Evaluation of the patient with HIV and hepatobiliary complaints

INTRODUCTION — The era of potent antiretroviral therapy has been associated with a marked decrease in morbidity and mortality in patients with human immunodeficiency virus (HIV).

However, those who present with advanced immunosuppression are at risk for a wide variety of opportunistic infections, such as Cryptosporidium, Isospora, Microsporidium, Mycobacterium avium complex, and cytomegalovirus and hepatobiliary complications, such as acalculous cholecystitis and acquired immunodeficiency syndrome (AIDS)-related cholangiopathy [1]. Those patients who undergo therapy are also at risk for treatment-related adverse events, such as lactic acidosis, hepatic steatosis, and drug-induced hepatotoxicity. Finally, a significant proportion of patients are infected with hepatitis B and/or C virus, due to shared routes of transmission.

This topic will discuss a guided approach to the evaluation of the patient with HIV and hepatobiliary complaints. More detailed information regarding viral hepatitis B and hepatitis C infections and AIDS cholangiopathy are found elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV" and "AIDS cholangiopathy".)

HEPATOBILIARY COMPLICATIONS

Chronic viral hepatitis — The most common cause of hepatomegaly in patients with HIV is chronic viral hepatitis with either hepatitis B virus (HBV) and/or hepatitis C virus (HCV) infections [2]. End-stage liver disease is a major cause for inpatient admissions and mortality in the era of antiretroviral therapy (ART) [3,4]. In patients with chronic HBV or HCV infection, concomitant HIV infection is associated with higher rates of morbidity and mortality related to liver disease. (See "Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV".)

Depending on the risk group studied and the geographic region, it is estimated that approximately 30 to 80 percent of patients with HIV have concomitant hepatitis C and approximately 5 to 10 percent have chronic hepatitis B [5]. There are few data on the seroprevalence of multiple hepatitides, such as hepatitis B and C combined; one study of 423 patients with HIV in Spain found that approximately 5 percent of patients had HBV, HCV, and delta virus infections [6] The most common risk factor for acquisition of HCV is injection drug use, while HBV can be acquired both sexually and parenterally. However, there are emerging data on acute HCV infection among men who have sex with men who report sex with trauma or in association with other genital ulcer disease [7,8].

The most common symptom in patients with chronic viral hepatitis is fatigue; however, most patients are often asymptomatic and unaware of their infection until they develop decompensated cirrhosis or hepatocellular carcinoma (HCC). As shown in a large retrospective study (n = 24,040), the incidence of compensated and decompensated cirrhosis and HCC has risen significantly since 1996 to 2009 [9]. Risk factors for advanced disease included HCV infection, HBV infection, Hispanic ethnicity, alcohol use and diabetes, while protective factors included treatment-induced HCV eradication and Black race [9]. Risk factors associated with the development of hepatocellular carcinoma include nonalcoholic steatohepatitis (NASH), HBV, HCV, and a low CD4 cell count. ART, which may slow the rate of fibrosis progression [10], is now recommended in all patients with HIV, regardless of CD4 cell count [2].  

Hepatitis E is an uncommon cause of abnormal aminotransferases in the patient with HIV [11]; it has been rarely reported to cause persistent infection in patients with advanced immunosuppression [12]. Hepatitis A does not cause chronic liver disease regardless of HIV status.

The use of vaccination to prevent hepatitis A and B infection in patients with HIV is discussed elsewhere. (See "Immunizations in persons with HIV", section on 'Hepatitis A vaccine' and "Immunizations in persons with HIV", section on 'Hepatitis B vaccine'.).

Infiltrative liver disease — Patients with HIV are at risk for AIDS and non-AIDS-related malignancies, which can metastasize to the hepatobiliary system [13]. Immunosuppression from HIV infection appears to play an important role in the development of both Kaposi's sarcoma and non-Hodgkin lymphoma. However, the introduction of ART has been associated with substantial decreases in the incidence of both of these diseases. (See "HIV infection and malignancy: Epidemiology and pathogenesis".)

As patients have survived longer with AIDS, the frequency of non-AIDS-defining malignancies (such as lung cancer with metastasis to the liver) has increased compared with the population without HIV. Cancer deaths now account for an increasing fraction of overall deaths in individuals with HIV, including a rise in viral hepatitis-associated hepatocellular cancer [14]. (See "HIV infection and malignancy: Management considerations".)

Patients with AIDS are also at risk for infiltrative hepatic disease secondary to opportunistic infections [15]. (See 'Opportunistic infections' below.)

Primary liver cancers related to hepatitis B or C infection are discussed above. (See 'Chronic viral hepatitis' above.)

Opportunistic infections — Some disseminated opportunistic infections have prominent hepatobiliary manifestations, such as M. avium complex (MAC).

The risk of MAC in patients with HIV increases as the CD4 cell number declines below 100 cells/microL. Constitutional symptoms include fever, night sweats, weight loss, and abdominal pain. Laboratory abnormalities frequently include anemia and elevated alkaline phosphatase. The diagnosis of MAC is made by isolation of the organism in culture usually of the blood or lymph node. (See "Mycobacterium avium complex (MAC) infections in persons with HIV".)

Histoplasmosis is the most common endemic fungal infection in patients with HIV and advanced immunosuppression. Common symptoms of histoplasmosis include fever, night sweats, weight loss, cough, nausea, and vomiting. Physical examination may demonstrate hepatosplenomegaly and adenopathy along with skin and mucosal lesions. Pancytopenia, elevated aminotransferases, and a marked elevation in serum lactate dehydrogenase (LDH) are commonly seen. Diagnostic tests for disseminated Histoplasma capsulatum infection include culture, serology, antigen testing, and direct microscopy. (See "Epidemiology, clinical manifestations, and diagnosis of histoplasmosis in patients with HIV".)

Other less common infectious etiologies of hepatitis in immunosuppressed patients with HIV include: Candida, tuberculosis, Pneumocystis, Bartonella henselae (causing peliosis hepatis), and visceral leishmaniasis [16-18]. (See appropriate topic reviews).

Hepatic steatosis — As in the general population, the number of patients with nonalcoholic fatty liver disease (NAFLD) has risen substantially. In patients with HIV, observational studies suggest prevalence rates greater than 30 percent, making it the most common form of liver disease. Factors for NAFLD include diabetes, hypertension, and most importantly increased body mass index (BMI) [19]. An algorithm for assessing the risk factors for hepatic steatosis among patients with HIV has been proposed (figure 1) [20]. Patients with HIV may be at increased risk for hepatic steatosis compared with those who do not have HIV [21,22], although the mechanisms for this association including the use of ART is incompletely understood. As an example, one study found that patients with HIV and HCV are at increased risk for hepatic steatosis when compared with patients with HCV alone [21]. Although this association may be due to underlying obesity [23] there are also some studies demonstrating that the rates of obesity in patients with HIV may be less than in patients without HIV, suggesting perhaps a higher prevalence of "lean NAFLD". Furthermore, lipodystrophy may also be a contributing factor to HIV-associated NAFLD. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults", section on 'Epidemiology'.)

Most patients with hepatic steatosis are asymptomatic; fatty liver is often an incidental finding on imaging or is first identified on ultrasound during evaluation for gastrointestinal complaints or abnormal aminotransferases. Steatosis is associated with higher stages of fibrosis in patients with HIV and underlying hepatitis C [24]. In older studies, ART was associated with steatosis. However, with newer agents, this appears to be less common, and these drugs may be beneficial. The diagnosis of NAFLD and NASH includes the noninvasive use of ultrasound, elastography controlled attenuation parameter, magnetic resonance imaging proton density fat fraction, and fibrosis-4 score [25].

Hepatic steatosis has also been associated with abnormal aminotransferases among patients with HIV and without evidence of chronic hepatitis C infection; these patients most likely have NASH [26]. In the setting of significant necroinflammation, hepatic steatosis can lead to steatohepatitis and cirrhosis. (See "Epidemiology, clinical features, and diagnosis of nonalcoholic fatty liver disease in adults".)

Drug-induced liver injury — Patients with HIV may develop drug-induced liver injury from antiretroviral medications or from commonly used drugs, such as isoniazid, fluconazole, or trimethoprim-sulfamethoxazole. Several studies have demonstrated that patients with HIV, chronic viral hepatitis, and baseline elevations of aminotransferases are at increased risk of ART-induced hepatotoxicity than patients with HIV and without hepatitis B or C infection [27].

Drug-induced liver injury may lead to right upper quadrant pain, nausea, fatigue, and poor appetite. In severe cases, it can also be associated with jaundice, which increases the risk of mortality; this is a clinical observation known as "Hy's law" [28].

Occasionally, mild jaundice can be induced by certain antiretroviral medications due to an elevation of indirect bilirubin (eg, indinavir or atazanavir) caused by inhibition of UDP-glucuronosyl transferase (UGT). The elevation in indirect bilirubin is reversible and not associated with liver injury or elevations in other liver tests (eg, transaminases or alkaline phosphatase). (See "Overview of antiretroviral agents used to treat HIV", section on 'Protease inhibitors (PIs)'.)

If an antiretroviral medication that is dually active against hepatitis B and HIV (eg, tenofovir, lamivudine, or emtricitabine) is discontinued for any reason, a patient with concomitant chronic hepatitis B may experience a severe flare of aminotransferases. This can be associated with significant morbidity, and even mortality, in a patient with pre-existing cirrhosis. (See "Treatment of chronic hepatitis B in patients with HIV".)

AIDS cholangiopathy — AIDS cholangiopathy is a syndrome of biliary obstruction resulting from infection-associated strictures of the biliary tract. It is usually seen in patients with a CD4 count well below 100 cells/microL. AIDS cholangiopathy occurred in as many as one-fourth of AIDS patients prior to the advent of potent ART; the current incidence with active treatment of human immunodeficiency virus (HIV) infection has clearly decreased but is not known. (See "AIDS cholangiopathy".)

The organism found most commonly is Cryptosporidium parvum; other pathogens that have been identified include Microsporidium, cytomegalovirus (CMV), Cyclospora cayetanensis, Isospora, and Giardia. However, in approximately 20 to 40 percent of cases, no etiology can be found.

AIDS cholangiopathy should be suspected in the patient with HIV and advanced immunosuppression who presents with right upper quadrant abdominal pain, fever, and an elevated serum alkaline phosphatase [29]. Frank jaundice is unusual. Diarrhea is a frequent concomitant complaint since the infectious agent often involves the small intestine as well. Imaging with ultrasound or a CT scan may demonstrate biliary tract dilation or thickening of the common bile duct wall. (See "AIDS cholangiopathy", section on 'Diagnostic approach' and "AIDS cholangiopathy", section on 'Differential diagnosis'.)

Right upper quadrant pain with or without jaundice may be a presenting complaint in papillary stenosis, acalculous cholecystitis, cholelithiasis/choledocholithiasis, or drug-induced liver injury. (See 'Drug-induced liver injury' above.)

Atazanavir-associated cholelithiasis — Atazanavir appears to be associated with complicated cholelithiasis. In a series of 14 patients with HIV and cholelithiasis who were receiving an atazanavir-based antiretroviral regimen, eight had significant concentrations of atazanavir detected from biliary stones [30]. Cholelithiasis-related symptoms occurred after a median duration of 42 months of receiving an atazanavir-based regimen (range 1 to 90 months). Cholelithiasis-related complications included cholecystitis (in 11 patients), cholangitis (in 1 patient), and acute pancreatitis (in 4 patients).

HISTORY AND PHYSICAL EXAMINATION — Initial efforts in the evaluation of the patient with HIV and symptoms or signs consistent with hepatobiliary disease (eg, right upper quadrant pain, nausea, jaundice) should be directed at determining whether there is intrahepatic and/or extrahepatic disease. Knowledge of the patient's CD4 cell count is critical in guiding the differential diagnosis recognizing that patients with HIV can also have disorders not related to immune deficiency (eg, gallstones). The clinical presentation will also guide the appropriate laboratory and radiographic evaluation.  

●A history of mild jaundice and constitutional symptoms (eg, fatigue, nausea), is more consistent with intrahepatic disease, such as acute viral hepatitis (eg, hepatitis A, hepatitis B, or hepatitis C infections)

●The subacute onset of fevers, chills, anorexia, and weight loss in a patient with advanced AIDS and hepatosplenomegaly may be related to disseminated infections, such as MAC, tuberculosis, Bartonella henselae, visceral leishmaniasis, histoplasmosis, or lymphoma. (See appropriate topic reviews).

●In contrast, signs of jaundice accompanied by relatively acute abdominal pain suggest extrahepatic disease, such as a solid tumor or lymphadenopathy at the porta hepatis.

●Right upper quadrant pain with or without jaundice may be a presenting complaint in AIDS-related cholangiopathy, papillary stenosis, acalculous cholecystitis, cholelithiasis/choledocholithiasis, or drug-induced liver injury. Choledocholithiasis may present similarly (epigastric pain is common) but generally causes less elevation of alkaline phosphatase and with greater elevation of aspartate aminotransferase and alanine aminotransferase.

A careful review of medications, both prescription and non-prescription, should be performed in patients with new symptoms or signs of hepatitis to address the possibility of drug toxicity. Travel history and TB skin testing status should be evaluated.

DIAGNOSTIC STUDIES

Liver function tests — Liver function tests traditionally refer to aminotransferases, which do not measure liver function at all. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are usually elevated in the setting of liver injury. Measures of synthetic liver function include prothrombin time and serum albumin. (See "Approach to the patient with abnormal liver biochemical and function tests".)

Elevations of aminotransferases are common in patients with chronic viral hepatitis, lactic acidosis, choledocholithiasis, and drug-induced liver injury. In these clinical scenarios, ALT is usually greater than AST; however, this finding alone will not help differentiate the immediate cause of hepatobiliary disease. Marked elevations of aminotransferases should raise the possibility of acute viral hepatitis.

When AST is greater than ALT, alcoholic liver injury should be considered (see "Alcoholic hepatitis: Clinical manifestations and diagnosis"). If there is no history of alcohol abuse, advanced liver disease is another diagnostic consideration. In the latter case, synthetic function may be impaired (as reflected by low serum albumin and prolonged prothrombin time). However, hypoalbuminemia can also be seen in patients with advanced AIDS and wasting.

A cholestatic pattern or isolated elevations of one particular marker (eg, alkaline phosphatase or bilirubin) can be particularly helpful:

●A cholestatic picture may be seen with AIDS cholangiopathy; papillary stenosis combined with ductal sclerosis; or high-grade obstruction from other causes such as tumor or drug-induced liver injury (eg, amoxicillin-clavulanate). Marked elevation of alkaline phosphatase in a patient with AIDS and right upper quadrant pain may suggest AIDS cholangiopathy. (See 'AIDS cholangiopathy' above.)

●Marked elevation of alkaline phosphatase, in the absence of extrahepatic obstruction, is suggestive of MAC infection in the liver in patients with AIDS [31]. Concomitant bone-marrow suppression is frequent and the degree of anemia can be severe [32].

●A rising bilirubin in the setting of cirrhosis may signal the onset of decompensated liver disease. Alternatively, an elevated bilirubin can be related to certain antiretroviral medications, such as atazanavir (or indinavir, which is uncommonly used today) [33,34]. It is helpful to fractionate the bilirubin in these cases, since a drug-induced effect results in elevation of the indirect portion, in contrast to the direct hyperbilirubinemia seen in liver failure.

●In the patient with elevated serum transaminases, viral hepatitis should be excluded. Appropriate testing for hepatitis B and C in the patient with HIV is discussed elsewhere. (See "Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV".)

●Drug-induced causes of elevated aminotransferases include prescription, over-the-counter, and herbal remedies.

Blood cultures — If an infectious cause is being considered in the immunosuppressed host, blood cultures for MAC and Bartonella henselae should be performed. CMV polymerase chain reaction or antigen testing is preferred to CMV cultures for more rapid diagnosis. (See "Approach to the diagnosis of cytomegalovirus infection".)

Skin testing — Skin testing for tuberculosis should be considered. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults with HIV infection".)

Imaging

Ultrasound — A right upper quadrant ultrasound can be helpful in identifying ductal dilatation, gallbladder pathology, and focal hepatic lesions, and/or abscesses, and nonalcoholic fatty liver disease. The presence of dilated ducts or other biliary abnormalities suggests an extrahepatic cause for jaundice, such as papillary stenosis in AIDS cholangiopathy. If an ultrasound demonstrates multiple lucencies within the liver in a patient with advanced immunosuppression, fever, anemia, and skin lesions, peliosis hepatis secondary to Bartonella infection should be considered.

CT scanning — Computed tomography (CT) scanning is useful for evaluating infiltrative disease, including hepatic steatosis (see "Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors"). CT is also helpful in evaluating for mass lesions such as hepatocellular carcinoma in a patient with chronic liver disease.

Hepatobiliary scintigraphy — Additional imaging procedures are sometimes indicated. In patients with acalculous cholecystitis, a right-upper quadrant ultrasound is usually non-specific, with findings consistent with gallbladder thickening or pericholecystic fluid, and absence of gallstones. Hepatobiliary scintigraphy (HIDA) is more useful in this situation since it will demonstrate a non-functioning gallbladder [1]. A contrast-enhanced abdominal CT scan can provide additional information concerning the liver, pancreas, or presence of lymphadenopathy and/or mass lesions. (See "AIDS cholangiopathy" and "Bartonella infections in people with HIV".)

Endoscopic retrograde cholangiopancreatography — If CT or ultrasound demonstrates biliary duct pathology, stricturing, or dilated ducts, an endoscopic retrograde cholangiopancreatography (ERCP) may be indicated. In patients with papillary stenosis, a narrowing of the terminal common bile duct with proximal dilatation and extrahepatic or intrahepatic bile duct stricturing may be seen; in AIDS cholangiopathy, the ducts may have a classic beaded pattern [1].

ERCP permits diagnostic sampling of bile, which can be examined for neoplastic cells, protozoa, or cultured for viruses, as well as ductal biopsy. [35]. ERCP can be used for therapeutic interventions, such as sphincterotomy (effective for papillary stenosis) and removal of stones, or to stent strictures.

Although magnetic resonance cholangiopancreatography may also be helpful for imaging [36], ERCP still offers the advantage of tissue sampling and potential sphincterotomy, if needed.

Laparoscopy with biopsy — Laparoscopy may be useful to identify any peritoneal pathology, as seen in tuberculosis or malignancy.

Liver biopsy — Liver biopsy can be considered in patients with infiltrative processes, mitochondrial toxicity, chronic viral hepatitis, or neoplasm. This is generally a safe procedure in patients with HIV, provided coagulation parameters are normal or corrected [37]. The usefulness of liver biopsy in diagnosing drug-induced liver injury is limited to when eosinophils are present; otherwise many of the necroinflammatory changes that can be seen in drug-related hepatotoxicity can overlap with chronic viral hepatitis. Discontinuation of potential hepatotoxic medications with careful follow-up of aminotransferases over time is a useful strategy. A liver biopsy can be considered when aminotransferases remain abnormal.

If a liver biopsy is done, appropriate culture and special stains of the specimen will increase the yield when infection is suspected. Cultures should include testing for routine bacterial, mycobacterial, and fungal pathogens. All appropriate clinical information, including the degree of immunosuppression, should be communicated to the pathologist since granuloma formation can be quite poor in patients with advanced AIDS and MAC infection.

If mitochondrial toxicity is suspected, electron microscopy can confirm the presence of mitochondrial abnormalities (such as paracrystalline inclusions and swollen mitochondrial cristae).

However, in many of these circumstances, the liver biopsy may not be needed. For example:

●In the setting of disseminated infection, such as MAC, the diagnosis is often made by examination of other sites, such as blood or bone marrow.

●Mitochondrial toxicity is often strongly suggested by the presence of elevated serum lactate in a patient with abdominal bloating, weight loss, nausea, and fatigue.

In contrast, a liver biopsy may be helpful in the setting of chronic hepatitis B or hepatitis C to help stage the disease and to determine if treatment is necessary. The availability of noninvasive markers of fibrosis such as elastography controlled attenuation parameter have lessened the utility and need for liver biopsy. (See "Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV".)

SUMMARY AND RECOMMENDATIONS

●Patients with HIV and severe immunosuppression are at risk for AIDS cholangiopathy and opportunistic infections, such as Mycobacterium avium complex disease, which can cause significant hepatobiliary disease. Due to shared routes of infection, patients with HIV are also at risk for hepatitis B and hepatitis C virus infections, which are a major cause for morbidity and mortality, such as decompensated cirrhosis and hepatocellular carcinoma. (See 'Hepatobiliary complications' above.)

●Hepatic steatosis is associated with viral factors (eg, hepatitis C genotype 3 infection) and host factors (such as visceral adiposity, insulin resistance, and hyperlipidemia). In the setting of necroinflammation, hepatic steatosis can lead to liver fibrosis. (See 'Hepatobiliary complications' above.)

●Patients with HIV may develop drug-induced liver injury from antiretroviral medications or from commonly used medications, such as isoniazid, fluconazole, or trimethoprim-sulfamethoxazole. Several studies have demonstrated that patients with HIV, chronic viral hepatitis, and baseline elevations of aminotransferases are at increased risk of ART-induced hepatotoxicity than patients with HIV and without hepatitis B or C infection. (See 'Hepatobiliary complications' above.)

●Initial efforts in the evaluation of the patient with HIV and symptoms or signs consistent with hepatobiliary disease (eg, right upper quadrant pain, nausea, jaundice) should be directed at determining whether there is intrahepatic or extrahepatic disease. Knowledge of the patient's CD4 cell count will help guide the differential diagnosis. (See 'History and physical examination' above.)

●Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are usually elevated in the setting of liver injury (eg, drug-induced liver injury or viral hepatitis). Elevations of either alkaline phosphatase or bilirubin are suggestive of a cholestatic pattern or obstructive process (eg, tumor or lymphadenopathy at the porta hepatis). Measures of synthetic liver function include prothrombin time and serum albumin; abnormalities in these markers suggest advanced liver disease. (See 'Diagnostic studies' above.)

●Imaging is particularly helpful if an obstructive process, opportunistic infection, or malignancy is suspected. If CT or ultrasound demonstrates biliary duct pathology, stricturing, or dilated ducts, an endoscopic retrograde cholangiopancreatography (ERCP) may be indicated for diagnostic evaluation and therapeutic intervention. (See 'Diagnostic studies' above.)

●Liver biopsy can be considered in patients with infiltrative processes, mitochondrial toxicity, chronic viral hepatitis, or neoplasm. This is generally a safe procedure in patients with HIV, provided coagulation parameters are normal or corrected. (See 'Diagnostic studies' above.)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.