Introduction
 

Gastrointestinal and hepatobiliary disorders are among the most frequent complaints in patients with HIV disease. Advances in antiretroviral therapy are changing the nature of HIV disease and affecting many of the gastrointestinal manifestations. Before combination antiretroviral therapy, the best estimates suggested that 50 to 93% of all patients with HIV disease had marked GI symptoms during the course of their illness.Recent clinical experience suggests that effective anti-HIV therapy and chemoprophylaxis for Pneumocystis carinii (PCP), Mycobacterium avium (MAC), and cytomegalovirus(CMV) may delay/prevent the occurrence of gastrointestinal opportunistic infections. Given fewer late-stage immunocompromised patients, clinicians must recognize the shifts in the spectrum of pathogens, recognize the need to maintain good nutrition, and facilitate outpatient management directed at identifying treatable causes and ameliorating symptoms.

Gastrointestinal (GI) manifestations of HIV disease include diarrhea, dysphagia and odynophagia, nausea, vomiting, weight loss, abdominal pain, anorectal disease, jaundice and hepatomegaly, GI bleeding, interactions of HIV and hepatotropic viruses, and GI tumors (Kaposi's sarcoma and non-Hodgkin's lymphoma). The evaluation of specific gastrointestinal complaints must be based on an assessment of the degree of immunosuppression. Progressive immunocompromise is associated with increasing prevalence of GI symptoms(3) and remains the common endpoint for most individuals infected with HIV.


Evaluation of Gastrointestinal Symptoms

The following general points should be considered when evaluating GI symptoms in HIV-infected patients:



Opportunistic infection are rare in individuals with a "preserved" immune system (lowest CD4 count greater than 200 cells/mm3)


Clinical signs and symptoms alone rarely suggest a specific etiology. Consequently, clinicians should investigate all significant GI complaints, using sufficiently objective studies to identify specific treatable infections or neoplasms associated with advanced HIV disease. A notable exception is esophageal disease, in which empiric therapy for Candida may precede invasive work-up.


Multiple GI infections are common, making it important to distinguish between true pathogens and secondary colonization, and to evaluate patients further when initial therapies fail. Evidence of tissue invasion by an infectious agent is the hallmark of true pathogenicity.


The overriding goal of evaluation is to promptly identify treatable infections, ameliorate symptoms, and preserve functional/nutritional status.


Prolonged survival necessitates greater emphasis on maintaining adequate nutritional status and diagnosing and treating chronic co-morbid conditions including hepatitis C virus (HCV).


Among the more difficult management issues in the HIV-infected patient is deciding how extensively to investigate GI symptoms. The clinician must always weigh the discomfort and invasiveness of a procedure against the severity of the patient's complaints and the likelihood of identifying a treatable condition. Thus, for example, patients who are incapacitated by abdominal pain or diarrhea should be evaluated more extensively with endoscopic or imaging studies than patients whose symptoms do not interfere with daily activities.


Diarrhea

Diarrhea is the most common GI symptom in patients with HIV. In outpatient studies, the prevalence of diarrhea ranged from 0.9 to 14%. Prevalence was increased in homosexual men and individuals with lower CD4 cell counts. In hospitalized individuals with advanced HIV, 50% of all patients had diarrhea. Furthermore, there is considerable geographic variation in the frequency of diarrhea and the spectrum of enteric pathogens.


Differential Diagnosis

Prospective series have implicated a wide variety of protozoal, viral, and bacterial organisms as diarrheal pathogens (Table 1). Some pathogens, like Mycobacterium avium-complex (MAC), are unique to HIV disease. Others, like Cryptosporidium, cause self-limited diarrheal illness in healthy hosts but chronic diarrhea in immunosuppressed patients. The degree of immunodeficiency as expressed by the CD4 cell count is an important determinant of enteric pathogens. MAC and CMV infections are not observed in patients with CD4 cell count > 100/mm3.

In earlier studies, pathogens were identified in over half of patients with advanced HIV disease and diarrhea. Two large series have since demonstrated a changing clinical spectrum of diarrhea, with pathogen-negative diarrhea now representing the majority of patients.)In all series, simultaneous infections were common, emphasizing the need to exclude all pathogens thoroughly when evaluating diarrheal symptoms. Two studies have reported a dramatic decrease in cryptosporidial diarrhea over the past 5 years.

In patients with "early" HIV disease, medications are a common cause of diarrhea, especially protease inhibitors, including Nelfinavir and Saquinavir. The diarrhea is often self-limited, lasting less than 2 to 4 weeks from initiation of medication use. Chronic/uncontrollable diarrhea, however, does occur in spite of improved CD4 cell count and decreased viral load. Other etiologies of diarrhea include idiopathic colitis, enteropathogenic Escherichia coli, and small bowel bacterial overgrowth.


Small Bowel Overgrowth

Small bowel bacterial overgrowth results in a clinical syndrome consisting of diarrhea and malabsorption of fat, vitamin B12, and carbohydrates. The morphologic changes reported in patients with small bowel overgrowth include villous atrophy and inflammatory infiltrates (similar to the findings in "HIV enteropathy"). Intestinal disturbances common in patients with HIV, including gastric hypoacidity, impaired intestinal immunity, or impaired intestinal motility are known to predispose to bacterial overgrowth. In a pilot study, the prevalence of small bowel bacterial overgrowth (SBBO) in 16 patients with HIV-associated diarrhea was 38%; only one instance of SBBO was found among the control subjects. Whether broad-spectrum antibiotic treatment improves symptoms and for how long treatment should continue has not been studied.


AIDS Enteropathy

Reported evidence suggests that HIV itself may be an indirect diarrheal pathogen because viral proteins have been found in the gut. HIV has been identified in histologic specimens from the GI tract tissue in up to 40% of patients. The virus is confined to lamina propria macrophages and enterochromaffin cells and has not found in epithelial cells. Intestinal HIV infection may also affect local humoral immunity and cause motility disturbances via effects on autonomic nerves.

An "idiopathic AIDS enteropathy" has been proposed to account for the diarrhea in HIV-infected patients who lack an identifiable pathogen. This syndrome may result from indirect effects of HIV on enteric homeostasis. Although the precise features of the syndrome are not agreed on, the term implies a chronic diarrheal illness with no identified etiology in patients with advanced HIV disease. Some advocate the inclusion of mucosal hypoproliferation as a defining feature. Enteric HIV infection may lead to mucosal atrophy, which in turn impairs small-bowel absorption, causing diarrhea and weight loss.


Evaluation of Diarrhea

Before undertaking an extensive evaluation of diarrhea, clinicians should obtain a careful history to exclude medications, lactose or food/fatty food intolerance, inadvertent use of cathartics (e.g., megadoses of vitamin C, lactose-containing medications, sorbitol-containing foods), and symptoms suggestive of a systemic infection or neoplasm. Unfortunately, the clinical history alone is not likely to establish a specific diagnosis when due to infection. A careful history can aid in localizing the segment of luminal GI tract most severely involved. For example, symptoms of cramps, bloating, and nausea suggest gastric or small-bowel involvement, or both, raising the possibility of infection with Cryptosporidium, Microsporidium, Isospora belli, or Giardia organisms. Hematochezia and tenesmus imply large-bowel inflammation resulting from CMV, Shigella, Campylobacter, or Clostridium difficile infections. Tenesmus can occur as a result of herpes, Shigella, or Campylobacter infections. The character, frequency, color, and odor of the stool are relatively nonspecific in HIV-related GI syndromes and are therefore of little value in identifying specific infections. A history that includes multiple sexual contacts or receptive anal sex increases the possibility of sexually transmitted diarrheal pathogens.The physical examination also provides few diagnostic clues in the evaluation of HIV-related diarrhea. Lymphadenopathy, hepatosplenomegaly, and abdominal tenderness have little diagnostic value.

The most important goal in evaluating diarrhea in patients with HIV disease is to identify treatable infections or neoplasms with the minimum work-up necessary. Once dietary causes and medications are excluded, the initial evaluation should include stool culture for enteric bacteria, a specimen for Clostridium difficile toxin (in the setting of antibiotic use), and at least three stool specimens for ova and parasite examination (including acid-fast bacilli and trichrome stain). The importance of obtaining multiple specimens was re-affirmed in a recent study of 30 patients with a confirmed diagnosis of cryptosporidiosis. Only 53% of individual stool samples were positive, whereas 22 of 30 patients had at least one positive of three or more stool specimens tested.

If a diagnosis is not reached following careful stool analysis, sigmoidoscopy is appropriate to identify CMV infection. Biopsies should be obtained from abnormal regions or randomly from rectal mucosa if no abnormalities are apparent. Although colonoscopy has been advocated instead of sigmoidoscopy for diagnosis of isolated right colonic CMV, this approach is not likely to be as cost-effective as reserving the colonoscopy for patients in whom sigmoidoscopy is nondiagnostic. If sigmoidoscopic evaluation is negative, upper endoscopy or colonoscopy with intubation and biopsy of the terminal ileum may occasionally uncover small-bowel infection by Cryptosporidium, Microsporidium, or M. avium.) A small-bowel biopsy should be obtained in any HIV-infected patient undergoing upper endoscopy for evaluation of diarrhea; this method has largely supplanted small-bowel capsule biopsies. Duodenal fluid can also be aspirated during endoscopy and examined for protozoal infection or small-bowel overgrowth. Compared with endoscopic procedures, the diagnostic value of radiographic contrast studies in evaluating diarrhea is very low and therefore these studies are not indicated.


Management of Diarrhea in HIV Disease

When evaluation of diarrhea reveals an enteric pathogen, specific therapy should be administered if available . Chronic administration of alternating antibiotics may be necessary for recurrent Salmonella, Shigella, Campylobacter, or Isospora infections. An empiric trial of oral antibiotics or antiparasite therapy for the possibility of small bowel overgrowth, undetected Campylobacter, Isospora enteritis, or undetected protozoa can be considered. Sulfonamides, ciprofloxacin, tetracyclines, or metronidazole may be appropriate in this setting.

HIV-infected patients with chronic diarrhea should be treated symptomatically. Antidiarrheals, including Imodium, Lomotil, or tincture of opium drops, are often required and should be titrated individually. Lactose-containing foods should be avoided as a diagnostic and therapeutic trial. Bulk-forming agents, including effersyllium, bran, and pectin may be helpful. Nutritional repletion will increase the patient's sense of well-being, although a survival benefit has not been demonstrated. In cases of severe diarrhea, short- or long-term intravenous fluid repletion may be indicated.

Numerous agents have been tested in patients with HIV-associated diarrhea, and controlled studies have failed to define a definitive treatment for cryptosporidiosis, microsporidiosis or pathogen-negative diarrhea. Promising new data indicate that microsporidiosis and cryptosporidiosis infection may be cleared in patients receiving highly effective antiretroviral therapy. The changing clinical diagnosis witnessed in the era of antiretroviral therapy has limited research on anti-infective agents. One recent study of the effects of an extract from a tropical plant showed promising declines in stool weight over 4 days of treatment in patients with AIDS and virtually no pathogens.

The somatostatin analogue octreotide (administered subcutaneously) appears to be particularly effective in patients with diarrhea who lack a specific infection.This agent's putative mechanism of action is via inhibition of a broad array of GI hormones that regulate intestinal fluid and electrolyte secretion. As a result of its inhibition of cholecystokinin, gallbladder ileus with stone formation and increased fat malabsorption may occur.