The gastrointestinal tract is an especially common site for clinical expression of human immunodeficiency virus (HIV) infection and is an important factor in morbidity from opportunistic infections in late-stage disease, as well as gastrointestinal complications from antiretroviral agents or other drugs. Nearly all opportunistic infections occur when the CD4 count is less than 200/mm³ , and almost all seem to respond well to immune reconstitution when achieved with antiretroviral therapy.

Oral Lesions
Oral candidiasis (“thrush”) is encountered at some time in 80 to 90% of all patients with advanced stages of HIV infection. The usual finding is white patches that show yeast forms and pseudohyphae on KOH preparation. Thrush is often asymptomatic, and treatment in such cases is unnecessary. Common symptoms include mouth pain, dysphagia, and taste change. The diagnosis is usually made by visual appearance. Treatment consists of topical agents (nystatin, clotrimazole troches, or amphotericin B), oral therapy with azoles or amphotericin B, or in severe refractory cases, intravenous amphotericin. Relapse rates are high, so continuous therapy with topical agents or azoles is often necessary.

Oral hairy leukoplakia is characterized by white patches consisting of white fibrillar projections that are usually located on the tongue and are often confused with thrush. Oral hairy leukoplakia is usually asymptomatic, but occasional patients complain of pain or voice changes; symptomatic patients usually respond to treatment with acyclovir. Herpes simplex virus (HSV) often causes painful oral lesions that have the typical appearance of vesicles on an erythematous base and break down to form ulcers. Herpetic oral lesions are common in the general population, but they tend to be more severe and prolonged in patients with advanced HIV infection. The usual treatment is acyclovir, famciclovir, or valacyclovir given orally; severe cases may require intravenous acyclovir or, for acyclovir-resistant strains, foscarnet given parenterally. The major source of confusion is aphthous ulcers of unknown etiology, which seem to respond best to thalidomide or to corticosteroids given topically or systemically. Patients with Kaposi’s sarcoma often have involvement of the oral cavity, most frequently with typical purplish raised lesions on the palate, although any site in the oral cavity may be involved. Most are asymptomatic; symptomatic lesions generally respond to irradiation, laser treatments, or vinblastine injections. Periodontal disease is relatively common, with either gingivitis or periodontitis. Treatment consists of topical chlorhexidine (Peridex) or systemically administered metronidazole.

Esophagitis
Dysphagia or odynophagia generally indicates an esophageal lesion. The most common cause is candidiasis, and most such patients also have thrush. Patients with odynophagia in late-stage HIV infection are usually treated empirically with fluconazole. Alternative causes of esophagitis include herpes simplex, cytomegalovirus (CMV), or aphthous ulcers (

Table 413-1) . Endoscopy is recommended for patients with atypical symptoms and those who fail to respond to fluconazole. Occasional cases are due to fluconazole-resistant Candida spp. and require intravenous amphotericin B. Ulcerative esophagitis is usually due to CMV or aphthous ulceration; HSV esophagitis is unusual. Herpes simplex may be treated with acyclovir, CMV responds to ganciclovir, and aphthous ulcers are optimally treated with systemic corticosteroids or thalidomide.

Gastric Lesions
Patients with acquired immunodeficiency syndrome (AIDS) often have gastric achlorhydria; less common gastric lesions are Kaposi’s sarcoma and opportunistic infections. Gastric intolerance to medications is common, especially with zidovudine, ritonavir, didanosine, indinavir, saquinavir, macrolides, trimethoprim-sulfamethoxazole, and pentamidine. Symptoms include nausea, vomiting, anorexia, and epigastric pain and usually resolve promptly when use of the implicated drug is discontinued.

Small Bowel and Colon Lesions
Acute and/or chronic diarrhea is a frequent complication and may be due to medications, opportunistic infections, or common causes seen in the general population such as viral gastroenteritis or irritable bowel syndrome. The antiretroviral agent that most commonly causes diarrhea is nelfinavir. Treatment with bacterial agents may be complicated by Clostridium difficile-associated diarrhea or colitis, but the frequency and severity do not appear to be increased by immunosuppression per se.

Diagnostic Evaluation
The approach to patients with HIV infection and diarrhea requires knowledge of four factors: medication history, CD4 count, a distinction between acute and chronic diarrhea, and emphasis on features that distinguish between colitis and enteritis. Regarding the latter, patients with colitis usually have cramps, fever, fecal leukocytes, and small-volume “fraction” stools. Enteritis is characterized by large-volume watery stools without fecal leukocytes or cramps and often without fever.

The most common microbial causes of acute diarrhea in HIV-infected patients are Salmonella spp., C. difficile, and enteric viruses. Common opportunistic pathogens that cause chronic diarrhea in late-stage HIV include cryptosporidia, microsporidia, CMV, and Mycobacterium avium (

Table 413-2) . The diagnostic evaluation begins with a review of medications and discontinuation of treatment with suspected agents. Many patients with other forms ofdiarrhea respond to symptomatic therapy, so diagnostic studies for infectious causes are usually restricted to patients with severe symptoms, symptoms suggesting colitis, or chronic diarrhea. Standard tests include stool for culture, ova and parasite examination, including acid-fast bacillus stain, and C. difficile toxin. Endoscopy is recommended for undiagnosed cases with symptoms that are severe or persist. Patients with diarrhea should have a diet of frequent small-volume feedings, bland food, and avoidance of fat, caffeine, milk, and milk products. Antiperistaltic agents such as loperamide are often given for symptomatic relief.
Cryptosporidia tend to cause intermittent diarrhea that persists for months and may be responsible for severe fluid losses, dehydration, and electrolyte abnormalities. Small bowel biopsies show villous atrophy, crypt hyperplasia, and intraepithelial lymphocytes with typical schizonts that appear to be adherent to the brush border. Functional tests show D-xylose malabsorption, and stools show no fecal leukocytes. The usual diagnostic test is a stool examination for oocysts that appear like yeast but are easily detected with modified acid-fast stains. Complications include papillary stenosis with obstruction of the common bile duct. The usual treatment of cryptosporidial diarrhea is supportive care and paromomycin with or without azithromycin, but the response is variable and temporary. The best response is achieved with immune reconstitution.

Microsporidia are a group of small unicellular parasites; the two pathogens in AIDS patients are Enterocytozoon bieneusi, which accounts for about 80% of cases, and Enterocytozoon intestinalis. The organism can be detected in stool with a trichrome stain. Histopathologic changes are similar to those noted with cryptosporidiosis except for the unique morphologic features and location of the organism within the cytoplasm of the enterocyte. Treatment with albendazole is effective in the majority of cases caused by E. intestinalis; E. bieneusi is usually refractory to antimicrobials and responds best to immune reconstitution.

M. avium may cause pathologic changes in the small bowel that appear identical to those of Whipple’s disease, with foamy macrophages distended by vesicles containing periodic acid-Schiff-positive material in the lamina propria. However, unlike Whipple’s disease, the putative agents in the macrophage are acid fast and do not cross-react with antibacterial typing sera. The diagnosis is usually made with blood cultures for mycobacteria. M. avium generally responds to treatment with clarithromycin plus ethambutol.

CMV commonly causes disseminated infection in the late stages of HIV infection at any level of the gastrointestinal tract, including the mouth, esophagus, stomach, small bowel, colon, and perirectal region. The most common infection is a diffuse colitis with superficial ulcerations. Common symptoms ascribed to this infection include fever, diarrhea, abdominal pain, and bloody stools. Less common is a solitary ulcer, toxic megacolon, or intestinal perforation. CMV is the most common opportunistic pathogen in late-stage AIDS that causes colitis; the major alternative diagnostic consideration is C. difficile-associated colitis. The diagnosis of CMV is generally established by demonstrating typical viral inclusions in intestinal biopsies, but the role of this organism as a cause of symptomatic disease is sometimes controversial even when seen. A large number of inclusion bodies per square millimeter of tissue and the presence of high-grade inflammation or typical CMV vasculitis are possibly important correlates in interpretation. Ganciclovir or foscarnet is effective therapy, but patients may require continuous treatment to prevent relapse.

Isospora belli is another enteric pathogen that is found with increased frequency in patients with advanced stages of HIV infection. It is a protozoan parasite that may cause symptoms similar to those described for cryptosporidiosis. The diagnosis is established by recognition of large acid-fast oocysts (20 to 30 × 10 to 20 mum) in stool. This organism responds well to treatment with trimethoprim-sulfamethoxazole, although the relapse rate is high, so long-term maintenance treatment is often necessary.

Tumors of the gastrointestinal tract associated with HIV infection include Kaposi’s sarcoma, non-Hodgkin’s lymphoma, cloacogenic carcinoma of the rectum, and squamous cell carcinoma of the rectum and anus. The most common of these is Kaposi’s sarcoma, which has been found in gut tissue at autopsy in 40 to 50% of persons with typical cutaneous lesions. Endoscopy typically shows raised red nodules, but histologic confirmation is difficult owing to the depth of pathologic changes. The great majority are asymptomatic; less common manifestations include diarrhea, subacute intestinal obstruction, protein-losing enteropathy, and rectal ulcer. The lymphomas associated with HIV infection are usually high-grade B-cell lymphomas that are extranodal in origin. The gastrointestinal tract is affected in up to 20%, and any site may be involved from the oral cavity to the rectum.

AIDS Enteropathy
Endoscopy in patients with advanced AIDS often shows morphologic changes in the small bowel in the absence of evidence of a superimposed opportunistic infection. Characteristic features are villous blunting, a reduced villus-crypt ratio, and an inappropriately low number of mitotic figures. In the absence of an enteric pathogen, the findings are sometimes referred to as “AIDS enteropathy.” Studies of gastrointestinal function in the presence of AIDS enteropathy usually show malabsorption with abnormal D-xylose and C-glycerol-tripalmitin absorption tests. The cause of these changes is not known, but the major considerations include direct invasion by HIV, an opportunistic infection that has not been detected, or a consequence of immune suppression.

Malnutrition and Wasting
The average patient with late-stage AIDS loses 15 to 20% of baseline weight. Protein-calorie malnutrition is a common and important sequela that may accelerate progressive immunosuppression. Factors contributing to malnutrition include a hypermetabolic state associated with chronic infection (especially with fever), oral lesions causing pain, esophageal lesions resulting in dysphagia, reduced taste sensation, depression, HIV-associated subcortical dementia, gastrointestinal side effects of medications, and AIDS enteropathy.

Many patients lose weight with sequential opportunistic infections that is not regained during asymptomatic intervals. Therapy for wasting depends on the severity, cause, patient gender, and response. Immune reconstitution with antiretroviral therapy has been associated with remarkable weight gain. Prevention of opportunistic infections is an important factor in stabilizing weight. A number of pharmacologic agents are in common use, with variable responses in terms of the amount and the quality of the weight gained (fat versus muscle). The most commonly used agents for wasting are appetite stimulants (megestrol acetate, dronabinol), anabolic steroids (oxandrolone, nandrolone), testosterone, or thalidomide.

Hepatobiliary Disease
The prevalence of markers for hepatitis B (hepatitis B surface antigen [HBsAg], antibody to HBsAg, or antibody to hepatitis B core antigen) is 35 to 80% in AIDS patients, which is a reflection of their prevalence among homosexual men, intravenous drug abusers, and hemophiliacs. HBsAg is found in 5 to 10%. Hepatitis C antibody indicates chronic infection in most patients and is found in up to 90% of injection drug users. The seroprevalence of hepatitis C virus is low in other HIV risk categories. Chronic hepatitis B or C virus infection does not appear to notably alter the course of HIV infection, although HIV may accelerate the course of chronic hepatitis C.

Other viral causes of hepatitis include herpes simplex virus and CMV. Granulomatous hepatitis is most often due to M. avium; less common are histoplasmosis, cryptococcosis, and tuberculosis. Hepatotoxic drugs commonly taken by HIV-infected patients include protease inhibitors, azoles, sulfonamides, isoniazid, and rifampin. Cholestasis secondary to papillary stenosis and sclerosing cholangitis are most often due to Cryptosporidium, Microsporida, or CMV or are idiopathic.

Conditions Necessitating Abdominal Surgery
The most common clinical syndromes in persons with HIV infection that require abdominal surgery are peritonitis associated with perforation secondary to CMV infection, lymphoma of the gut (most frequently manifested as involvement of the terminal ileum by obstruction or bleeding), Kaposi’s sarcoma, and M. avium infection involving the retroperitoneal lymph nodes or spleen. Patients with AIDS cholangiopathy usually respond to endoscopic retrograde cholangiopancreatography, but the benefit is usually temporary. The experience with abdominal surgery indicates that patients with HIV infection tolerate surgical procedures well and do not have an unusually high incidence of postoperative complications.

References
_{Greenson JK, Belitsos PC, Yardley JH, et al: AIDS enteropathy: Occult infections and duodenal mucosal alterations in chronic diarrhea. Ann Intern Med 114:366, 1991. The authors review histopathologic changes and etiologic agents of AIDS patients with chronic diarrhea.}

Johanson JF, Sonnenberg A: Efficient management of diarrhea in the acquired immunodeficiency syndrome (AIDS). Ann Intern Med 112:942, 1990. Review of the efficacy and cost-effectiveness of various strategies for evaluating diarrhea in AIDS patients suggests that endoscopy and other costly tests are infrequently warranted.

Kotler DP, Clayton F, Scholes JV, Orenstein JM: Small intestinal injury and parasitic diseases in AIDS. Ann Intern Med 113:444, 1990. The authors review histopathologic findings, including electron microscopy, in AIDS patients with cryptosporidiosis and microsporidiosis.

Laughon BE, Druckman DA, Vernon A, et al: Prevalence of enteric pathogens in homosexual men with and without acquired immunodeficiency syndrome. Gastroenterology 94:984, 1988. This is an exhaustive study of stool to detect bacterial, viral, fungal, and parasitic pathogens in homosexual men without AIDS, with AIDS, and with proctitis or diarrhea.

Sharpstone D, Gazzard B: Gastrointestinal manifestations of HIV infection. Lancet 348:379, 1996. The authors review the clinical features of gastrointestinal complications of HIV infection, including esophageal disease, diarrhea, and wasting.

Soave R, Johnson WD Jr: Cryptosporidium and Isospora belli infections. J Infect Dis 157:225, 1988. The authors review Cryptosporidium and Isospora with particular attention to their role in AIDS patients.

Weinert M, Grimes RM, Lynch DP: Oral manifestations of HIV infection. Ann Intern Med 125:485, 1996. The authors provide guidelines for recognizing, diagnosing, and managing oral complications of HIV infection.

Neal S. Penneys