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Gastrointestinal and Hepatobiliary Diseases

Gastrointestinal and Hepatobiliary Diseases in Patients with human immunodeficiency virus and acquired immunodeficiency syndrome

Gastrointestinal diseases associated with human immunodeficiency virus infection

Gastrointestinal and Hepatobiliary DiseasesThe treatment of human immunodeficiency virus infection has dramatically improved over the last several years with the use of combination therapy of potent antiretroviral agents including protease inhibitors. With this highly active antiviral therapy, human immunodeficiency virus replication can be profoundly suppressed and in some patients, circulating human immunodeficiency virus becomes undetectable. Even patients with advanced human immunodeficiency virus disease, the CD4 lymphocyte count rises reflecting a redistribution of CD4 cells. Clinically, with regression of immune suppression, patients become more immunocompetent, the risk for opportunistic infections and processes becomes reduced, and overall survival is improved. Thus, at this time, the long-term prognosis is dictated by the severity of the immunodeficiency (absolute number of CD4 cells) and the level of the circulation virus.

Because of highly active antiviral therapy, there has been a major change in the management of opportunistic infections in human immunodeficiency virus and acquired immunodeficiency syndrome. When opportunistic infections are diagnosed and treated, both the opportunistic infection and the underlying human immunodeficiency virus infection are treated. In fact, in some patients, treatment with highly active antiviral therapy alone results in a remission of opportunistic infection and reduction of relapses. Because of the remarkable success of highly active antiviral therapy in reconstitution of the immune system in these patients, the etiology, diagnostic approach, and management of human immunodeficiency virus-associated gastrointestinal diseases learned in the pre-highly active antiviral therapy era may not be accurate at this time.

Gastrointestinal complaints and problems are still quite common in human immunodeficiency virus-infected patients, however, etiology has shifted toward disorders not associated with human immunodeficiency virus induced immunodeficiency. Also, some of the medications used in highly active antiviral therapy regimens have been associated with gastrointestinal and hepatic side effects. Table GASTROINTESTINAL PATHOGENS IN HUMAN IMMUNODEFICIENCY VIRUS -INFECTED PATIENTS lists gastrointestinal pathogens/diseases by location in human immunodeficiency virus-infected patients.

Diseases of the esophagus

Before highly active antiviral therapy, approximately one third of human immunodeficiency virus-infected patients developed esophageal disease. In patients treated with highly active antiviral therapy, the frequency of opportunistic infection of the entire gastrointestinal tract, including the esophagus, has been dramatically reduced. However, as with other opportunistic infections, the incidence of opportunistic disorders increases as the immunodeficiency worsens. The esophagus may often be the site of the first acquired immunodeficiency syndrome-defining opportunistic disease. Opportunistic infections are the most common causes of esophageal disease. However, cytomegalovirus and idiopathic esophageal ulceration are rarely seen until the CD4 count falls below 100/ml. Almost all esophageal infections in patients with acquired immunodeficiency syndrome are treatable. A definitive diagnosis and treatment usually results in better nutrition, weight gain, and a better quality of life for the patient.

Etiologies

Fungi. Prior to the use of highly active antiviral therapy, Candidiasis was the most common cause of esophageal disease in human immunodeficiency virus-infected patients. Esophageal involvement by fungi other than Candida is very rare.

Viruses. cytomegalovirus is the most common cause of esophagitis in patients with acquired immunodeficiency syndrome. In contrast to other immunocompromised states, such as in post transplant patients, infection with herpes simplex virus (herpes simplex virus) is uncommon in human immunodeficiency virus-infected patients. In a prospective study of 100 patients infected with human immunodeficiency virus, herpes simplex virus esophagitis was found only in 5% of these patients compared to a 50% prevalence of cytomegalovirus esophagitis.

Idiopathic esophageal ulcers are an important cause of dysphagia and odynophagia in patients with acquired immunodeficiency syndrome. Idiopathic Esophageal Ulcer is nearly as common as cytomegalovirus esophagitis, comprising about 40% of esophageal ulcers. The etiology of Idiopathic Esophageal Ulcer is unknown and includes disordered immune regulation, increased apoptosis, local human immunodeficiency virus infection, and unidentified viruses.

TABLE. GASTROINTESTINAL PATHOGENS IN HUMAN IMMUNODEFICIENCY VIRUS -INFECTED PATIENTS
Site Organism
Esophagus Candida albicans
herpes simplex virus
cytomegalovirus
Stomach cytomegalovirus
Mycobacterium avium complex
Small intestine Salmonella
Campylobacter
Mycobacterium avium complex
Cryptosporidium
Microsporidia (Enterocytozoon bieneus)
Isospora belli
Giardia lamblia
Large intestine cytomegalovirus
Adenovirus
Histoplasma
Shigella
Salmonella
Clostridium difficile
Campylobactor
Mycobacterium avium complex
Cryptosporidium
Microsporidia
Entamoeba histolytica
Anus herpes simplex virus, Human papilloma virus
human immunodeficiency virus, human immunodeficiency virus; herpes simplex virus, herpes simplex virus; cytomegalovirus, cytomegalovirus; Mycobacterium avium complex, Mycobacterium avium-complex.

Gastroesophageal reflux disease, in the era of highly active antiviral therapy, probably represents one of the most common causes of esophageal disease.

Pill-induced esophagitis is not uncommon in human immunodeficiency virus-infected patients on highly active antiviral therapy. Medications unique to these patients include zidovudine (AZT) and zalcitabine (ddC).

Clinical presentation

The history is usually helpful in determining the cause and severity of the esophageal disease. Difficulty swallowing (dysphagia), painful swallowing (odynophagia), loss of appetite, and weight loss are the most common complaints. When the pain is unilateral and localized to the neck or hypopharynx, oropharyngeal rather than esophageal disease is likely.

Physical examination. The presence of oropharyngeal lesions may provide a clue to the underlying cause of esophageal complaints. Approximately two thirds of patients with esophageal candidiasis have concomitant thrush. However, the presence of thrush does not necessarily indicate Candida esophagitis. Also, Candida esophagitis may coexist with other esophageal diseases in at least 25% of patients. Oropharyngeal ulcers are rarely associated with esophageal ulcers. KS lesions may be seen in the oropharynx and are associated with gastrointestinal KS.

Laboratory tests. The stage of immunodeficiency determines the differential diagnosis of esophageal disease. The levels of human immunodeficiency virus viremia and CD4 lymphocyte count are the two most important laboratory tests. opportunistic infections of the esophagus are uncommon until the CD4 count falls below 200/mm3. Idiopathic Esophageal Ulcer and cytomegalovirus esophagitis are rarely seen until the CD4 count drops below 100/mm3.

Empiric therapy. Because candidiasis is the most common cause of esophageal disease in human immunodeficiency virus-infected patients, an empiric trial of antifungal therapy is reasonable. Further diagnostic testing is then based on the clinical response. Empirical therapy with fluconazole 200 mg per day followed by 100 mg per day for a 7- to 10-day treatment course is recommended. The clinical response of Candida esophagitis to the treatment with fluconazole is rapid (within 3 days). If no substantial improvement occurs in 3 to 5 days, endoscopy is recommended. Most patients who fail antifungal therapy do not have candidiasis, but rather esophageal ulcers. Additional empirical trials such as antiviral therapy with acyclovir sodium or ganciclovir sodium are discouraged. In patients with CD4 counts higher than 200/mm3 and with symptoms typical of Gastroesophageal reflux disease, a trial of gastric acid suppressive therapy with high-dose, proton-pump inhibiters is recommended.

Barium swallow/upper gastrointestinal series may document esophageal candidiasis or ulceration in symptomatic patients. However, because there are many causes of esophageal ulcers in acquired immunodeficiency syndrome, patients will require endoscopic examination for biopsies.

Endoscopy is a means of directly visualizing the upper gastrointestinal mucosa as well as for obtaining biopsies for histopathologic examination of the lesions visualized. The endoscopic appearance of a lesion often suggests the diagnosis. Candidiasis appears as cottage cheese-like plaques and coats most of the esophageal mucosa. However, because Candida coexists with other lesions at least in 25% of cases, multiple biopsies are required.

Viral esophagitis may present as diffuse esophagitis or small superficial ulcers with herpes simplex virus and as one or more large, well-circumscribed ulcers with cytomegalovirus. Biopsies of the ulcer margins and base are required for histopathologic diagnosis. Immunohistochemical stains of the biopsies will increase the diagnostic accuracy. Idiopathic Esophageal Ulcer may resemble cytomegalovirus ulcers. Multiple biopsies of the ulcer base and margins are required to exclude the presence of cytomegalovirus. KS appears as elevated blue-violatious nodules.

Treatment is to be directed to the etiology of the esophageal lesion. Esophageal candidiasis responds well to fluconazole or itraconazole. Both agents are also available in liquid formulation for patients who cannot swallow tablets or capsules.

Herpes simplex virus esophagitis is treated with acyclovir sodium or valacyclovir hydrochloride. For cytomegalovirus disease, ganciclovir sodium is effective. The newer drug, cidofovir may be administered by a once-weekly injection. Idiopathic Esophageal Ulcer may be treated with either prednisone or thalidomide: The response rate is higher than 90%. Patients should be treated or continued on highly active antiviral therapy to help expedite healing and to prevent relapse.

Diseases of the stomach

Gastric lesions. The most common opportunistic infection of the stomach is cytomegalovirus, which usually results in gastric ulceration. Gastric neoplasms include non-Hodgkin’s lymphoma and KS. The stomach is the most common site in the gastrointestinal tract for KS. Patients are usually asymptomatic. Gastric lymphoma may present with epigastric pain, nausea, and vomiting or bleeding. The prevalence of peptic ulcer disease with or without Helicobacter pylori and gastric adenocarcinoma is the same as in the general population.

Endoscopy with biopsies is the preferred diagnostic modality for gastric lesions. The indications for endoscopy include likelihood of an underlying opportunistic infection, severity of symptoms (nausea, vomiting, early satiety), and the possible need for endoscopic therapy.

Treatment should be directed to the cause of the problem.

Diseases of the small intestine and colon

Diarrhea is a common complaint in patients with human immunodeficiency virus infection especially in patients with CD4 counts of less than 100/mm3. As with the esophagus, opportunistic infection of the intestines has decreased in prevalence as a cause of diarrhea in human immunodeficiency virus-infected patients. However, the overall incidence of diarrhea has not decreased at the same rate because several of the antiviral agents used in highly active antiviral therapy regimens can cause diarrhea. In addition, patients with human immunodeficiency virus infections are also susceptible to infection by the same enteric pathogens that cause diarrhea in immunocompetent hosts. As the CD count decreases, however, these patients become more susceptible to a wide variety of opportunistic infection that affect both the small intestine and the colon.

Etiologic agents

The most common identifiable causes of diarrhea in human immunodeficiency virus-infected patients is enteric bacteria (e.g. Shigella flexneri, Salmonella enteritidis, Campylobacter jejuni and Clostridium difficile. When the CD count becomes less than 100/mm3, cytomegalovirus, cryptosporidiosis, microsporidia, Mycobacterium avium complex, and other opportunistic infections become more commonly seen in these patients.

Cytomegalovirus is the most common viral agent identified from mucosal biopsy specimens from human immunodeficiency virus-infected patients with diarrhea. Other viruses reported to involve the gastrointestinal tract in patients with acquired immunodeficiency syndrome include adenovirus, rotavirus, astrovirus, picorna virus and coronavirus. The clinical importance of these viruses has not been well established.

Among the protozoa Cryptosporidium parvum and microsporidia (Enterocytozoon bieneusi and Encephalitozoon intestinalis) are the most potent causes of chronic diarrhea in acquired immunodeficiency syndrome patients.

Mycobacterium avium complex, which was very commonly seen in patients with acquired immunodeficiency syndrome has become rare in patients undergoing highly active antiviral therapy. Neoplasms such as KS or lymphoma and other opportunistic infections such as histoplasmosis do not lead  to diarrhea.

Clinical Presentation

  • History. Diarrhea resulting from enteritis or the involvement of the small intestine is typically manifested by large-volume, watery stools associated with dehydration, electrolyte disturbances, and malabsorption. Abdominal pain and cramps are usually located in the periumbilical area. Associated symptoms include nausea, vomiting, abdominal bloating, and borborygmi. Diarrhea arising from colonic involvement and colitis is characterized by frequent, small-volume stools, which often contain mucus, blood, and pus. Symptoms include tenesmus, urgency, and rectoanal pain. Abdominal pain is less likely to be crampy and is usually located in the lower quadrants.
  • Physical exam. Physical findings are nonspecific. Fever usually suggests bacterial or mycobacterial infection. If cytomegalovirus is suspected, fundoscopic examination may reveal retinitis. Cytomegalovirus colitis/ulcers are more common in the ascending colon, thus the abdominal tenderness may be on the right lower quadrant.
  • Diagnostic studies. The initial evaluation of the human immunodeficiency virus-infected patient with diarrhea must be tailored to the clinical setting, patient’s symptoms, physical examination, and the CD4 count.

Stool studies should include examination for ova and parasites, culture for bacteria, C. difficile toxin assay, and the presence of fecal leukocytes. The positive yield of stool culture increases with repeated stool examination. If fecal leukocytes are absent, additional stool studies should include a modified acid-fast stain to evaluate for Cryptosporidia, special stains for microsporidia, and antigen for Giardia.

If Mycobacterium avium complex is suspected, blood cultures or bone marrow biopsy may be helpful in establishing disseminated Mycobacterium avium complex, but do not prove active gastrointestinal involvement. Entamoeba antibody titer is only useful in establishing invasive amebiasis (e.g., liver abscess) and not for colonic infection and colitis with ameba.

Radiologic studies. Neither barium enema nor small-bowel follow-Through examinations play a role in the evaluation of diarrhea in patients with acquired immunodeficiency syndrome. Abdominal and pelvic computed tomography scan may reveal colonic wall thickening suggesting colitis and the need for colonoscopy.

Endoscopic examination of the upper gastrointestinal tract and the colon are invaluable in the evaluation of diarrhea in patients with acquired immunodeficiency syndrome. In addition to direct visualization, biopsies are obtained for histologic examination.

Treatment

Drug-induced diarrhea must always be included in the differential diagnosis of diarrhea in patients undergoing highly active antiviral therapy. If diarrhea stops when the retroviral agents are stopped and returns when they are restarted, one or more of these drugs in implicated.

Even though cytomegalovirus colitis responds to ganciclovir sodium in over 50% of patients, effective therapy for many of the opportunistic infections in acquired immunodeficiency syndrome is lacking. So far, there is no effective treatment for microsporidia and Cryptosporidia infection. However, improvement of the immune function by highly active antiviral therapy is essential and may lead to remission of Cryptosporidia- and microsporidia-induced diarrhea. Symptomatic therapy with tincture of opium, Lomotil, and Imodium is recommended. Octreotide has not proven to be beneficial in patients with chronic unexplained diarrhea.

Hepatobiliary disease in acquired immunodeficiency syndrome. Abnormal results of liver chemistry tests occur in about 60% of patients with acquired immunodeficiency syndrome. Up to 80% of these patients have hepatomegaly, and nearly 85% have histologic changes in hepatic parenchyma.

The spectrum of hepatobiliary disease in patients with acquired immunodeficiency syndrome is summarized in Table ANTIMICROBIAL THERAPY FOR ENTERIC INFECTIONS IN HUMAN IMMUNODEFICIENCY VIRUS -INFECTED PATIENTS. This spectrum includes viral hepatitis; granulomatous liver disease secondary to drugs; fungal, protozoan, bacterial, and mycobacterial infections; steatosis; nonspecific portal inflammation; sinusoidal abnormalities including peliosis hepatis; neoplasms such as KS and non-Hodgkin’s lymphoma; and biliary diseases including acalculous cholecystitis, ampullary stenosis, and sclerosing cholangitis. These disorders may be superimposed on previous hepatobiliary disease resulting from alcoholism, intravenous drug abuse, and viral hepatitis.

Disorders

Viral infections

Hepatitis A virus is transmitted through the fecal-oral route. It is prevalent in both intravenous drug users and homosexual men. Many anti-human immunodeficiency virus-positive patients have anti-hepatitis A (IgG), which is the serologic evidence of past exposure to hepatitis A virus, with full recovery. There is no chronic form of Hepatitis A virus  and no evidence that the clinical course of an acute Hepatitis A virus  infection is altered in patients with acquired immunodeficiency syndrome. Treatment is supportive.

Hepatitis B virus is transmitted parenterally by contaminated needles and sexually from infected people. Intravenous drug users and homosexual men are at high risk of the development of Hepatitis B virus infection. In fact, approximately 90% of patients with acquired immunodeficiency syndrome have serologic evidence of Hepatitis B virus infection, and 10% to 20% are chronic carriers. Patients with acquired immunodeficiency syndrome and previous Hepatitis B virus infection have normal or slightly elevated serum transaminase levels. This is because Hepatitis B virus is not directly cytopathic to the infected hepatocytes, and the degree of inflammatory response and liver damage is largely dependent on the host’s immunologic status.

Patients with human immunodeficiency virus-induced immune suppression are likely to have less inflammatory response and an improvement in the biochemical and histologic features of chronic Hepatitis B virus infection. However, it has been noted that there is increased replication of Hepatitis B virus in human immunodeficiency virus-infected individuals, determined by an increase in the Hepatitis B virus deoxyribonucleic acid polymerase activity and an increase in HBe antigen levels and HB core antigen-positive hepatocyte nuclei.

Patients with acquired immunodeficiency syndrome who have acute hepatitis B have increased viremia and an increased risk of the development of chronic hepatitis B.

Patients with hepatitis B who are also infected with human immunodeficiency virus respond poorly to interferon therapy, even in the absence of acquired immunodeficiency syndrome. The presence of human immunodeficiency virus antibodies is also associated with a suboptimal response to Hepatitis B virus vaccination in terms of both the level of anti-HBs and the percentage of patients responding to the vaccine. Higher doses of the vaccine may need to be used in this population. Measurement of HB surface antibody titers is recommended in human immunodeficiency virus-positive people to determine whether the desirable titer of greater than 10 mlU/L is present.

TABLE. ANTIMICROBIAL THERAPY FOR ENTERIC INFECTIONS IN HUMAN IMMUNODEFICIENCY VIRUS -INFECTED PATIENTS
Organism Antimicrobial Therapy
Bacteria
Campylobacter Erythromycin 250-500 mg p.o. q.i.d. for 7 d or ciprofloxacin 500 mg p.o. b.i.d. for 7 d
Salmonella Amoxicillin 1 g p.o. t.i.d. for 3-14 d or trimethoprim/ sulfamethoxazole DS p.o. b.i.d. for 14 d or ciprofloxacin 500 mg p.o. b.i.d. for 7 d
Shigella Trimethoprim/sulfamethoxazole DS p.o. b.i.d. for 5-15 d or ampicillin 500 mg p.o. q.i.d. for 5 d or ciprofloxacin hydrochloride 500 mg p.o.b.i.d. for 7 d
Clostridium difficile Metronidazole 500 mg p.o. t.i.d. for 7-10 d or vancomycin hydrochloride 125-500 mg p.o. q.i.d. for 7-10 d
Fungi
Candida Ketoconazole 100-200 mg b.i.d. for 10-14 d or fluconazole 50-100 mg b.i.d. for 10-14 days or amphotericin B 0.3-0.6 mg/kg/body weight daily
Viruses
Herpes simplex Acyclovir 200-800 mg 5 times a day for 7 d or 5-12 mg/kg q8h for 7 d
Cytomegalovirus Ganciclovir 5 mg/kg intravenous b.i.d. for 14-21 d or foscarnet sodium 60 mg/kg intravenous q8h for 14 d, then 90-120 mg/kg daily; maintenance 6 mg/kg intravenous daily 5 d per week
Protozoa
Giardia Metronidazole 250 mg p.o. t.i.d. for 5 d or quinacrine hydrochloride 100 mg t.i.d. for 5 d
Entamoeba Metronidazole 750 mg p.o. t.i.d. for 10 d, then iodoquinol 650 mg t.i.d. for 20 d
Isospora Trimethoprim/sulfamethoxazole DS p.o. t.i.d. for 10 d then twice weekly for 3 weeks
Cryptosporidium Unknown (trials with azithromycin hydrochloride, letrazuril, and paromomycin)
Microsporidia Unknown (trials with metronidazole and albendazole)
Mycobacteria
Mycobacterium aviu-complex Unknown (trials with clarithromycin 500-1000 mg p.o. b.i.d. for 2-4 weeks and ethambutin 15-20 mg/kg/d, rifabutin 300-600 mg daily, clofazimine 100-200 mg daily, ciprofloxacin hydrochloride 750 mg daily, and amikacin 7.5 mg/kg daily or b.i.d.)
human immunodeficiency virus, human immunodeficiency virus; p.o., per os; b.i.d., twice daily; q.i.d., four times daily; t.i.d., three times daily; intravenous, intravenous.

Delta hepatitis

Hepatitis delta virus is a hepatotropic RNA virus dependent on HB surface antigen for its replication and expression. It is known to cause coinfection with Hepatitis B virus or superinfection in patients with chronic hepatitis B. Patients with human immunodeficiency virus infection have slightly higher serum aminotransferase levels with Hepatitis delta virus infection. Reactivation of Hepatitis delta virus after human immunodeficiency virus infection has been reported.

TABLE. HEPATOBILIARY DISORDERS IN PATIENTS WITH HUMAN IMMUNODEFICIENCY VIRUS INFECTION
Hepatitis
Hepatitis A
Hepatitis B (acute and chronic)
Hepatitis C (acute and chronic)
Hepatitis D (delta virus)
Cytomegalovirus
Epstein-Barr virus
Herpes simplex virus
Drugs
Granulomatous liver disease
Mycobacterium tuberculosis
Mycobacterium avium-intracellulare
Cryptococcus neoformans
Histoplasma capsulatum
Microsporidia
Biliary tract disease
Ampullary stenosis
Sclerosing cholangitis
Cytomegalovirus
Cryptosporidium
Candida
Acalculous chloecystitis
Neoplasms
Lymphoma
Kaposi’s sarcoma

Hepatitis C virus infection and positive serologic studies for Hepatitis C virus antibody are often seen in patients infected with human immunodeficiency virus. Most patients have Hepatitis C virus, chronic active hepatitis, or cirrhosis. The response to antiviral therapy and interferon has been poor in these patients. Additional studies are in progress.

Gastrointestinal and Hepatobiliary DiseasesHerpes simplex virus

More than 95% of homosexual men with acquired immunodeficiency syndrome have serologic evidence of herpes simplex virus infection. Patients with acquired immunodeficiency syndrome may have herpes simplex virus encephalitis, esophagitis, or orolabial or genital herpes simplex virus infections with pain, ulceration, and progressive tissue destruction. Hepatitis may occur with widely disseminated herpes simplex virus infection. In most of these conditions, patients manifest orocutaneous or genital vesicles or both, ulcers, fever, hepatomegaly, and leukopenia. Fulminant hepatitis may develop with overwhelming infection, and patients may have coagulopathy, hepatic encephalopathy, and shock. Diagnosis may be established by histopathologic examination of a liver biopsy specimen. The virus may be cultured from the blood, urine, cutaneous lesions, or liver. Mortality is very high despite therapy with acyclovir sodium or vidarabine.

Epstein-Barr virus infection

The course of hepatitis in patients with acquired immunodeficiency syndrome who also have the Epstein-Barr virus has not been well characterized.

Cytomegalovirus infection usually produces subclinical disease in immunocompetent adults. Occasionally patients have fever, hepatomegaly, and slightly elevated aminotransferase levels. Cytomegalovirus infection may remain latent after primary infection and recur with immunocompromise.

Approximately 95% of homosexual men have serologic evidence of previous cytomegalovirus infection. In human immunodeficiency virus-infected patients, cytomegalovirus may produce colitis, esophagitis, pneumonitis, and retinitis. It is usually disseminated when the liver is involved. In patients with cytomegalovirus hepatitis, the serum alkaline phosphatase and aminotransferase levels are moderately increased. Hepatic involvement ranges from the asymptomatic carrier state to fulminant hepatic necrosis. The diagnosis is made by liver biopsy in affected patients. Cytomegalovirus commonly produces a parenchymal and portal mononuclear cell infiltrate and focal hepatic necrosis. Occasionally granulomas are present. Cytoplasmic inclusion bodies seen in the hepatocytes and in situ hybridization and immune fluorescence techniques can rapidly detect cytomegalovirus. Cytomegalovirus can be cultured from urine, blood, and tissue from infected sites.

Treatment is with intravenous ganciclovir sodium, which may stabilize the clinical course of patients with cytomegalovirus infection but may cause neutropenia. Foscarnet may be used as an alternative therapy without associated neutropenia.

Bacterial and mycobacterial infections

Mycobacterium avium-intracellulare is the most common opportunistic pathogen causing hepatic infection in acquired immunodeficiency syndrome. It is usually found in patients with acquired immunodeficiency syndrome who have had previous opportunistic infections. The presentation is often with fever, malaise, anorexia, weight loss, diarrhea, hepatomegaly, and widely disseminated disease. The alkaline phosphatase level is usually highly elevated, with mildly elevated transaminases.

The diagnosis is confirmed by liver biopsy and the typical findings of acid-fast bacilli and poorly formed granulomas due to the suppressed activity of T lymphocytes. The organism may be obtained from cultures of liver, blood, lung, gastrointestinal mucosa, bone marrow, and lymph nodes. The prognosis is poor due to severe immunosuppression in the patients. Therapeutic trials using a four-drug regimen consisting of rifampin, ethambutol, clofazimine, and ciprofloxacin hydrochloride have given promising results in bacteremia with Mycobacterium avium-intracellulare.

Mycobacterium tuberculosis

As their immunosuppression progresses, human immunodeficiency virus-infected patients have an increased risk of the development of tuberculosis, usually from reactivation of a latent infection. In addition to the pulmonary infection, extrapulmonary tuberculosis involving peripheral lymph nodes, bone marrow, blood, and liver may occur. The liver involvement may be biliary, with disseminated infection or with formation of granulomas and frank abscesses. Hepatic failure may develop. Occasionally bile duct obstruction by tuberculosis or enlarged lymph nodes may present as cholestasis. Infections with drug-resistant strains of tuberculosis are being reported, especially in patients living in inner-city settings.

Symptoms and signs include fever, night sweats, weight loss, productive cough, pleuritic chest pain, abdominal pain, lymphadenopathy, hepatosplenomegaly, and jaundice. Chest x-rays may show only hilar or mediastinal lymphadenopathy. The purified protein derivative  is usually negative with concomitant cutaneous anergy. Serum alkaline phosphatase level is usually significantly elevated, but the transaminase and bilirubin levels are only mildly elevated in most patients.

The diagnosis is usually made by culture of sputum, urine, blood, lymph node, bone marrow, or liver tissue. Histologic stains for acid-fast bacilli are not as sensitive. Liver biopsy may show granulomas, Kupffer’s cell hyperplasia, focal necrosis, parenchymal inflammation, sinusoidal dilatation, and occasionally peliosis hepatis.

Therapy includes isoniazid, rifampin, ethambutol, and pyrazinamide. Although most patients respond well to therapy, adverse drug reactions are common. The Centers for Disease Control recommends that human immunodeficiency virus-seropositive patients with a history of exposure to tuberculosis, or with a positive purified protein derivative even in the absence of active tuberculosis, receive prophylactic isoniazid therapy for at least 6 months.

Other mycobacteria

Infections with atypical mycobacteria such as Mycobacterium xenopi or Mycobacterium kansasil may rarely cause infection. Disseminated disease may occur in patients with hematologic malignancies, chronic renal failure, or advanced immunosuppression. Hepatic infection usually presents with hepatomegaly and greatly elevated serum alkaline phosphatase levels. Diagnosis requires positive cultures from infected tissues.

Salmonella

Patients with acquired immunodeficiency syndrome frequently have extraintestinal salmonellosis with bacteremia and frequently relapse despite antibiotic therapy. Patients usually have fever, headaches, diarrhea, nausea, abdominal pain, bloating, hepatomegaly, and abnormal results on liver chemistry tests. Diagnosis may be established by cultures of blood, stool, and liver tissue. Therapy includes ampicillin, chloramphenicol, trimethoprim/sulfamethoxazole, Ciprofloxacin hydrochloride, or a third-generation cephalosporin.

Fungal infections

Cryptococcus neoformans. Patients with acquired immunodeficiency syndrome who are infected with C. neoformans usually have meningoencephalitis and pulmonary infections. With hematogenous dissemination, cryptococcal hepatitis may develop. The symptoms and signs are predominantly due to the neurologic, pulmonic, or disseminated infection. Chronic low-grade fever, headache, altered sensorium, meningismus, cough, dyspnea, and pleuritic chest pain may be present.

Diagnosis can be made by cultures and histochemical stains of involved tissue or by detection of cryptococcal antigen. Poorly formed granulomas may be seen in liver biopsy specimens. Therapy includes amphotericin B, flucytosine, and fluconazole. Patients with acquired immunodeficiency syndrome frequently relapse after initial therapy and may require chronic preventive therapy.

Histoplasma capsulatum

Gastrointestinal and Hepatobiliary DiseasesHepatic histoplasmosis in patients with acquired immunodeficiency syndrome usually develops from widely disseminated disease of which the origin is often in the lungs. Most patients have either lived or traveled in endemic areas such as midwestern United States river valleys or Puerto Rico.

Symptoms include severe weight loss, malaise, chronic fever, and sometimes cough and dyspnea. Cutaneous lesions, lymphadenopathy, and hepatosplenomegaly may be present. Liver chemistry and serum alkaline phosphatase levels are moderately elevated. The diagnosis may be made by blood cultures or by biopsy of the bone marrow, liver, lymph node, or lung. Smears with Gomori’s methenamine silver stain show the presence of budding yeast. Granulomas may also be present in the liver.

Treatment with amphotericin B often results in a dramatic response, but the disease may recur. Prophylactic therapy with ketoconazole or fluconazole may be necessary.

Candida albicans

Hepatic candidiasis in patients with acquired immunodeficiency syndrome should be suspected in the setting of dissemination from invasive esophagitis or another source or after chemotherapy for lymphoma or leukemia. Patients may have prolonged fever, right upper quadrant pain, tenderness, and hepatomegaly. The serum alkaline phosphatase level is usually greatly elevated, compared to a mild elevation in the transaminases. Microabscess may form in the liver and spleen. These lesions may be seen on computed tomography as radiolucent areas and on ultrasonography as bull’s-eye lesions with central hyperechoic foci within hypoechoic lesions.

Diagnosis may be established by cultures of blood or liver and histologic demonstration of granulomas and yeast forms or pseudohyphae with a silver stain. Treatment includes amphotericin B, 5-fluorocytosine, ketoconazole, or fluconazole.

Other fungal infections

Systemic sporotrichosis with hepatic infection has been reported in patients with acquired immunodeficiency syndrome, but it is rare. Coccidioidomycosis may become systemic in immunosuppressed patients including those with acquired immunodeficiency syndrome. In addition to pulmonary nodules seen on chest x ray, the diagnosis is usually made by histologic examination with periodic acid-Schiff (periodic acid – Schiff) stain of sputum, specimens obtained at bronchoscopy, bone marrow, and liver. The organism may be cultured from tissues, blood, and urine. The liver biopsy shows granulomas.

Treatment of sporotrichosis and coccidioidomycosis is with long-term therapy with amphotericin B.

Protozoan infections

Pneumocystis carinii. Diffuse interstitial pneumonia is the most common serious opportunistic infection caused by P. carinii in patients infected with human immunodeficiency virus. Immunodeficient patients may have concomitant hepatic infection with granuloma formation. These patients have elevated serum alkaline phosphatase and aminotransferase levels, usually associated with severe hypoalbuminemia. Therapy is with trimethoprim/sulfamethoxazole or pentamidine.

Microsporidia. Homosexual men have a high incidence of exposure to microsporidia, and immunosuppressed patients with acquired immunodeficiency syndrome are particularly susceptible to development of gastrointestinal infection. Hepatic infection is rare but may occur. Histologic examination of the liver biopsy may show focal granulomas in the portal areas. The parasites or their spores may be seen with special stains within histiocytes and in extracellular locations.

Cryptosporidium. Infection of the liver with Cryptosporidium mainly involves the gallbladder and the biliary tract.

Drug-induced hepatitis

Approximately 90% of patients who have acquired immunodeficiency syndrome take at least one potentially hepatotoxic drug during the course of their illness. Drug-induced hepatotoxicity tends to present subclinically. It is often difficult to differentiate drug-induced hepatitis from that caused by infections or malignancies. Withdrawal of hepatotoxic drugs may result in normalization of the liver chemistry tests and clinical improvement. A liver biopsy or other appropriate workup may be necessary to determine the precise nature of the hepatobiliary abnormality in patients in whom the suspected drug is needed or in those in whom withdrawal of the drug does not result in improvement.

Hepatic neoplasms

KS is the most common neoplasm found in patients with acquired immunodeficiency syndrome. It occurs primarily in homosexual men, in whom it behaves as an aggressive malignancy with visceral and cutaneous lesions. About one half of the patients have gastrointestinal lesions, which appear as violaceous macules on endoscopy. The lesions are generally submucosal and may present with bleeding or obstruction.

About one third of the patients have hepatic involvement. The liver chemistry tests may be normal, or there may be an elevation of the serum alkaline phosphatase levels. On computed tomography scan, hepatic lesions have a nonspecific appearance. Unguided percutaneous liver biopsy is insensitive in the diagnosis of KS. Occasionally KS lesions can be seen on laparoscopy if the lesions are superficial and anteriorly located. In general, hepatic involvement is rarely documented antemortem.

Macroscopically, the lesions are multifocal and may occur at subcapsular hilar and intrahepatic locations. Histologically, KS is seen as multifocal areas of vascular endothelial cell proliferation with pleomorphic spindle-shaped cells and extravasated red blood cells. Sinusoidal dilatation with vascular lakes may be present. The clinical spectrum may include peliosis hepatis and angiosarcomatous lesions.

Treatment includes radiotherapy or chemotherapy with vinblastine, vincristine, or etoposide. Interferon therapy also may produce considerable tumor reduction.

Lymphoma. In human immunodeficiency virus-infected patients, the development of lymphoma is considered a criterion for acquired immunodeficiency syndrome. Patients with acquired immunodeficiency syndrome, like other immunosuppressed patients, have an increased risk of the development of non-Hodgkin’s lymphoma, often of B-cell origin. Patients with acquired immunodeficiency syndrome in whom lymphoma develops are usually homosexuals.

Lymphoma in patients with acquired immunodeficiency syndrome is often extranodal with involvement of unusual sites such as the central nervous system or rectum.

Most patients have multiorgan involvement. Primary hepatic lymphoma also may occur.

Patients initially may have lymphadenopathy, hepatomegaly, jaundice, right upper quadrant pain, and systemic symptoms such as fever, malaise, and night sweats.

Hyperbilirubinemia and considerable elevations of serum alkaline phosphatase levels usually occur in advanced illness. Computed tomography and ultrasound are helpful imaging techniques in the diagnosis of hepatic lymphoma. The lesions are usually multifocal and may obstruct the biliary tract and result in ductal dilatation.

Histologic examination of liver biopsy specimens obtained with computed tomography or laparoscopic guidance confirms the diagnosis. The lymphomas are usually high grade and respond less well to chemotherapy than they do in immunocompetent patients.

Other malignancies. Hepatic metastasis from cancers developing in other sites has been seen in patients with acquired immunodeficiency syndrome. These include malignant melanoma, adenocarcinoma, and small cell cancers. The immunodeficiency may permit dissemination to distant sites, including the liver.

Bilary tract disease

In addition to diseases of the biliary tract seen in immunocompetent patients, opportunistic infections involving the gallbladder and the biliary tract occur in patients with acquired immunodeficiency syndrome and may present with atypical findings, sepsis, or acute abdomen.

Acalculous cholecystitis is rarely seen in immunocompetent people. It is sometimes associated with total parenteral nutrition and biliary sludge. In patients with acquired immunodeficiency syndrome, it may have a subacute clinical course or may present with fever and right upper quadrant abdominal pain. Patients may also have concurrent diarrhea. The disease is usually caused by cytomegalovirus, Cryptosporidium, or Candida.

Most patients do not have a leukocytosis. The levels of serum alkaline phosphatase and transaminase are moderately elevated. Ultrasound and computed tomography typically show a dilated gallbladder with thickened wall and no gallstones. Therapy is surgical excision of the inflamed gallbladder. Pathologic examination reveals an inflamed, edematous gallbladder wall with mucosal ulceration. Often cytomegalovirus inclusion bodies are seen near the mucosal ulcers. Coinfection with bacteria, Cryptosporidium, and C. albicans may be present.

Cholangitis secondary to papillary stenosis (stenosis of the ampulla of Vater) and sclerosing cholangitislike findings are well-recognized complications in patients who have acquired immunodeficiency syndrome. Patients have fever, right upper quadrant pain, and elevated serum alkaline phosphatase levels. Computed tomography and ultrasonography are relatively insensitive in detecting these abnormalities. Retrograde endoscopic cholangiopancreatography usually defines the lesions, and endoscopic sphincterotomy, balloon dilation, and stent placement in the strictures may treat and remove the obstruction to bile flow.

The infectious organisms causing periampullary, choledochal, and cholangiolar narrowing and dilatation are cytomegalovirus, Cryptosporidium, Candida, Mycobacterium avium-intracellulare, and human immunodeficiency virus. Lymphoma and KS may involve the ampulla and the biliary tract, resulting in obstruction.

Diagnostic workup. When patients with acquired immunodeficiency syndrome have hepatobiliary disease, considerations include, in addition to the conditions discussed previously, hepatic disease secondary to alcoholism, malnutrition, sepsis, hypotension, drugs, and previous viral infections. Appropriate serologic studies should be obtained to document viral disease.

An ultrasound or computed tomography examination of the liver may show ductal dilatation or mass-occupying lesions. Patients with ductal dilatation or suspected ductal disease should undergo endoscopic retrograde cholangiopancreatography. Mechanical decompression with sphincterotomy and stent placement may eliminate the obstruction.

Biopsies of the involved areas should be cultured and examined histologically. In patients with focal lesions, liver biopsy should be obtained under ultrasound or computed tomography guidance. Percutaneous liver biopsy is recommended when computed tomography or ultrasound is not helpful. In patients who have ascites, laparoscopic examination of the liver and guided biopsy decrease the risk of complications that occur with percutaneous biopsy techniques. Liver biopsy specimens should be cultured and histologically examined with special stains. In about 50% of these patients, the liver biopsy helps to establish the diagnosis and provides a more rational basis for patient management.

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