Approach to 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).

Hepatobiliary problems may arise due to advanced immunosuppression, treatment-related adverse effects, underlying coinfections, or underlying comorbidities [1]. This topic will address the differential diagnosis and initial clinical and diagnostic evaluation of hepatobiliary complaints in patients with HIV, particularly in those with CD4 counts <200 cells/microL. Occasionally, patients with HIV and CD4 counts between 200 and 500 cells/microL who are not taking ART can also present with opportunistic infections and/or other acquired immunodeficiency syndrome (AIDS)-defining illnesses. Liver disease in patients with HIV and CD4 counts >500 cells/microL presents the same as in people without HIV; the approach to hepatobiliary complaints in these patients is discussed separately. (See "Approach to the patient with abnormal liver tests".)

More detailed information regarding coinfection with hepatitis B and hepatitis C virus is found elsewhere.

●(See "Monitoring the patient with HIV and chronic hepatitis B virus infection".)

●(See "Pretreatment evaluation of chronic hepatitis B virus infection in the patient with HIV".)

●(See "Prevention of hepatitis B virus infection in adults with HIV".)

●(See "Treatment of chronic hepatitis B in patients with HIV".)

●(See "Epidemiology, clinical manifestations, and diagnosis of hepatitis B in patients living with HIV".)

●(See "Treatment of chronic hepatitis C virus infection in the patient with HIV".)

INITIAL EVALUATION FOR ALL PATIENTS

Assess for acute liver failure — Acute liver failure is characterized by elevated serum transaminases >10 times the upper limit of normal, coagulopathy (international normalized ratio [INR] ≥1.5), and evidence of hepatic encephalopathy (altered mental status). These patients require urgent hospitalization, workup, management, and consultation with hepatology. (See 'When to admit to the hospital' below and "Acute liver failure in adults: Etiology, clinical manifestations, and diagnosis", section on 'Diagnosing acute liver failure'.)

History — When taking a history of a patient with hepatobiliary complaints, certain symptoms and/or historical clues should prompt consideration for certain illnesses. Some of these associations are mentioned below for etiologies that should be considered in a patient with low CD4 counts.

●Constitutional symptoms – History should assess the presence of constitutional symptoms, such as fevers, night sweats, fatigue, and weight loss. Presence of these is suggestive of an infection or malignancy (eg, non-Hodgkin lymphoma).

Hepatobiliary opportunistic infections include disseminated Mycobacterium avium complex (MAC) infection, Bartonella henselae infection, disseminated histoplasmosis, tuberculosis, cystoisosporiasis, and visceral leishmaniasis. Disseminated varicella zoster virus (VZV) or herpes simplex virus (HSV) and cytomegalovirus (CMV) hepatitis also can present with constitutional symptoms.

●Diarrhea – Presence of diarrhea along with right upper quadrant abdominal pain and abnormal liver function tests should raise suspicion for enteric infections, such as cryptosporidium, microsporidium, cyclosporiasis, and cystoisosporiasis, as well as disseminated infections such as disseminated MAC or talaromycosis (formerly penicilliosis).

●Adherence to antiretroviral therapy and antibiotic prophylaxis – We discuss adherence to antiretroviral therapy (ART) with the patient, since opportunistic infections, in general, are unlikely in patients who are virally suppressed (low or undetectable HIV viral load) on a stable ART regimen, even if CD4 cell counts are <200 cells/microL.

●Travel/residence history – We obtain a history of travel and residence to assess risk for certain endemic infections. Even remote history of travel and residence is important as some infections may be a reactivation of prior infection in the setting of severe immunocompromise from HIV (eg, histoplasmosis, tuberculosis).

•Hepatitis A is endemic in many places around the world (with outbreaks seen in the United States), especially in areas with poor sanitation, and can cause acute liver injury in non-vaccinated individuals. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

•Histoplasma capsulatum is found in midwestern and central United States, southern Mexico, parts of Central and South America (including the Caribbean), Southeast Asia, most of Africa, and Australia and is associated with exposure to soil contaminated with bird or bat excreta (eg, demolition and construction sites, gardening and farming, caves). (See "Epidemiology, clinical manifestations, and diagnosis of histoplasmosis in patients with HIV", section on 'When to suspect histoplasmosis'.)

•Talaromyces (formerly Penicillium) marneffei is found in Southeast Asia, Northeast India, southern China, Hong Kong, and Taiwan and is associated with exposure to soil during the rainy season. (See "Diagnosis and treatment of Talaromyces (Penicillium) marneffei infection", section on 'Approach to diagnosis'.)

•Visceral leishmaniasis is transmitted by sandflies in East Africa, Middle East, India, and South America (figure 1). (See "Visceral leishmaniasis: Clinical manifestations and diagnosis", section on 'Diagnosis'.)

●Exposure to cats – Exposure to cats and cat scratches in a patient with AIDS should prompt suspicion for B. henselae infection. (See "Microbiology, epidemiology, clinical manifestations, and diagnosis of cat scratch disease", section on 'Making a presumptive diagnosis'.)

Physical examination — When conducting a physical examination of a patient with hepatobiliary complaints, certain symptoms and/or historical clues should prompt consideration for certain illnesses. Some of these associations are mentioned below for etiologies that should be considered in a patient with low CD4 counts.

●Jaundice – A yellowing of the skin and sclera is indicative of an elevated bilirubin, which can occur in both intrahepatic and extrahepatic disease. Presence of jaundice should prompt consideration for biliary disease (eg, AIDS cholangiopathy), hemolysis, or impaired hepatic uptake or conjugation of bilirubin (eg, atazanavir-related hyperbilirubinemia). (See "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia" and "Classification and causes of jaundice or asymptomatic hyperbilirubinemia".)

●Hepatosplenomegaly – Presence of hepatosplenomegaly in patients with HIV and CD4 counts <200 cells/microL should prompt suspicion for lymphoma or opportunistic infections, such as disseminated histoplasmosis, disseminated MAC, talaromycosis, visceral leishmaniasis, or B. henselae. These patients typically also present with subacute onset of constitutional symptoms. (See "Splenomegaly and other splenic disorders in adults", section on 'How to examine the spleen' and "Overview of the evaluation of hepatomegaly in adults", section on 'Examining the liver'.)

●Lymphadenopathy – Presence of lymphadenopathy should prompt consideration for non-Hodgkin lymphoma, disseminated MAC, or talaromycosis. Lymphadenopathy can be localized or generalized in all these conditions. (See "Evaluation of peripheral lymphadenopathy in adults".)

●Mucocutaneous lesions – Presence of a rash can be a helpful clue to narrowing the differential diagnosis. Presence of violaceous lesions (picture 1A-C) are suggestive of B. henselae infection. Umbilicated erythematous papules (picture 2A-B) in the context of recent travel to/residence in Southeast Asia should prompt consideration for talaromycosis. Histoplasmosis is also known to cause a variety of skin lesions, especially in patients with AIDS (picture 3A-B) [2-4].

Disseminated herpes zoster virus almost always presents right after or concomitantly with a localized or diffuse herpes zoster rash (picture 4A-B). Presence of typical oral and/or genital HSV lesions is a helpful diagnostic clue for disseminated HSV infection, although the lesions are only present in one-third of patients with disseminated infection [5].

Evaluation of patients with HIV presenting with fever and rash is discussed separately. (See "Fever and rash in patients with HIV".)

Initial workup — All patients with HIV and suspected hepatobiliary disease should have the following laboratory tests sent:

●Complete blood count (CBC) – A CBC is helpful in determining platelet numbers and the likelihood of infection or immunosuppression. An elevated white blood cell (WBC) count can be suggestive of an infectious process, although patients with low CD4 counts may not rise enough of a response to demonstrate leukocytosis and may instead present with a normal WBC. A low WBC count may be indicative of significant immunosuppression or a viral illness, as infections (especially viruses) can occasionally present with leukopenia rather than leukocytosis. When a CD4 cell count is not available, a low absolute lymphocyte count can be suggestive of a low CD4 cell count.

Thrombocytosis is suggestive of an inflammatory and/or infectious response while thrombocytopenia can be caused by low thrombopoietin levels and impaired liver function. Presence of anemia suggests a disease that is affecting more than just the hepatobiliary system.

●Renal function panel – Measures of electrolytes and serum creatinine can be helpful in assessing the acuity of the disease and determining the presence of any renal impairment.

●Liver function panel – This panel typically includes alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase, total and direct bilirubin, and total protein and albumin. A differential diagnosis can be constructed based on the pattern of abnormalities seen on the liver function panel. If alkaline phosphatase is elevated and the cause is unclear, a gamma-glutamyl transferase (GGT) can be helpful in differentiating whether the alkaline phosphatase (ALP) is elevated due to liver or bone dysfunction. An elevated GGT level is indicative of a liver problem, while a normal GGT level suggests the elevated ALP may be due to a non-liver cause. (See 'Differential diagnosis' below and "Approach to the patient with abnormal liver tests".)

●HIV viral load and CD4 count – These tests should be sent if there are no recent results within the past three months or if there is concern for non-adherence to ART. Knowledge of the patient's CD4 cell count and/or percentage is critical in guiding the differential diagnosis recognizing that patients with HIV can also have disorders not related to immune deficiency (eg, gallstones). Additionally, an undetectable HIV viral load, even in the setting of low CD4 cell counts, makes opportunistic infections and AIDS-associated malignancies unlikely (table 1).

Further evaluation and imaging — We determine further diagnostic testing based on the pattern of liver abnormalities and our level of suspicion for different conditions, as determined by exposures and other risk factors. For example, patients with elevated transaminases will likely need a liver ultrasound and/or computed tomography (CT) imaging to evaluate for any structural liver abnormalities (eg, cysts, solid masses, hepatomegaly) as well as further diagnostic laboratory tests (see "Approach to the patient with abnormal liver tests"). In contrast, patients with a cholestatic pattern will most likely require a right upper quadrant ultrasound or a magnetic resonance cholangiopancreatography (MRCP) to further evaluate the biliary tract. (See "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia", section on 'Subsequent testing based on pattern of liver injury'.)

DIFFERENTIAL DIAGNOSIS — 

The differential diagnosis is determined by the degree of immunosuppression (eg, CD4 count) (table 1), whether the patient is on a stable and suppressive antiretroviral (ART) regimen, exposure history (eg, travel history, animal exposure), and the pattern of abnormality on the hepatic function panel. Occasionally, multiple etiologies can coexist in an immunosuppressed individual.

The differential diagnosis listed below describes the common etiologies of hepatobiliary complaints in people with HIV-related immunosuppression (eg, CD4 counts less than 200 to 300 cells/microL). We grouped the conditions based on their most salient liver-related abnormality (eg, elevated transaminases, hyperbilirubinemia, presence of liver lesions, and/or hepatomegaly). However, these categories are not exclusive, and some conditions can present in a variety of ways, especially in patients with advanced HIV.

Elevated transaminases — Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are usually elevated in the setting of liver injury.

Steatotic (fatty) liver disease — Steatotic liver disease is the presence of fat in the liver. Fat deposition in the liver can be caused by a variety of factors, including alcohol use, viral hepatitis, medication use, and/or metabolic dysfunction (eg, obesity, diabetes mellitus, hyperlipidemia) [6,7]. The fat in the liver can eventually cause liver inflammation that promotes fibrosis and can eventually lead to cirrhosis. Individuals with HIV may be at increased risk than those without HIV of progressing to liver fibrosis and cirrhosis [8-11].

●Epidemiology – In the ART era, steatotic liver disease is becoming much more prevalent among people with HIV, mirroring the trends seen in the uninfected general population. In patients with HIV, observational studies suggest prevalence rates between 15 to 40 percent, making it the most common form of liver disease [8,12,13]. Sometimes, steatotic liver disease is the principal cause of elevated transaminases. Although it is more commonly seen in people with well-controlled HIV, it should still be considered in patients with low CD4 counts.

●Impact of ART – Older ART regimens were associated with steatosis. However, this appears to be less common with newer agents, which instead may be beneficial. Contemporary ART regimens have been shown to slow the rate of hepatic fibrosis progression [14,15].

If a patient has recently started on a new ART drug and now presents with elevated transaminases and presence of fat in the liver, this should raise suspicion for lactic acidosis syndrome. Although overall rare, this most often occurs with nucleoside reverse transcriptase inhibitors (NRTIs). (See "Mitochondrial toxicity of HIV nucleoside reverse transcriptase inhibitors", section on 'Hyperlactatemia and lactic acidosis'.)

There are limited data on whether switching ART in the setting of steatotic liver disease is beneficial. In general, we continue the ART regimen if the patient is tolerating it well and is virally suppressed. In a small, randomized trial of 31 patients (half of which were on non-nucleoside reverse transcriptase inhibitor [NNRTI]-based regimens and the other half on protease inhibitor-based regimens), those who switched to a raltegravir-based regimen had similar rates of steatotic liver disease resolution compared with those who remained on their initial ART regimens (56 versus 53 percent) [16]. The role of integrase strand transfer inhibitors (INSTIs) in steatotic liver disease is unclear. One observational study found both INSTIs and tenofovir alafenamide (TAF) to be a risk factor for hepatic steatosis [17]. Another observational study of 99 ART-naïve patients who started INSTI-based ART regimens did not find increased rates of liver steatosis 12 months after initiation [18]. All these studies are susceptible to risk of bias and confounding.

●Clinical manifestations, diagnosis, and management – The clinical manifestations, diagnosis, and management of steatotic liver disease are the same as in the general population. Most patients are asymptomatic, although some patients may report fatigue, malaise, and vague right upper abdominal discomfort, and some present with hepatomegaly. Liver enzymes are typically mildly to moderately elevated with an AST:ALT ratio <1. Alkaline phosphatase (ALP) can be either normal or elevated, and bilirubin is generally within the normal range. Initial diagnostic workup for steatotic liver disease is liver imaging and calculation of a fibrosis score based on laboratory results. (See "Clinical features and diagnosis of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults" and "Management of metabolic dysfunction-associated steatotic liver disease (nonalcoholic fatty liver disease) in adults".)

Acute viral hepatitis — People with HIV often have risk factors for hepatitis A, B, and C. Acute viral hepatitis may present with constitutional symptoms, abdominal pain, jaundice, and markedly elevated liver transaminases (often above 1000 units/L). Hepatomegaly and right upper quadrant tenderness on palpation are often present. Patients can present with acute liver failure. (See 'Assess for acute liver failure' above.)

●Hepatitis A virus (HAV) mostly transmits via the fecal-oral route. Risk factors for hepatitis A include residing in/traveling to endemic areas with poor sanitation, experiencing homelessness, eating unwashed and/or undercooked food in unsanitary conditions, or engaging in anilingus (rimming). A positive hepatitis A immunoglobulin (Ig)M confirms the diagnosis. (See "Hepatitis A virus infection in adults: Epidemiology, clinical manifestations, and diagnosis".)

●Hepatitis B virus (HBV) is a bloodborne and sexually transmitted pathogen. Risk factors include injection drug use, sexual intercourse with a partner with active HBV infection, living in the same household as a person with active HBV infection, receiving dialysis, and receiving medical treatment in a setting with poor sanitary conditions (eg, needlestick, surgery, blood transfusion). A positive hepatitis B surface antigen (HBsAg) confirms the diagnosis. (See "Hepatitis B virus: Clinical manifestations and natural history", section on 'Acute hepatitis'.)

●Hepatitis C virus (HCV) is a bloodborne and sexually transmitted pathogen. Risk factors include injection drug use, sexual intercourse with a partner with HCV infection, and receiving dialysis. (See "Clinical manifestations, diagnosis, and treatment of acute hepatitis C virus infection in adults".)

HBV rebound in patients with chronic HBV infection — Patients with both HIV and HBV receive treatment against both viruses. If an ART 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 HBV infection, demonstrated by a sharp rise in aminotransferases. Initial diagnostic workup includes obtaining serum HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR), which would be elevated in a patient with HBV rebound. (See "Treatment of chronic hepatitis B in patients with HIV".)

Drug-induced liver injury — Patients with HIV may develop drug-induced liver injury from ART medications, herbal supplements, or from commonly used antimicrobial drugs, such as isoniazid, rifampin, fluconazole, or trimethoprim-sulfamethoxazole. ART drugs that have been associated with drug-induced liver injuries (DILI) include darunavir, efavirenz, and nevirapine [19], none of which are first-line options for treatment of HIV infection. DILI may lead to right upper quadrant pain, nausea, fatigue, and poor appetite. In severe cases, it can also be associated with jaundice. LiverTox is a database on medications and their risk of DILI. DILI is often diagnosed clinically with removal of the suspected causative drug. (See "Drug-induced liver injury".)

Herpesviruses hepatitis — Herpesviruses occasionally cause hepatitis, often in the setting of a disseminated infection in patients with advanced immunosuppression.

●Cytomegalovirus (CMV) hepatitis – CMV can rarely cause hepatitis in immunocompromised individuals. Signs and symptoms are non-specific but typically include other infectious mononucleosis-like symptoms (eg, fever, fatigue, sore throat). Further diagnostic testing includes identification of CMV either in the serum or ideally, in the liver itself, although this requires a liver biopsy that is invasive and rarely performed unless necessary. CMV PCR or antigen testing is preferred over CMV cultures for initial diagnostic testing because of their faster turn-around time. Definitive diagnosis of CMV hepatitis requires a liver biopsy. (See "Approach to the diagnosis of cytomegalovirus infection".)

●Disseminated varicella zoster virus (VZV) infection – Herpes zoster virus can cause a disseminated infection in severely immunocompromised individuals. When disseminated, the virus typically affects the lungs, liver, and/or central nervous system (CNS). Constitutional symptoms are common (eg, fevers, malaise). Disseminated herpes zoster virus almost always presents right after or concomitantly with a localized or diffuse herpes zoster rash (picture 4A-B). Further diagnostic testing includes obtaining a serum VZV DNA PCR.

●Disseminated herpes simplex virus (HSV) infection – Fulminant hepatitis is a rare complication of HSV infection. Presence of typical oral and/or genital HSV lesions is a helpful diagnostic clue for disseminated HSV infection, although the lesions are only present in one-third of patients with disseminated infection [5]. Constitutional symptoms are common (eg, fevers, malaise). Further diagnostic testing includes obtaining a serum HSV DNA PCR. (See "Epidemiology, clinical manifestations, and diagnosis of herpes simplex virus type 1 infection", section on 'Hepatitis'.)

Syphilis hepatitis — Syphilis hepatitis is a rare clinical presentation of secondary syphilis. It can be asymptomatic or present with constitutional symptoms and/or right upper quadrant abdominal pain. Transaminases are usually mildly or moderately elevated. Although diagnosis of syphilis hepatitis requires a biopsy, most often a diagnosis of secondary syphilis by serology and/or rapid plasma reagin (RPR) followed by resolution of hepatobiliary signs and symptoms with treatment of syphilis is sufficient. (See "Syphilis in persons with HIV", section on 'Diagnosis'.)

Non-Hodgkin lymphoma — Non-Hodgkin lymphoma of the liver is rare. It typically occurs in patients with CD4 counts <200 cells/microL. When the liver is involved, it may present with pain, ascites, weight loss, nausea, jaundice, lymphadenopathy, and hepatomegaly. Non-Hodgkin lymphoma requires a biopsy for diagnosis. (See "HIV-related lymphomas: Clinical manifestations and diagnosis", section on 'GI tract and liver'.)

Disseminated histoplasmosis — Histoplasmosis is one of the most common endemic fungal infection in patients with HIV and CD4 counts <150 cells/microL [20,21]. The infection is endemic to the eastern part of North America, most of Central and South America (including the Caribbean), sub-Saharan Africa, and certain areas of Southeast Asia, and is associated with exposure to soil contaminated with bird or bat excreta (eg, demolition and construction sites, gardening and farming, caves). Common signs and symptoms of histoplasmosis include fever, night sweats, weight loss, cough, nausea, vomiting, hepatosplenomegaly, adenopathy, and skin and mucosal lesions (picture 3A-B). Pancytopenia, elevated aminotransferases, and a marked elevation in serum lactate dehydrogenase (LDH) are commonly seen. Further initial diagnostic testing usually involves obtaining a serum and urine Histoplasma antigen or visualizing the fungus on histology and/or culture. (See "Epidemiology, clinical manifestations, and diagnosis of histoplasmosis in patients with HIV".)

Talaromycosis (formerly penicilliosis) — Talaromycosis is a fungal infection endemic to Southeast Asia and is associated with exposure to soil during the rainy season. It typically occurs in patients with CD4 counts <100 cells/microL. The infection typically presents with generalized lymphadenopathy, hepatosplenomegaly, respiratory signs and symptoms, and an umbilicated papular rash (picture 2A-B). Occasionally, diarrhea may be present. Diagnosis of talaromycosis requires identification of the fungus on blood smear and/or biopsy specimen. (See "Epidemiology and clinical manifestations of Talaromyces (Penicillium) marneffei infection" and "Diagnosis and treatment of Talaromyces (Penicillium) marneffei infection".)

Visceral leishmaniasis — Visceral leishmaniasis is transmitted by sandflies in East Africa, Middle East, India, and South America (figure 1). It presents as a subacute progression of fever, malaise, weight loss, and splenomegaly. Further diagnostic testing includes serology, parasite DNA PCR, and/or visualization of the parasite in blood smears or tissue. (See "Visceral leishmaniasis: Clinical manifestations and diagnosis", section on 'HIV-VL coinfection'.)

Hyperbilirubinemia and/or elevated ALP — Hyperbilirubinemia and/or elevated alkaline phosphatase (ALP) can be seen with AIDS cholangiopathy, disseminated M. avium complex (MAC), B. henselae infection, and with atazanavir-associated asymptomatic hyperbilirubinemia. Other causes of cholestasis that are also seen in the general population (eg, cholecystitis, cholangitis) should be considered as well. Additionally, patients with predominantly elevated transaminases can have elevated bilirubin as the disease progresses and liver function worsens. Further discussion on the diagnostic approach to hyperbilirubinemia and/or elevated ALP in the general population is found elsewhere. (See "Approach to the patient with abnormal liver tests", section on 'Isolated hyperbilirubinemia' and "Approach to the patient with abnormal liver tests", section on 'Elevated alkaline phosphatase' and "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia".)

AIDS cholangiopathy — Marked elevation of ALP in a patient with AIDS and right upper quadrant pain suggests AIDS cholangiopathy. AIDS cholangiopathy is a syndrome of biliary obstruction resulting from infection-associated strictures of the biliary tract. The most common cause is Cryptosporidium parvum. Other common causes include Microsporidium, Cyclospora, Cystoisospora (formerly Isospora), Giardia, Histoplasma capsulatum, and MAC.

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 patients with AIDS prior to the advent of potent ART; the incidence has clearly decreased in the era of modern ART but is not known.

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 ALP [22]. 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'.)

Disseminated MAC infection — Marked elevation of ALP in the absence of extrahepatic obstruction in patients with AIDS is suggestive of M. avium complex (MAC) infection in the liver [23]. The risk of MAC in patients with HIV increases as the CD4 count declines below 100 cells/microL, with most infected patients having CD4 counts <50 cells/microL. Symptoms include fever, night sweats, weight loss, diarrhea, and abdominal pain. Hepatosplenomegaly and lymphadenopathy may be present. Laboratory abnormalities frequently include anemia and bone marrow suppression [24].

If disseminated MAC is suspected, we obtain a mycobacterial blood culture and alert the microbiology laboratory to the suspicion of MAC. The diagnosis of MAC is made by isolation of the organism in culture usually of the blood or lymph node. If a liver biopsy is done, appropriate culture and special acid-fast stains of the specimen can increase the yield. Cultures should include testing for routine bacterial, mycobacterial, and fungal pathogens.

Immune reconstitution inflammatory syndrome due to underlying MAC infection can also cause similar findings (eg, lymphadenopathy and lymphadenitis, fever, granulomatous hepatitis); however, cultures are usually negative, and histology reveals well-formed granulomas with few (if any) organisms. (See "Mycobacterium avium complex (MAC) infections in persons with HIV".)

Bartonella henselae infection — B. henselae infection of the liver (bacillary peliosis hepatis) should be suspected in a patient with HIV and advanced immunosuppression, fever, anemia, skin lesions, and multiple lucencies noted within the liver on ultrasound.

Bartonella infections often affect people with CD4 counts <100 cells/microL and typically presents as bacillary angiomatosis in the form of cutaneous violaceous lesions (picture 1A-C). Occasionally, it can affect the liver as well (bacillary peliosis hepatis). Patients present with abdominal pain with or without systemic symptoms (eg, fever) and hepatosplenomegaly. Cutaneous lesions are also often seen but not always. Laboratory abnormalities include an elevated ALP with or without mild transaminitis, as well as pancytopenia or just thrombocytopenia. Imaging typically shows lesions scattered throughout the liver and spleen.

If B. henselae infection is suspected, we obtain Bartonella serology, blood PCR, and a blood culture and inform the microbiology laboratory of the suspected organism so the blood culture can be appropriately collected and processed. (See "Bartonella infections in people with HIV".)

Atazanavir-associated hyperbilirubinemia — Atazanavir is a rarely used ART drug that can cause indirect hyperbilirubinemia by inhibiting UDP-glucuronosyl transferase (UGT) [25]. Occasionally, mild jaundice can be seen. The elevation in indirect bilirubin is reversible and not associated with liver injury or elevations in other liver tests (eg, transaminases or ALP) and usually does not require drug discontinuation. (See "Overview of antiretroviral agents used to treat HIV", section on 'Protease inhibitors (PIs)'.)

Atazanavir also appears to be associated with complicated cholelithiasis. In a series of 14 patients with HIV and cholelithiasis who were receiving an atazanavir-based ART regimen, eight had significant concentrations of atazanavir detected from biliary stones [26]. 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).

Atazanavir-associated hyperbilirubinemia is often diagnosed clinically and confirmed with resolution of hyperbilirubinemia after cessation of atazanavir.

Liver lesions — The differential diagnosis for liver lesions in a patient with HIV-associated immunosuppression includes disseminated cryptococcosis, Bartonella peliosis hepatis, or malignancy with metastasis to the liver. The two most common AIDS-associated malignancies to affect the liver are non-Hodgkin lymphoma and Kaposi sarcoma with liver involvement. Other causes that commonly affect the general population, such as a pyogenic liver abscess, echinococcal cysts, or hepatocellular carcinoma can also be seen. (See "Approach to the adult patient with an incidental solid liver lesion" and "Diagnosis and management of cystic lesions of the liver".)

Hepatomegaly and hepatosplenomegaly — The most common cause of hepatomegaly in patients with HIV is chronic viral hepatitis with either HBV and/or HCV infections [27]. Metabolic dysfunction-associated steatohepatitis (MASH) can also cause hepatomegaly. Hepatosplenomegaly can be seen in patients with disseminated histoplasmosis, B. henselae infection, visceral leishmaniasis, talaromycosis, and non-Hodgkin lymphoma. (See "Overview of the evaluation of hepatomegaly in adults" and "Splenomegaly and other splenic disorders in adults", section on 'Splenomegaly'.)

ADDITIONAL CONSIDERATIONS

When to admit to the hospital — The decision regarding whether to admit a patient to the hospital depends on various factors, including the clinical presentation, degree of immunosuppression (eg, CD4 count), the degree of hepatobiliary abnormality, and the patient's ability to undergo further workup as an outpatient.

●Clinical presentation – Patients with hemodynamic instability, evidence of acute liver failure (eg, encephalopathy), new-onset ascites, jaundice, or suspicion for disseminated disease (eg, lymphadenopathy, hepatosplenomegaly, skin lesions) should prompt admission to an inpatient setting.

●Degree of immunosuppression – Patients with severe immunosuppression may not mount the typical symptoms associated with severe infections and may appear clinically well while actually being severely ill. We typically have a low threshold for admitting patients with advanced immunosuppression because they can quickly worsen.

●Severity of laboratory abnormalities – Markedly elevated transaminases (>5 to 10 times the upper limit of normal) and/or markedly elevated bilirubin should prompt consideration for hospitalization. Although presence of liver lesions or hepatosplenomegaly does not necessarily warrant hospitalization, we sometimes prefer to admit these patients as the workup can often be expedited in the inpatient setting.

●Social structure – The ability of the patient to take care of themselves at home, the presence of caretakers, the likelihood of adherence to follow-up diagnostic testing, and the distance between home and the nearest hospital and/or clinic are other factors to consider when determining whether to admit a patient to the hospital.

When to refer to or consult a specialist — Referral to a gastroenterologist or hepatologist should be considered for acute liver failure, advanced fibrosis on metabolic-associated fatty liver disease risk stratification scores, for patients with markedly elevated transaminases (>5 to 10 times the upper limit of normal) or persistently elevated liver tests (≥2 times the upper limit of normal for aminotransferases or 1.5 times the upper limit of normal for alkaline phosphatase [ALP]), and for patients being considered for liver biopsy. (See "Approach to the patient with abnormal liver tests", section on 'When to refer to a specialist'.)

SUMMARY AND RECOMMENDATIONS

●Initial evaluation – Initial evaluation of a patient with HIV and hepatobiliary complaints should include assessment for acute liver failure, as well as a comprehensive history and physical that includes an antiretroviral (ART) history and detailed epidemiologic and environmental exposure history (eg, travel, animal exposures). Initial laboratory workup includes a complete blood count (CBC), renal and liver function panels, and HIV viral load and CD4 count. We determine further diagnostic testing based on the pattern of liver abnormalities and our level of suspicion for different conditions. (See 'Initial evaluation for all patients' above.)

●Role of CD4 cell count – Certain etiologies have CD4 cell cutoffs below which the etiology is much more likely. These CD4 cell count cutoffs are outlined in the table (table 1). (See 'Differential diagnosis' above.)

●Differential diagnosis by liver abnormality pattern

•Elevated transaminases – Liver abnormalities dominated by an elevation in transaminases are suggestive of liver injury. Often, as liver injury progresses, the biliary tract is affected as well, causing a rise in bilirubin. Etiologies to consider include steatotic liver disease, acute viral hepatitis (hepatitis A virus [HAV], hepatitis B virus [HBV], hepatitis C virus [HCV]), chronic HBV rebound in the setting of ART interruption, drug-induced liver injury, herpesviruses hepatitis, and AIDS-associated malignancies and opportunistic infections. (See 'Elevated transaminases' above.)

•Hyperbilirubinemia and/or elevated ALP – Liver abnormalities dominated by hyperbilirubinemia and/or an elevated alkaline phosphatase (ALP) are suggestive of cholestatic injury. Often, a cholestatic pattern of abnormalities is caused by the same conditions as that seen in the general population (eg, cholecystitis, cholelithiasis). However, certain opportunistic infections, such as disseminated Mycobacterium avium complex (MAC) infection or Bartonella henselae infection, can also cause a similar pattern of abnormality. (See 'Hyperbilirubinemia and/or elevated ALP' above.)

●Differential diagnosis of liver lesions – The differential diagnosis for liver lesions in a patient with low CD4 counts includes disseminated cryptococcosis, Bartonella peliosis hepatis, non-Hodgkin lymphoma, Kaposi sarcoma; pyogenic liver abscess, echinococcal cysts, or hepatocellular carcinoma can also be seen. (See 'Liver lesions' above.)

●Differential diagnosis of hepatomegaly and hepatosplenomegaly – The most common cause of hepatomegaly in patients with HIV is chronic viral hepatitis with either HBV and/or HCV infections, mass lesions, or alcohol-related hepatitis. Hepatosplenomegaly can be seen in patients with disseminated histoplasmosis, visceral leishmaniasis, talaromycosis, and non-Hodgkin lymphoma. (See 'Hepatomegaly and hepatosplenomegaly' 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.