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Gastrointestinal Manifestations of HIV
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Introduction
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Evaluation of Gastrointestinal Symptoms
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Diarrhea
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transparent imageDifferential Diagnosis
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transparent imageSmall Bowel Overgrowth
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transparent imageAIDS Enteropathy
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transparent imageEvaluation of Diarrhea
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transparent imageManagement of Diarrhea in HIV Disease
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Weight Loss
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transparent imageEvaluation of Weight Loss
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transparent imageTreatment of Weight Loss
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Dysphagia and Odynophagia Due to Esophagitis
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transparent imageGeneral Considerations
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transparent imageEvaluation of Dysphagia and Odynophagia
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transparent imageTreatment of Odynophagia and Dysphagia
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Abdominal Pain
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transparent imageGeneral Considerations
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transparent imageEvaluation of Abdominal Pain
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transparent imageTreatment of Abdominal Pain
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Anorectal Disease in HIV-Infected Patients
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transparent imageGeneral Considerations
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transparent imageEvaluation and Treatment of Anorectal Disease
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Gastrointestinal Bleeding
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transparent imageGeneral Considerations
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transparent imageEvaluation and Treatment of GI Bleeding
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Gastrointestinal Kaposi's Sarcoma and Non-Hodgkin's Lymphoma
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transparent imageKaposi's Sarcoma
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transparent imageGeneral Considerations
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transparent imageClinical Features
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transparent imageTreatment of GI Kaposi's Sarcoma
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transparent imageLymphoma
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transparent imageGeneral Considerations
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transparent imageClinical Features
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transparent imageDiagnosis of GI Non-Hodgkin's Lymphoma
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transparent imageTreatment of GI Non-Hodgkin's Lymphoma
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Hepatobiliary Abnormalities
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transparent imageHepatic Disorders
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transparent imageHIV and Hepatitis B (HBV)
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transparent imageHIV and Hepatitis C (HCV)
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transparent imageBiliary Tract Disorders
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transparent imageGeneral Considerations
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transparent imageClinical Evaluation of Hepatobiliary Disease
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Conclusion
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References
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Tables
Table 1.Causes of Diarrhea in HIV-Infected Patients and Patients with Advanced HIV Disease
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Table 2.Management of Diarrhea in HIV Disease
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Table 3.Possible Causes of Malnutrition in HIV Disease
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Table 4.Abdominal Pain: Differential Diagnosis
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Table 5.Evaluation of Abdominal Pain: Pain "Syndromes"
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Table 6.Causes of Anorectal Disease in HIV-Infected Patients
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Introduction
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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.(1,2) Recent clinicalexperience 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.

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Evaluation of Gastrointestinal Symptoms
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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.

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Diarrhea
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Diarrhea is the most common GI symptom in patients with HIV. In outpatient studies, the prevalence of diarrhea ranged from 0.9 to 14%.(4) 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.(5) Furthermore, there is considerable geographic variation in the frequency of diarrhea and the spectrum of enteric pathogens.

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Differential Diagnosis
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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.(6) 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.(7,8)

In earlier studies, pathogens were identified in over half of patients with advanced HIV disease and diarrhea.(9,10) Two large series have since demonstrated a changing clinical spectrum of diarrhea, with pathogen-negative diarrhea now representing the majority of patients.(11,12) 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.(13,14)

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.(15)

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Small Bowel Overgrowth
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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.(16-18) 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.(15) Whether broad-spectrum antibiotic treatment improves symptoms and for how long treatment should continue has not been studied.

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AIDS Enteropathy
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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.(19-21) 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(22) and cause motility disturbances via effects on autonomic nerves.(23,24)

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,(25) the term implies a chronic diarrheal illness with no identified etiology in patients with advanced HIV disease.(25) Some advocate the inclusion of mucosal hypoproliferation as a defining feature.(19,25-27) Enteric HIV infection may lead to mucosal atrophy, which in turn impairs small-bowel absorption, causing diarrhea and weight loss.(28,29)

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Evaluation of Diarrhea
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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.(30,31) 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.(32) 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,(33) 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.(12,32) 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.

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Management of Diarrhea in HIV Disease
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When evaluation of diarrhea reveals an enteric pathogen, specific therapy should be administered if available (Table 2). Chronic administration of alternating antibiotics may be necessary for recurrent Salmonella, Shigella, Campylobacter, or Isospora infections.(34,35) 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.(36) 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.(37)

The somatostatin analogue octreotide (administered subcutaneously) appears to be particularly effective in patients with diarrhea who lack a specific infection.(38-42) This agent's putative mechanism of action is via inhibition of a broad array of GI hormones that regulate intestinal fluid and electrolyte secretion.(43) As a result of its inhibition of cholecystokinin, gallbladder ileus with stone formation(44) and increased fat malabsorption may occur.(39)

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Weight Loss
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Involuntary weight loss is a common condition associated with advancing HIV disease and gastrointestinal symptoms. The CDC classifies wasting as an AIDS diagnosis when a patient presents with involuntary weight loss of more than 10% of baseline body weight, plus either chronic diarrhea or chronic weakness and fever in the absence of infection or a condition other than HIV disease.(45) Wasting syndrome accounted for 20% of AIDS-defining diagnoses in 1995.(46)

In the setting of progressive weight loss, death is inevitable once body weight falls below roughly 66% of ideal body weight.(47) Weight loss above 5 to 10% from usual weight predicts mortality, independent of CD4 count.(48-50) Body cell mass (BCM), the metabolically active body component, is an earlier and more specific predictor of mortality.(47)

Involuntary weight loss can be classified into two different etiologies, caloric deficit and metabolic disturbance (Table 3). Inadequate caloric intake and weight loss may be due to upper intestinal abnormalities (anorexia, nausea, vomiting), psychosocial and economic factors, fatigue, mental status changes, and medications. Patients frequently reduce their oral intake to decrease symptoms of diarrhea or abdominal pain. Caloric deficit results in a selective utilization of body fat stores for energy, an adaptive process to preserve lean body mass (starvation model). In contrast, metabolic derangements leading to increased energy expenditure or abnormal energy substrate utilization due to opportunistic infection (or other disease state) result in a disproportionate loss of lean body mass with relative preservation of body fat stores.

Caloric deficit is one cause of weight loss that may be due to odynophagia, dysphagia, anorexia, altered sense of taste, early satiety, nausea, vomiting, diarrhea, fever, fatigue, apathy and/or depression. Pharmacologic side effects, opportunistic infections that result in lesions in the mouth or esophagus, and malabsorption of nutrients can be the underlying causes of reported symptoms.(51) Self-restriction of caloric intake to reduce diarrhea, nausea, and vomiting is also common among patients.

Abnormal resting energy expenditure (REE) has also been associated with abnormal weight loss. Grunfeld and associates found REE to be increased compared to controls by 11% in patients who were HIV positive, 25% in patients with AIDS, and 29% in patients with AIDS who had a secondary infection. Over the course of the 28-day study, patients in the control, HIV-positive, and AIDS group each maintained caloric intake, while patients with AIDS and a secondary infection had a decreased caloric intake of 36% and a 5% weight loss.(52)

While REE increases throughout the course of disease, Macallan et al. reported that decreases in caloric intake and total energy expenditure (TEE) are the primary determinants of weight loss. These investigators completed 51 assessments of energy metabolism on 27 men with HIV infection at different stages of their disease: rapid weight loss, slow weight loss, stable weight, or weight gain. In addition to finding an increased REE in all groups, the determinant of weight loss patterns was clearly caloric deficit and TEE. The rapid weight loss group had an average deficit of 800 kcals, whereas the weight gain group was 400 kcals above energy expenditure.(53)

Macallan and associates have also recognized weight loss to be either rapid or slow in patients with stage IV HIV disease. In a study of 30 men, serial weight measurements were followed closely. An association was found between acute weight loss episodes and opportunistic infections, with weight loss preceding the infection; caloric deficit and increased REE was also noted. Patients who were found to have chronic weight loss had associated gastrointestinal disease; 68% of these patients had documented malabsorption. Weight regain without nutrition support is not uncommon in patients with acute weight loss, especially after the resolution of an infection. Patients with chronic weight loss can regain weight, however, but most likely will require liquid nutrition supplements long-term.(54)

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Evaluation of Weight Loss
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All patients infected with HIV should have a regular nutritional and functional assessment. Weight loss, body composition changes, and exercise/functional limitations are indicators of advancing disease that may be reversible. All patients who have lost weight should have a thorough evaluation for symptoms contributing to inadequate intake and interventions to promote weight gain should be initiated promptly.

The clinical assessment should identify markers and predictors of malnutrition. A careful review of symptoms will identify barriers to adequate oral intake: anorexia, early satiety, dysgeusia, nausea, vomiting, weakness/fatigue, odynophagia, dysphagia, poor dentition, diarrhea, and abdominal pain. In addition, conditions that increase energy requirements should also be noted, including: fever, tachypnea, systemic infections, increased physical activity.

A detailed review of medications and "alternative therapies" (including herbal therapy and megadosing of vitamins and minerals) may provide insight into potential side-effects. A social history is also important to identify environmental or financial obstacles to obtaining, storing, and preparing food.

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Treatment of Weight Loss
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The goal of nutrition therapy is to preserve lean body mass.(55) Routine evaluations by a registered dietitian who can monitor changes in weight, body composition (body cell mass), caloric intake, and activity levels are extremely useful to prevent weight loss and malnutrition. Based on the evaluation of the patient, estimated caloric intake should be determined and 3-day food records should be administered to review patients actual intake. While guidelines for carbohydrate and fat have not been established, protein requirements should be at least 1.0 to 1.2 g/kg in the absence of secondary infection.(56) Nutrient intake should be at least 100% of the Recommended Dietary Allowance; a multivitamin is commonly suggested for patients with HIV to ensure these requirements are met.

Appetite stimulants are often effective in treating anorexia, a major cause of involuntary weight loss. Dronabinol (Marinol), a synthetic derivative of marijuana, and Megastrol acetate (Megace), a synthetic progestational drug, have been associated with increased appetite and weight.(57,58) In addition to its effects as an appetite stimulant, Marinol may also improve mood and decrease nausea.(58)

Diarrhea associated with malabsorption requires careful nutrition management. A balance must be found between controlling symptoms with a low-fat diet and maintaining caloric intake with fat-containing foods that offer caloric density. Patients with diarrhea unable to meet caloric requirements may benefit from a liquid nutrition supplement containing medium-chain triglycerides. Dietary or supplemental soluble fiber may help bind water and improve diarrhea.

If nonvolitional weight loss cannot be reduced or reversed by oral intake and oral liquid nutritional supplements, enteral alimentation should be initiated. Unless otherwise indicated, the gastrointestinal tract should be used for nutrient absorption. Kotler et al. found that patients fed by endoscopically placed gastrostomy were able to replete body cell mass, but only if the underlying illness is treated concurrently.(59) Percutaneous endoscopic gastrostomy (PEG) feeding tubes are also effective in settings of severe weight loss.(60,61)

Parenteral nutrition should be reserved for severe intestinal dysfunction, such as large volume secretory diarrhea. A clinical trial that randomized participants to total parenteral nutrition (TPN) or nutrition counseling resulted in increased weight and body cell mass in patients who received TPN, however, rehospitalization and survival were the same in both groups.(62)

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Dysphagia and Odynophagia Due to Esophagitis
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General Considerations
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Dysphagia, odynophagia, or both, due to esophagitis are very common among patients with advanced HIV disease. Both were recognized as prominent symptoms in early reports of HIV disease.(63) Their exact frequency is unknown, and not all patients with esophagitis are symptomatic.(64) The majority of patients with dysphagia or odynophagia have candidal esophagitis alone or in association with other infectious pathogens,(65-67) including cytomegalovirus (CMV), herpes simplex virus (HSV), idiopathic (nonspecific) ulceration, and Mycobacterium avium-intracellulare. Malignancies, such as KS and lymphoma, and non-HIV-related disorders, such as acid-reflux esophagitis, can also occur. Heartburn and regurgitation are usually indicative of esophageal reflux disease.

As with infections in other parts of the intestinal tract, the CD4 count can be used to direct the evaluation. Candida and HSV esophagitis are predominantly identified in patients with CD4 cell count less than 200 cells/mm3. CMV and idiopathic ulcers are noted almost exclusively below a CD4 cell count of 100 cells/mm3.

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Evaluation of Dysphagia and Odynophagia
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There is no way to identify the specific cause of odynophagia in the HIV-infected patient based on symptoms or physical examination alone. Like other GI symptoms, odynophagia in the presence of multiple co-infecting organisms makes it impossible to ascribe a symptom or sign to a single pathogen. Barium swallow (double-contrast) findings may be suggestive of infection or neoplasm but not diagnostic. Endoscopy with biopsy is the best method of establishing a specific etiology for dysphagia or odynophagia. During the endoscopy, careful examination of the entire mucosa must be undertaken. If a confluent candidal exudate is noted, removing the exudate to examine the underlying mucosa for concomitant pathology should be considered. Patients with esophageal ulcers should have more than six biopsy specimens obtained from the ulcer(s). In a study of 100 patients with esophageal ulcers, Wilcox et al. reported that the first three biopsy samples yielded a CMV diagnosis in 80% (40 of 50 patients with CMV).(68) In 5 patients (10%) with CMV and 3 of 4 patients with concomitant HSV and CMV, 7 to 10 biopsies were needed to make the diagnosis.

In general, cultures of esophageal biopsy specimens for fungi and viruses are less useful than biopsies, because cultures alone do not distinguish between true pathogens and colonizing organisms.

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Treatment of Odynophagia and Dysphagia
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An empiric approach to managing esophageal symptoms is the most reasonable approach in the patient with AIDS. Given the preponderance of candidal infection, patients with odynophagia who have oral thrush should be treated empirically with fluconazole (100 to 200 mg/day) or itraconazole (200 mg/day) given their superior efficacy compared to ketoconazole (200 mg/day). Esophageal symptoms due to Candida will sometimes improve with treatment even though endoscopic evidence of infection persists.(69) Furthermore, symptomatic improvement of esophageal symptoms is probably the most important goal, because it leads to increased oral intake and better nutritional status.

Refractory Candida esophagitis requires treatment with amphotericin B. Herpes esophagitis responds to acyclovir (200-mg capsules every 4 hours). Rare instances of acyclovir-resistant herpes have been reported in patients with advanced HIV disease.(70) Such patients may respond to foscarnet.(71) Documented infections with CMV generally respond to a 2- to 3-week course of ganciclovir. Relapses may require an additional course of therapy, a maintenance regimen, or both.(72,73) The efficacy of foscarnet is comparable to that of ganciclovir,(73) with possible adverse effects including nephrotoxicity and hypocalcemia.(74)

Nonspecific ulcerations may be treated with a short course of oral corticosteroids (40 mg/day, tapered over 3 weeks)(75,76) or thalidomide (200 mg/day),(77,78) or with combinations of H-2 antagonists and sucralfate.(79) The basis for the response of these lesions to corticosteroids is unknown; infectious causes should be assiduously excluded before administering steroids in this setting.

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Abdominal Pain
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General Considerations
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Abdominal pain is common in patients with HIV infection, and it may portend a catastrophic complication. No data exist on the exact frequency of this symptom.(80,81) When generating a differential diagnosis for an HIV-infected patient with abdominal pain, the clinician must consider not only the manifestations of opportunistic infections and neoplasms but also the more common causes of abdominal pain that occur in otherwise healthy persons. Several published studies specifically address the diagnosis of abdominal pain in HIV disease and underscore the broad spectrum of potential causes.(82-86)

The differential diagnosis for abdominal pain in HIV-infected patients presented in (Table 4) is organized by the pain's site of origin. For each organ system, a list of potential complications and their likely causes is noted. This information is based primarily on case reports, which are noted in the table. The table excludes non-HIV-related diagnoses, which are more common causes of abdominal pain even in patients with HIV disease. Overall, cytomegalovirus (CMV) infection of the bowel and biliary tract are the most common HIV-associated causes of abdominal pain.

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Evaluation of Abdominal Pain
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The patient's history is important in identifying the origin of abdominal pain. In general, the associated symptoms and signs should help identify the particular organ involved. The specific work-up is similar to that for a patient without HIV infection. An exception is that abdominal sonography and computed tomography scanning are useful early in the assessment of abdominal pain in HIV-infected patients and may highlight regions of disease not usually suspected clinically.(87) Unsuspected findings have often included thickening of the gallbladder or colonic wall, focal hepatic lesions, biliary ductal dilatation, pancreatic infiltration, adenopathy, and peritoneal thickening. Abnormal bowel wall thickening in patients with HIV infection should be pursued with endoscopic biopsies. Rockey et al. reported a specific diagnosis in 7 of 15 patients (64%), including CMV, lymphoma, and MAC.(88)

The quality and duration of the abdominal pain may implicate specific diseases. In general, perforation results most often from CMV infection and occurs frequently in the distal small bowel or colon. Lymphoma or KS may also perforate, either spontaneously if the tumor is bulky or due to tumor lysis following chemotherapy or radiation. Obstruction is most likely to develop from an intestinal neoplasm but may also develop from an inflammatory mass or stricture. Intussusception may be an unusual form of lymphomatous obstruction. Infectious enteritis may lead to dull, intermittent abdominal pain in the absence of obstruction or perforation. This is particularly true of infection by Cryptosporidium and Mycobacterium avium-intracellulare complex (MAC) but may also occur in infections from other protozoa, as well as from enteric bacteria including Salmonella, Shigella, and Campylobacter.

Infectious or nonspecific peritonitis in the absence of bowel perforation is increasingly recognized. Infectious etiologies may include histoplasmosis,(89) tuberculosis,(82) MAC, Vibrio vulnificus,(90) toxoplasmosis,(91) and Cryptococcus,(92) in addition to lymphoma.(93) High-protein ascites of uncertain etiology has also been reported and may necessitate laparoscopy to identify a cause.(92)

Pancreatitis can cause abdominal pain in patients with advanced HIV disease and may arise for a variety of reasons. Affected patients usually have elevations of amylase and lipase, unless acute inflammation occurs in a patient with pre-existing underlying chronic pancreatitis. Amylase elevations in the absence of pancreatic disease may indicate macroamylasemia, which occurs in patients with and without HIV disease.(94) Medications are the most common cause of pancreatitis in HIV, particularly pentamidine,(95,96,97) dideoxyinosine (ddI),(98,99) and trimethoprim-sulfamethoxazole.(100) Pentamidine-induced pancreatitis may develop following either inhaled(96) or parenteral administration,(97) and it is associated with the typical clinical features of pancreatitis.(95) The clinical course may be mild, severe, or fatal; it is often accompanied by dysregulation of glucose metabolism.(101,102,95)

Potential infectious causes of pancreatitis in HIV disease are multiple. Most common is CMV,(103) followed by M. tuberculosis,(104) M. avium,(105) Cryptococcus,(106) and herpes simplex (HSV).(107) Infectious pancreatitis may not always be clinically obvious; it should be suspected in any patient with abdominal pain and elevated amylase.(103) In CMV-induced pancreatitis, inclusions may be demonstrable either in ductal epithelium or acinar cells. Fine-needle aspiration may be able to uncover these findings antemortem in patients in whom this infection is suspected. Pancreatic infiltration by lymphoma(108) and KS(109) occurs occasionally, manifested either by mass effect on adjacent duodenum or exocrine insufficiency if the pancreatic duct is obstructed.

Table 5 defines abdominal pain in terms of the four most common pain syndromes, likely causes, and diagnostic methods. The duration and severity of symptoms dictate the urgency of evaluation. For example, patients with dull, insidious abdominal pain can be evaluated with less urgency than patients who develop acute, severe abdominal pain with evidence of peritonitis.

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Treatment of Abdominal Pain
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Managing abdominal pain begins with deciding if the patient requires surgery.(101) In general, the indications for surgical intervention in HIV-infected patients are similar to those in patients without HIV infection. Intestinal perforation or obstruction almost always requires surgical management, despite the increased perioperative and postoperative risk for patients with advanced HIV disease. Clinicians must submit all tissue specimens for viral and fungal culture and for pathologic examination, and mesenteric nodes should be biopsied.(110) Laparoscopic surgery may provide a less invasive alternative in select patients, such as those with cholecystitis. The main goal of any surgical procedure should be the palliation of symptoms. Prolonged anesthesia and extensive tissue resection should be avoided if possible.

The morbidity and mortality in early reports of surgical procedures in patients with advanced HIV disease have been exceedingly high.(83,86) This is due partly to the underlying poor health of patients with advanced HIV disease who require laparotomy; most have CMV infection, which tends to occur in late-stage HIV disease. Complications and mortality are far less likely in patients with asymptomatic HIV infection,(111) although the exact frequency relative to comparable non-HIV-infected persons has not been reported.(83) The result of clinical evaluation determines the nonsurgical management of abdominal pain. Any treatable infection contributing to the symptoms should be managed appropriately. Symptoms due to lymphoma or KS may respond to chemotherapy or radiation therapy. Symptomatic treatment with analgesics may be indicated in addition to specific antibiotic or antineoplastic regimens. HIV-related conditions and chronic opportunistic infections may improve with HAART.

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Anorectal Disease in HIV-Infected Patients
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General Considerations
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Anorectal problems may occur in any HIV-infected patient, but they are particularly common among homosexual men. A broad array of anorectal problems are prevalent in the healthy homosexual male population, in part because of the prevalence of anal intercourse and anilingus.(101,112) Anal warts and fissures, infections with lymphogranuloma venereum, gonorrhea, syphilis, and herpes viruses are well-recognized pathogens, although they do not necessarily imply immunodeficiency in their hosts (Table 6). They have been the subject of numerous reports antedating the HIV epidemic.(31,113,114)

The frequency of anorectal disease among homosexual male patients with advanced HIV disease is quite high. In a large New York City series of 340 such patients, the incidence of anorectal disease was 34%.(115) Perirectal abscesses, anal fistulae, and infectious proctitis were the most common findings, but lymphoma, ulcerations due to tuberculosis, and histoplasmosis were also present. Idiopathic ulcerations in this region similar to those seen in the esophagus in HIV disease occur with increased frequency.(116)

Anorectal carcinomas are more common in homosexual men than in other members of the population.(117-121) These neoplasms appear to result from chronic perianal herpes or papillomavirus infections acquired through sexual contact.(122) HIV-infected subgroups other than homosexual men do not appear to have an increased incidence of anorectal carcinoma.

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Evaluation and Treatment of Anorectal Disease
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In HIV-infected patients, physical examination should include careful inspection of the skin and mucous membranes as well as palpation of the lymph nodes. Careful visual inspection of the anus for fissures and masses should precede digital examination. Palpation of the anal canal may reveal masses or fissures not otherwise evident. All patients with anorectal symptoms should have anoscopy and sigmoidoscopy (rigid or flexible) with mucosal biopsy, even if the mucosa appears unremarkable by gross examination.

The stage of HIV disease largely determines healing of anorectal disease following surgical or nonsurgical therapy. Surgery is most likely to succeed in patients in the earlier versus later stages of HIV infection,(111,123,124) although the healing rates may still be slower than in immunocompetent patients. In patients with idiopathic ulcerations, debridement and use of either systemic or intralesional corticosteroids has been successful. In chronically ill patients, a more conservative approach to surgical management seems warranted depending on the extent of debility. All efforts should be directed toward identifying infections and providing symptomatic relief, reserving more aggressive measure for those in whom less invasive efforts fail.

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Gastrointestinal Bleeding
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General Considerations
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Although gastrointestinal (GI) bleeding occurs in less than 1% of patients with HIV disease, it may pose difficult diagnostic and therapeutic challenges. Moreover, GI bleeding is independently associated with reduced survival.(125) GI bleeding in patients with HIV disease is as likely to arise from lesions not unique to HIV infection as from HIV-associated opportunistic infections or neoplasms.(125-127) Common lesions not unique to HIV infection include peptic or stress-related ulcer disease, variceal hemorrhage due to portal hypertension, inflammatory bowel disease, diverticular disease and colonic polyps, and neoplasia. None of these diseases occurs more commonly in HIV-infected patients than in healthy persons. This review addresses only those infectious processes and neoplasms associated exclusively with HIV infection that may on rare occasion cause GI bleeding.

Cytomegalovirus (CMV) involvement of the GI tract may cause bleeding by inducing vasculitis in affected tissue. The vasculitis results in ischemia, infarction, or both and occurs most commonly in the colon or distal small bowel.(128,129) A similar mechanism probably accounts for the bleeding associated with CMV infection of the esophagus and stomach.(130) Hemorrhage from colonic or esophageal infection may be due to either focal or diffuse inflammation.(129,130) Occasionally, patients can develop a pancolitis that is clinically similar to the colitis seen in patients with inflammatory bowel disease or mesenteric ischemia.(129) Candida albicans may sometimes induce esophageal hemorrhage via direct fungal invasion, causing a severe erosive esophagitis.(131)

Herpes esophagitis has only rarely caused esophageal hemorrhage in non-HIV-infected patients.(132) In HIV-infected patients, however, the later stages of herpes infection of the esophagus are associated with mucosal ulcerations that may coalesce into a diffuse hemorrhagic esophagitis.

Cryptosporidiosis occasionally causes enteritis associated with hematochezia,(133) although the majority of patients with cryptosporidiosis have severe diarrhea with little or no hemorrhage.(134)

Enteritis associated with Salmonella, Shigella, or Campylobacter occurs with increased frequency in HIV-infected patients, as compared with non-HIV-infected patients.(135) These infections are associated with watery diarrhea that may be grossly or microscopically bloody.

Several other enteric infections associated with hemorrhage occur with increased frequency in sexually active homosexual men, regardless of whether they are infected with HIV. These organisms include Entamoeba histolytica and chlamydia.(31) The clinical features of such infections in patients with HIV disease are similar to those seen in otherwise healthy homosexual men. Rarely, histoplasmosis leads to colonic ulcerations that bleed.

Neoplasms associated with HIV disease may cause intestinal bleeding. In a small series from San Francisco, KS was the most common lesion found in patients with HIV-related GI bleeding.(127) Reports describe isolated cases in which ulcerated GI KS lesions bled spontaneously.(85,127,136) In general, however, KS lesions are asymptomatic. In a series of 20 patients with intestinal KS and HIV disease from San Francisco General Hospital, no episodes of GI bleeding occurred either spontaneously or after endoscopic biopsy.(136)

Primary intestinal lymphoma occurs more often in HIV-infected patients than in non-HIV-infected patients.(137) Bleeding from these tumors may occur.

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Evaluation and Treatment of GI Bleeding
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Gastrointestinal bleeding in a patient with HIV infection should be evaluated with the same approach used in assessing a non-HIV-infected patient. The utility of endoscopy and the patient's prognosis depend on the number and severity of concomitant diseases.(126) First, one should determine how brisk the bleeding is and whether it arises from an upper- or lower-tract lesion. Upper endoscopy is usually necessary to define the source of any severe upper-tract bleeding. To evaluate acute lower-tract hemorrhage, a nuclear red blood cell scan to define the approximate site of bleeding is more useful than immediate colonoscopy. Endoscopic mucosal biopsy of briskly bleeding lesions is generally not appropriate because of the risk of precipitating more severe hemorrhage. After the bleeding subsides, a repeat of the examination with mucosal biopsy can be performed. Barium contrast studies in evaluating GI bleeding are of limited value.

Appropriate management of severe GI bleeding due to HIV-related diseases does not require a specific diagnosis. Treatment consists of blood-product support and, if necessary, surgery. Hemostasis should be achieved by nonsurgical endoscopic means wherever possible, including direct injection of bleeding lesions with sclerosant or epinephrine or use of heater-probe cautery or electrocautery. Intermittent blood-product replacement may be necessary in patients with chronic, idiopathic blood loss to prevent severely symptomatic anemia. Surgery should be avoided if possible but should be undertaken if noninvasive means fail.

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Gastrointestinal Kaposi's Sarcoma and Non-Hodgkin's Lymphoma
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Kaposi's sarcoma (KS) has been the most common neoplasm associated with HIV infection affecting predominantly homosexual men. Between 1987and 1994, the prevalence has declined from 55% to 5% in the United States.(138) While the incidence of KS has declined, non-Hodgkin's lymphoma (NHL) continues to rise.(138) Kaposi's sarcoma and HIV-associated lymphoma are discussed extensively in other chapters, hence only the features related to gastrointestinal disease are reviewed.

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Kaposi's Sarcoma
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General Considerations
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GI involvement by KS is frequent in patients with advanced HIV disease.(136) In two autopsy series, GI KS was seen in 56 to 70% of all patients who had KS.(64,139) Most clinical series probably underestimate the overall incidence of luminal GI involvement with KS, since intestinal lesions rarely lead to symptoms. In a prospective endoscopic evaluation of 50 homosexual men with AIDS and KS of the skin or lymph node, 20 patients (40%) had evidence of GI KS within the range of the flexible sigmoidoscope or upper endoscope.(109) The indolent variant of KS previously recognized in elderly men of European origin is only rarely associated with GI involvement.(140)

The location of nonvisceral sites of KS (skin, lymph nodes) does not predict the likelihood of GI KS, although in general, patients with extensive cutaneous lesions are more likely to have GI involvement.(109,141) The absence of skin or lymph node KS, however, does not exclude the possibility of GI involvement, since some patients have been seen with GI disease without cutaneous lesions.(142) Patients with oral KS lesions are no more likely to have GI KS than patients without oral lesions.(109)

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Clinical Features
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GI KS is often widely disseminated yet rarely leads to symptoms. KS lesions are usually small and multiple but may occasionally be bulky masses.(109) Several autopsy series have failed to demonstrate a single instance of death due primarily to a GI KS lesion.(139,143) Similarly, in a prospective study, there were no proven clinical sequelae of GI lesions in 20 patients with endoscopic evidence of KS.(109) Rare clinical consequences of GI KS lesions have been reported before and since the AIDS epidemic. GI bleeding has been attributed to ulcerated KS lesions.(85,127) Intestinal KS has also occurred in association with protein-losing enteropathy,(144) and malabsorption.(145)

Reports also describe hepatobiliary KS. In fact, KS has been found in almost every solid organ.(146) Lesions in the liver are predominantly periportal and are usually asymptomatic,(146) but conceivably they could cause biliary obstruction if located in the distal common bile duct or lymph nodes near the hepatic hilus. Pancreatic KS lesions also occur(109) but have not been shown to cause pancreatitis. Although visceral KS lesions rarely cause symptoms, patients with advanced HIV disease and GI involvement by KS have a poorer prognosis than those without GI KS.(109)

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Treatment of GI Kaposi's Sarcoma
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Clinicians must tailor treatment of GI KS to individual patients. Treatment may consist of observation only, immunomodulatory agents (e.g., interferon-alpha), chemotherapy, and/or radiotherapy, depending on the extent and location of the tumor as well as the underlying condition of the patient.(109) Response of GI KS generally parallels the response of cutaneous lesions; endoscopic staging may be useful in this setting.(147) Bleeding from gastric lesions often can be controlled by endoscopic injection of a sclerosant of the type usually used in variceal sclerotherapy (e.g., ethanolamine oleate).(148)

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Lymphoma
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General Considerations
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A striking increase in NHL, often accompanied by GI involvement, has occurred in persons with advanced HIV disease. Almost all the tumors are of B cell origin.(146) Most are high grade, with sheets of large cells displaying cellular pleomorphism and nuclear distortion. GI or hepatobiliary involvement occurs in 27 to 74% of all HIV-infected patients with NHL; it is not uncommon for the gastroenterologist to make the initial diagnosis. The tumor may develop at any stage of HIV disease, and the prognosis generally correlates with the extent of underlying immunocompromise and Karnofsky performance score rather than characteristics of the lymphoma itself.(146,149)

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Clinical Features
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Almost all patients present with extranodal disease; approximately one third have primary lymphoma of the GI tract or hepatobiliary tree.(146) Any region may be involved, although hepatic parenchymal lesions or rectal tumors are particularly common. Lymphoma has occurred in the oral mucosa,(146) esophagus,(150) stomach,(151,152) duodenum,(152) small bowel,(153) and colon.(153) Tumors may be single or multiple fungatory masses, often with associated hemorrhage. Rectal tumors may be insidious and can be mistaken for benign tissues or fistulae.(154)

Clinical sequelae of GI NHL depend on the tumor's location and size. Because these tumors are very aggressive, they are unlikely to remain asymptomatic for very long. Luminal lesions can lead to diarrhea, pain, obstruction, bleeding, or perforation, whereas hepatic disease may cause dull pain in association with fevers and a rising alkaline phosphatase. Rectal involvement can be subtle, with discharge or nonhealing ulcerations as the only manifestations.

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Diagnosis of GI Non-Hodgkin's Lymphoma
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Noninvasive imaging studies can be useful in identifying suspicious lesions, although tissue evaluation is always required to establish the diagnosis of NHL. Computerized tomographic scanning and ultrasound are particularly useful for hepatobiliary lesions, whereas barium contrast studies or endoscopy is more appropriate for luminal tumors. Endoscopic biopsies are often positive when tumor is detectable by contrast studies. Tissue should be submitted in a manner that allows special staining to categorize the lymphoma (e.g., on saline-soaked gauze or in plastic embedding) and staining with leukocyte common antigen.(155) Fine-needle aspiration of masses or enlarged lymph nodes has proven an extremely useful technique at San Francisco General Hospital.(156) An experienced cytologist and close interdisciplinary cooperation are essential for success.

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Treatment of GI Non-Hodgkin's Lymphoma
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Treatment of lymphomas is a difficult issue because of the conflict between the need to use immunosuppressive chemotherapy and the concern over hastening the acquisition of opportunistic infections.(109) Of particular concern is the risk of inducing perforation by tumor lysis following treatment of bulky luminal lesions. In such situations, consider the risks and benefits of surgical resection before initiating radiation therapy or chemotherapy.

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Hepatobiliary Abnormalities
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Hepatic Disorders
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Most patients will experience hepatobiliary manifestations at some point during the course of their HIV disease, with hepatomegaly and/or jaundice in 50% and abnormal liver function tests in over 80%. Despite their frequency, however, the approach to patients with such abnormalities remains problematic. Although most conditions found on liver biopsy represent systemic opportunistic infections or neoplasms, liver disease itself is rarely the cause of death.(157) Instead, the clinical and histologic expression of most diseases in the liver is attenuated because of the impaired immune response. In addition, most liver disorders that are diagnosed in patients with AIDS reflect advanced immunosuppression and occur late in the natural history of AIDS, when little can be done to improve overall outcome.

HIV can involve the liver directly, as demonstrated by the presence of HIV p24 within Kupffer cells and hepatic endothelial cells(158) and HIV messenger RNA within hepatocytes.(159) Hepatic macrophages and endothelial cells express the CD4 surface molecule and have been shown to support viral replication in vitro.(160) It remains unclear, however, whether HIV itself directly damages the liver. The quantity of HIV antigens in immunohistochemical studies does not correlate with the degree of histologic abnormalities, and normal histology can be seen.(161)

Mycobacterium avium complex (MAC) is the most common opportunistic pathogen found when liver biopsy is performed in patients with HIV disease, accounting for 38% of diagnoses in one series.(162) Infection with MAC occurs late in the natural history of AIDS, with CD4 counts generally less than 50 x 106 cells/ml. Because hepatic involvement occurs in the setting of disseminated disease, systemic symptoms dominate the clinical picture,(163) although a prominent elevation of serum alkaline phosphatase is common.(164) Treatment with multiple antibiotics generally produces an initial response; however, because of the advanced immunosuppression in these patients, the long-term outcome remains poor.

Hepatic involvement with MAC must be distinguished from infection with Mycobacterium tuberculosis. Extrapulmonary tuberculosis occurs in over 50% of infected patients with AIDS.(163) Infection occurs at a less advanced stage of immunocompromise than MAC, which may account for differences seen histopathologically, including well-formed granulomas and caseation. Tuberculosis cannot be distinguished from MAC by clinical features or histopathology alone; therefore, culture is required for positive diagnosis. In addition, determination of antimicrobial sensitivities is necessary to guide appropriate therapy. Unless a multidrug-resistant strain is present, response to treatment is good, with a median survival of 16 months.(165)

Peliosis hepatis has been recognized as a bacterial syndrome in patients with AIDS, following the discovery of its causative agent, Bartonella hensalae. Early in the AIDS epidemic, a syndrome consisting of dilated, blood-filled hepatic sinusoids and elevated liver function tests was recognized in conjunction with cutaneous bacillary angiomatosis.(166) Histopathologic studies revealed clumpy granular, purple material within both hepatic and cutaneous lesions, which proved to be bacteria by electron microscopic analysis. Further investigations employing polymerase chain reaction tests (PCR) identified the organism as a gram-negative bacillus closely related to Bartonella quintana, the causative agent of trench fever. In a recent case-control study, infection with B. Henselae has been epidemiologically linked to exposure to cats.(167) Histologically, peliosis consists of numerous blood-filled cystic spaces within the hepatic parenchyma without an endothelial lining. Serum transaminase levels are modestly elevated, with more prominent elevations of serum alkaline phosphatase. In addition to cutaneous lesions, patients can experience fevers, sweats, rigors, right upper quadrant pain, or pain from bony lytic lesions. Successful treatment regimens have included erythromycin, doxycycline, ciprofloxacin, and antituberculous regimens, although prolonged therapy for several months may be required.

Fungi usually involve the liver only with disseminated disease. These infections share a nonspecific clinical presentation, including unexplained fever, hepatomegaly, and elevated alkaline phosphatase levels, although large fungal abscesses are occasionally seen on imaging studies. Hepatic involvement can accompany cryptococcal meningitis in the setting of hematogenous dissemination. Opportunistic infections with Histoplasma, Coccidioides, Candida, and Sporothrix organisms occur less commonly. Although a nonspecific attenuated granulomatous reaction is characteristic, liver biopsy is generally not required fro diagnosis.(168) Response to prolonged antifungal therapy is variable, with death resulting from disseminated infection rather than from hepatic involvement itself.

Pneumocystis carinii is the most common protozoal pathogen among patients with AIDS, and liver involvement occurs in 38% of patients.(169) Pulmonary symptoms dominate the clinical presentation, although a few cases of primary hepatic involvement have been reported.(163) On liver biopsy, a foamy eosinophilic exudate is characteristic, with the organism demonstrable on silver stain.(170) Response to treatment with parenteral pentamidine or trimethoprim-sulfamethoxazole has been reported, although no controlled trials have been conducted.

Kaposi's sarcoma is seen almost exclusively in homosexual men with AIDS, as opposed to other risk groups. Disseminated disease is common, with hepatic involvement in one-third of patients at autopsy.(171) Although serum alkaline phosphatase may be elevated, visceral disease is often asymptomatic, even with extensive involvement. Histologically, the lesions are easily identified as solid dark red to purple nodules in the portal regions, filled with densely packed spindle-shaped endothelial cells that form slitlike vascular channels.(172) Although lesions may respond to radiotherapy or chemotherapy, hepatic disease is not treated unless symptomatic, because the nodules themselves rarely are a direct cause of death or severe morbidity.

Extranodal presentation of non-Hodgkin's lymphoma is common in patients with advanced AIDS, with liver disease typically in the setting of multiorgan involvement.(172) Infection with Epstein-Barr virus (EBV) has been implicated with the finding of EBV genomic fragments within tumor cells by DNA hybridization as well as the universal presence of anti-EBV antibodies in patients with NHL.(136) Serum alkaline phosphatase elevations are most sensitive for hepatic involvement, with elevated transaminases and bilirubin in advanced disease. Although approximately 50% of patients have been reported to respond to various chemotherapeutic regimens, disease-free intervals have been short and recurrence rates high.(173) Overall survival, however, is no worse than in AIDS patients without lymphoma, most likely because NHL usually accompanies advanced immunocompromise.

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HIV and Hepatitis B (HBV)
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That coinfection with HBV and HIV is common is not surprising given their similar modes of acquisition. The prevalence of seropositivity for past or present infection with HBV approaches 90% in HIV-infected homosexuals.(174) Similarly high rates of coinfection have been seen in injection drug users.(175) The prevalence of HBV seropositivity among HIV-infected patients, however, is no higher than that seen in control patients without HIV, suggesting that coinfection likely reflects lifestyle practices that predispose to both infections.(176)

In patients with past or present HBV infection, HIV infection leads to alterations in HBV serology and viral replication. Following acute HBV infection, the virus is cleared in 95% of immunocompetent patients. In contrast, 50% of HIV-coinfected patients will develop chronic infection.(177) Several reports have described reappearance of HbsAg in HIV-infected patients previously thought to be immune to HBV, as indicated by the presence of anti-Hbs.(178,179) In addition, there is an accelerated loss of naturally acquired anti-HBs even in patients who remain HBsAg negative.(180,181) Associated with this reduction in immunity to HBV is increased prevalence of HBeAg expression, elevated mean levels of DNA polymerase, and increased titers of anti HBc.(177,178,182,183) Thus, more patients with HIV and HBV coinfection are in the chronic HBV carrier state, with highly infectious serum and body fluids, as compared with those who are not infected with HIV.(184)

The impact of HIV on the severity of chronic HBV infection is less clear. Several case series have suggested that HIV-coinfected patients have milder clinical disease, with reduced severity on histologic examination and less pronounced elevations of serum aspartate aminotransferase (AST) and alanine aminotransferase.(177,182,185) Corroborating these results, Scharschmidt et al. found no difference in survival up to 48 months between 35 patients with HIV/HBV coinfection and 70 patients infected with HIV alone, regardless of whether progression to overt acquired immunodeficiency syndrome (AIDS) occurred.(182) In a similar study, however, Housset et al. obtained contradictory results, with significantly shorter survival among HIV/HBV coinfected patients compared with those infected with HIV alone. Furthermore, liver disease was the most common cause of death among these patients.(185)

Vaccination against HBV has been recommended for all patients infected with HIV. Unfortunately, HIV infection reduces the efficacy of vaccination in these patients. Several studies have demonstrated suboptimal response to plasma-derived vaccine in both magnitude and duration of the antibody response.(186-188) Lack of responsiveness does not clearly correlate with CD4 count. Among those patients who do respond, loss of protective anti-HBs is seen in 43% at 4 years, compared to 8% of immunocompetent controls.(181)

Historically, there has been little enthusiasm or rationale to treat HBV infection in HIV-coinfected individuals since the latter disease rather than the former had been the major determinant of life expectancy for most patients. This situation is changing rapidly, however, as therapies for HIV improve and patients live longer, developing greater risk for decompensated liver disease. Unfortunately, treatment options remain limited. Interferon-alpha is the only drug currently approved for treatment of chronic HBV. In immunocompetent patients, a standard course of treatment leads to loss of HBeAg and HBV-DNA in 35%, but if such a response can be induced, it is generally maintained long-term. HIV-coinfected patients, however, have been identified in a meta-analysis as a subgroup with poor response to interferon.(189) This has been confirmed in a small controlled trial, in which an 8% response was seen in HIV-positive subjects, compared with 39% in controls.(190) Newer antiviral drugs such as lamivudine, which directly inhibit HBV replication rather than modulating the immune response, may hold more promise for effective treatment of these patients in the future.

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HIV and Hepatitis C (HCV)
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Hepatitis C (HCV) shares a parenteral mode of transmission with HIV and is seen more commonly among intravenous drug users than in other risk groups. The reported prevalence of HIV and HCV coinfection(191-193) has ranged between 7% in a university clinic setting and 89% among intravenous drug users. Such estimates are imperfect, however. Most studies have utilized first-generation HCV antibody assays; in addition, seroreversion with loss of anti-HCV antibody has been reported in up to 20% of patients.(194) In this population, the detection of HCV RNA by hybridization assays or by polymerase chain reaction is the gold standard for diagnosis.

In the presence of an intact immune system, HCV is an indolent disease, with progression to liver failure in a minority of patients over a time span measured in decades. This natural history appears to be accelerated in immunocompromised patients. Similar to HBV, viral replication as measured by HCV-RNA level is greater in patients with HIV coinfection, and a higher prevalence of liver failure has been seen in HIV-coinfected hemophiliacs compared to those with HCV infection alone.(195,196) Furthermore, the risk of clinical liver disease increases with progression of AIDS as measured by p24 antigenemia and decreased CD4 counts. In a cross-sectional study of 512 HIV-infected patients, however, Wright et al. found no difference in overall mortality between those with and without HCV.(197) This result suggests that, as with HBV, it is the infection with HIV rather than viral hepatitis that ultimately determines the outcome in these patients.

Currently, interferon-alpha is the only drug approved by the FDA for treatment of HCV. Even among immunocompetent patients, the long-term benefit of such therapy remains unclear. Data on the treatment of immunocompromised patients remain extremely limited. Two small uncontrolled studies have been performed to investigate interferon-alpha treatment of HCV in HIV-coinfected patients.(198,199) Although these studies showed reduction in HCV RNA levels and improvements in histology, more definitive trials are needed. Given the absence of any clearly effective regimens and the questionable impact of HCV infection on the overall prognosis of patients coinfected with HIV, aggressive treatment cannot be recommended at the present time.

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Biliary Tract Disorders
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General Considerations
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Biliary abnormalities in patients with AIDS fall into three general categories: non-HIV-associated conditions of the bile duct, acalculous cholecystitis, and AIDS cholangiopathy. A significant proportion of patients with features suggestive of biliary tract disease will be found to have common conditions such as cholelithiasis, benign bile duct strictures, or even periampullary neoplasms of the bile duct. Such readily treatable conditions must be excluded prior to searching for an AIDS-associated diagnosis.

Acalculous cholecystitis is not common in patients with advanced AIDS, and has been linked to infection with cytomegalovirus (CMV) or Cryptosporidium.(200,201) In contrast to nonimmunocompromised patients with acalculous cholecystitis, these patients are young and ambulatory, and present with right upper quadrant pain and abnormal liver function tests. A history of prior infection with CMV or C. parvum is common, as is associated sclerosing cholangitis and/or papillary stenosis of the distal common bile duct. The diagnosis may be made by ultrasonography or technetium scintigraphy, and cholecystectomy is therapeutic.

As with other biliary manifestations, AIDS cholangiopathy presents as right upper pain and markedly elevated alkaline phosphatase levels. Serum bilirubin elevation is modest, however, and patients are rarely icteric. Sonography or computed tomography reveal dilated intra- and/or extrahepatic bile ducts in 81% of patients.(202,203) On endoscopic retrograde cholangiopancreatography (ERCP), four patterns may be seen. Papillary stenosis alone is seen in 28%, sclerosing cholangitis alone in 12%, papillary stenosis combined with sclerosing cholangitis in 49%, and isolated long extrahepatic duct strictures in 10%. Universal and sustained pain relief is achieved in patients with papillary stenosis who undergo sphincterotomy, regardless of whether sclerosing cholangitis is also present. Biochemical abnormalities are unaffected, however, as is overall survival.(202) The association of AIDS cholangiopathy with specific pathogens is less clear. Cryptosporidia and CMV have been described most frequently, with microsporidia and MAC also reported; however, no pathogens were isolated in 42% of reported cases.(204-208)

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Clinical Evaluation of Hepatobiliary Disease
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Several caveats should guide the evaluation of abnormal liver function tests or hepatobiliary symptoms in patients with AIDS. First, histologic and biochemical abnormalities are ubiquitous, but liver disease itself seldom causes significant morbidity. Second, hepatic involvement by opportunistic infections and neoplasms is generally part of a disseminated process. Such diseases can usually be diagnosed at an extrahepatic site and are often poorly amenable to treatment. In contrast, biliary complications of AIDS require an aggressive approach, because they frequently are symptomatic and are potentially fatal. Moreover, effective palliation is available for most of these patients by endoscopic or surgical means.

The role of liver biopsy in patients with AIDS has been especially controversial. Several reported series have shown that histologic abnormalities are seen on almost all biopsy specimens, the majority of which are nonspecific.(170) The yield of specific, treatable diagnoses is quite low, however, and most of these diagnoses could be made by less invasive means, including blood cultures and aspirates of bone marrow or lymph nodes.(162) Because liver biopsy rarely provides unique information to influence therapy or improve survival, it cannot be recommended for routine evaluation of abnormal tests of hepatic function in patients with AIDS. Liver biopsy may be indicated in certain situations, however, when severe symptoms and marked biochemical abnormalities are present, and after less invasive investigations have proved unrevealing.

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Conclusion
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In the setting of highly active antiretroviral therapy, the clinical spectrum of HIV disease has dramatically changed. Fewer late-stage immunocompromised patients and more "early stage" patients have led to an even greater emphasis on primary providers and outpatient management. The spectrum of disease pathogens has shifted with fewer severely immunocompromised patients, more effective prophylaxis, and the effects of "immune reconstitution" on GI tract pathophysiology. Prolonged survival leads to greater emphasis on chronic gastrointestinal/liver disease and neoplasms. The management of chronic HCV is becoming a major problem as is the increased incidence of lymphomas as a cause of death; many lesions are in the gastrointestinal tract or liver. The changing nature of HIV disease requires an ongoing review of a patient's immune function and a careful monitoring of overt and subtle gastrointestinal complaints. Intervention may be required to identify all reversible causes. As HIV disease becomes less a progressive and more a chronic condition, maintenance of good nutrition status remains essential to preserving the functional capacity and energy reserves of individuals infected with HIV.

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