal disease (260). High concentrations of potassium salts and hydrochlorothiazide cause venous smooth muscle spasm, producing ischemic ulcers, fibrosis, and strictures. Ingestion of oral contraceptives predisposes to superior mesenteric vein thrombosis. Ergotamine-induced vasoconstriction leads to small intestinal ulceration. Cocaine abuse results in bowel ischemia by blocking the reuptake of released norepinephrine and causing vasoconstriction and decreased blood flow. Patients experience sudden crampy abdominal pain and bloody diarrhea. Severe and prolonged ischemic episodes eventually result in bowel necrosis, perforation, peritonitis, or abscess formation. A different form of cocaine damage occurs in the so-called cocaine body packer syndrome. Body packers, or “mules,” ingest multiple small drug packets, which may rupture and cause death. Cocaine can also leak out from semipermeable wrappings to be absorbed through the mucosa (261).

Antineoplastic drugs often induce anorexia, diarrhea, and small intestinal morphologic changes secondary to massive cell death in the proliferative compartment. Cell death becomes apparent as apoptoses within an hour; the number of dead cells peaks within the first 8 hours (262). The dead cells or dead cell fragments are phagocytosed by neighboring healthy enterocytes and mucosal macrophages (263). Antineoplastic drugs also decrease crypt mitotic rate, villous height, and villous width. The morphologic changes superficially resemble those present in celiac disease. The epithelium becomes mucin depleted. Surface epithelial cells become foamy, brush borders are lost, and the enlarged pleomorphic nuclei contain prominent nucleoli. After a few days, lymphocytes and eosinophils infiltrate the lamina propria. In cases of severe damage, all crypts are affected and frank erosions or ulcers develop. Regeneration, recognizable by a burst in mitotic activity and marked variation in nuclear size, follows therapy cessation. Mitoses are present at all levels of the mucosa, even on the villous surface. These changes usually occur within 2 weeks, but inflammation and telangiectasia persist for up to a month. Megaloblastic nuclei develop in patients with vitamin B₁₂ or folate deficiency, particularly in patients on extended chemotherapeutic protocols (Fig. 6.125). Patients treated with adjuvant CTLA-4 monoclonal antibodies develop an autoimmune panarteritis that is characterized by aphthous ulcers, larger ulcers, intraepithelial lymphocytosis in the crypt bases, increased apoptoses, and a mononuclear cell infiltrate in the lamina propria (264).