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AIDS cholangiopathy

AIDS cholangiopathy
Literature review current through: Aug 2023.
This topic last updated: Aug 02, 2023.

INTRODUCTION — AIDS cholangiopathy is a syndrome of biliary obstruction resulting from infection-related strictures of the biliary tract [1-3]. This topic will review the epidemiology, etiology, clinical manifestations, diagnosis, and management of patients with AIDS cholangiopathy. Other hepatobiliary complications of HIV-infection and the evaluation of the HIV-patient with hepatobiliary complaints are discussed in detail separately. (See "Evaluation of the patient with HIV and hepatobiliary complaints".)

EPIDEMIOLOGY — The incidence of AIDS cholangiopathy has decreased since the initiation of potent antiretroviral therapy (ART) in the mid-1990s and the present incidence is unknown [4,5]. Prior to the advent of potent ART, AIDS cholangiopathy occurred in as many as 26 percent of AIDS patients [4,6].

AIDS cholangiopathy usually occurs in patients with a CD4 count well below 100 cells/microL and may be the presenting manifestation [7]. However, 20 percent of individuals with AIDS cholangiopathy have CD4 count greater than 100 cells/microL [8].

ETIOLOGY AND PATHOGENESIS — Cryptosporidium parvum is the most common pathogen associated with AIDS cholangiopathy and has been isolated in 20 to 57 percent of cases [9]. It is estimated that 10 to 20 percent of AIDS cholangitis is caused by cytomegalovirus (CMV). Other pathogens that have been identified include Microsporidium, Cyclospora cayetanensis, Isospora, Giardia, and Histoplasma [2,7,10-14]. Members of the Mycobacterium avium complex may also cause AIDS cholangiopathy [14]. However, in approximately 20 to 40 percent of cases, no infectious pathogen is identified.

Chronic inflammation by one or more opportunistic pathogens result in the development of biliary strictures in patients with AIDS cholangiopathy. It has been postulated that CMV causes vascular injury leading to ischemic damage. Bile duct strictures result in biliary obstruction and cholestatic liver damage. C. parvum and CMV infection are usually associated with involvement of the large intrahepatic ducts [15]. (See 'Diagnostic imaging' below.)

CLINICAL MANIFESTATIONS

Signs and symptoms — Affected patients typically present with right upper quadrant and epigastric pain and diarrhea. In one study of 95 patients with diarrhea due to Cryptosporidium, 20 (23 percent) subsequently developed biliary tract disease [16]. The severity of the abdominal pain varies with the biliary tract lesion. Abdominal pain is usually more severe in patients with papillary stenosis and milder in patients with intrahepatic and extrahepatic sclerosing cholangitis (image 1) [17].

Fever and jaundice from obstruction of the bile duct and acute bacterial cholangitis are less frequent, occurring in 10 to 20 percent of patients.

Laboratory findings — Liver tests in AIDS cholangiopathy are usually indicative of cholestasis with marked elevation in alkaline phosphatase and gamma-glutamyl transferase. In one series of 52 patients with AIDS cholangiopathy, serum alkaline phosphatase was elevated in 75 percent of individuals with a mean level of 700 to 800 int. unit/L [2]. In comparison, only mild to moderate elevation are observed in other liver chemistries, including alanine aminotransferase and aspartate aminotransferase. Serum bilirubin may be normal or elevated, depending on the severity of papillary duct stenosis. Elevations in bilirubin when present are usually mild with total bilirubin less than twice the upper limit of normal.

However, liver tests may be normal in approximately 20 percent of patients despite biliary tract abnormalities seen on cholangiography [13]. (See "Diagnostic approach to the adult with jaundice or asymptomatic hyperbilirubinemia".)

Chronic complications — Long-term complications of AIDS cholangiopathy include progression of sclerosing cholangitis, which can lead to complications of cholestasis and hepatic failure. Chronic biliary inflammation can initiate the dysplastic process in the biliary epithelium, leading to development of cholangiocarcinoma [18,19]. (See "Clinical manifestations and diagnosis of cholangiocarcinoma", section on 'Clinical presentation' and "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis", section on 'Cholestasis'.)

DIAGNOSTIC APPROACH

Clinical suspicion and diagnosis — AIDS cholangiopathy should be suspected in the HIV-infected patient with advanced immunosuppression (CD4 count<100 cells/microL) who presents with right upper quadrant abdominal pain and/or diarrhea with a cholestatic pattern of liver test abnormalities (particularly elevated serum alkaline phosphatase). As patients with advanced immunosuppression may have more than one cause of abdominal pain, we also obtain a complete blood count, serum lipase and amylase, electrolytes, calcium, and albumin to rule out other causes of acute abdominal pain. (See "Evaluation of the adult with abdominal pain" and 'Laboratory findings' above.)

The diagnosis is established by cholangiographic evidence of characteristic bile duct changes (multifocal strictures, segmental dilations) and exclusion of secondary causes of intrinsic obstruction or extrinsic compression. Typically, the evaluation begins with a transabdominal ultrasound. In addition, we perform magnetic resonance cholangiopancreatography (MRCP) to identify bile duct strictures and exclude other causes of abdominal pain and extrinsic compression causing cholestasis [8]. We perform an abdominal computed tomography scan only if MRCP is unavailable. (See 'Diagnostic imaging' below.)

In patients with abnormal cholangiography on MRCP, we perform an endoscopic retrograde cholangiopancreatography (ERCP). ERCP can be both diagnostic and if indicated, therapeutic. Biliary brushings and biopsy, biliary aspiration, and small bowel biopsy can also be performed to determine the underlying etiology and can exclude cholangiocarcinoma in atypical cases (eg, isolated dominant stricture) [20]. (See 'Endoscopic therapy' below.)

To identify the causative agent we suggest the following:

Biliary specimens obtained from the ERCP should be sent for histologic and microbiologic examination, and should be evaluated for cytomegalovirus (CMV), cryptosporidium, microsporidium, and acid fast bacilli, as well as routine bacterial and fungal organisms.

Blood should be sent for bacterial and mycobacterial culture and for CMV polymerase chain reaction.

For patients with diarrhea, stool tests should be performed, including stool culture for bacterial organisms, examination for ova and parasites, acid-fast smear or immunofluorescent staining for Cryptosporidium and Isospora, and trichrome staining for Microsporidium. An additional discussion of the evaluation of diarrhea in patients with HIV is presented elsewhere. (See "Evaluation of the patient with HIV and diarrhea", section on 'Diagnostic studies'.)

Diagnostic imaging

Ultrasound — Ultrasound can identify intra- and extrahepatic bile duct dilatation. Ultrasound has a sensitivity for cholangiopathy ranging from 75 to 97 percent and specificity of up to 100 percent [7,10,21]. The diagnostic utility of ultrasound is illustrated in a retrospective study that included 50 patients with suspected AIDS cholangiopathy, due to right upper quadrant pain and cholestatic liver function tests, who underwent evaluation with ultrasound and ERCP [21]. Normal ultrasound findings were noted in 18 patients, 17 of whom subsequently had a normal ERCP, while the other patient had changes suggestive of mild cholangiopathy. Of the 32 patients with abnormal findings on ultrasound, all had abnormalities on ERCP. The ERCP in 22 patients had typical changes of cholangiopathy; however in the other 10, ERCP findings were due to other causes.

MRCP/ERCP — Cholangiography reveals one of four patterns [2,7,10,15,22]:

Type 1: Papillary stenosis alone – 10 percent

Type 2: Combined intrahepatic and extrahepatic sclerosing cholangitis without papillary stenosis (image 1) – 20 percent or less

Type 3: Combined papillary stenosis and sclerosing cholangitis – 50 to 60 percent

Type 4: Long extrahepatic bile duct stricture with or without intrahepatic sclerosing cholangitis (6 to 15 percent)

Other infrequently performed tests

Liver biopsy – In patients with characteristic findings on cholangiography, a liver biopsy is typically not required. A percutaneous liver biopsy may support the diagnosis of AIDS cholangiopathy, but is rarely diagnostic. Histologic changes of AIDS cholangiopathy are not specific and are consistent with sclerosing cholangitis. (See "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis", section on 'Liver biopsy'.)

Hepatic iminodiacetic acid scan – A hepatobiliary imino-diacetic acid scan may demonstrate delayed excretion of the tracer, suggesting biliary obstruction, or a focal biliary strictures [23].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of AIDS cholangiopathy include other causes of cholestasis. These include choledocholithiasis, biliary trauma/ischemia, and chemicals/drugs. In patients with cholestasis with fever and jaundice, the differential diagnosis also includes acute cholecystitis and a liver abscess. AIDS cholangiopathy can usually be distinguished from these based on history and imaging. (See "Evaluation of the patient with HIV and hepatobiliary complaints" and "Approach to the patient with abnormal liver biochemical and function tests", section on 'Elevated alkaline phosphatase' and "Acute cholangitis: Clinical manifestations, diagnosis, and management", section on 'Differential diagnosis'.)

MANAGEMENT

Endoscopic therapy — The management of obstruction due to AIDS cholangiopathy is endoscopic and the approach varies with the anatomic abnormality.

Symptomatic papillary stenosis — In patients with abdominal pain, jaundice, or cholangitis associated with papillary stenosis, we perform endoscopic retrograde cholangiopancreatography with biliary sphincterotomy. In patients with AIDS cholangiopathy and abdominal pain, the proportion of patients who experience symptomatic relief ranges from 23 percent to 100 percent [2,10,15,17,24]. However, serum alkaline phosphatase concentrations may remain stable or continue to rise due to progression of intrahepatic sclerosing cholangitis [13,17]. In patients with papillary stenosis, pancreatic abnormalities (such as pancreatic duct dilatation) are frequently seen on pancreatogram, suggesting that underlying pancreatic disease may be responsible for persistent abdominal pain despite biliary sphincterotomy in a subset of patients [22].

Biliary stricture — Patients with isolated or dominant common bile duct strictures are treated with endoscopic stenting [25].

Ursodeoxycholic acid for intrahepatic cholestasis — We suggest ursodeoxycholic acid (UDCA) (300 mg three times daily), primarily in patients with intrahepatic ductal disease and markedly elevated liver tests. However, the role of UDCA in AIDS cholangiopathy is uncertain and data to support its use are limited. In a pilot study that included four patients with AIDS cholangiopathy treated with ursodiol, all patients had resolution in abdominal pain after two to four months of treatment and approximately half had a fall in serum alkaline phosphatase and gamma-glutamyl transpeptidase [26].

Treatment of the underlying infection — Treatment directed against C. parvum, Microsporidium, or cytomegalovirus (CMV), is typically indicated, although it has not been demonstrated to consistently improve symptoms or cholangiographic abnormalities [13,15,16]. However, if a specific etiology is diagnosed, pathogen-specific therapy should be given to prevent progression of the underlying opportunistic infection. (See "Microsporidiosis", section on 'Gastrointestinal infection' and "Epidemiology, clinical manifestations, and treatment of cytomegalovirus infection in immunocompetent adults", section on 'Therapy'.)

In patients with AIDS cholangiopathy and acute cholangitis (fever, abdominal pain, and jaundice) management includes monitoring for and treating sepsis, providing antibiotic coverage, and establishing biliary drainage with endoscopic decompression. (See "Acute cholangitis: Clinical manifestations, diagnosis, and management", section on 'Management'.)

If CMV is identified as the etiologic agent, patients should have an eye exam for evidence of retinitis. Patients with extraocular CMV disease often have concurrent retinitis that requires specific treatment. (See "Pathogenesis, clinical manifestations, and diagnosis of AIDS-related cytomegalovirus retinitis".)

Antiretroviral therapy — Patients with AIDS cholangiopathy should be started on antiretroviral therapy (ART) [14]. In general, we initiate treatment as soon as possible (and within two weeks). A detailed discussion of how to select an ART regimen is presented in a separate topic review. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

In the setting of most opportunistic infections, data support that initiation of ART within two weeks improves outcomes (reduced progression of AIDS and death) [27]. However, there are very limited data on the effect of ART on AIDS cholangiopathy, and it is unclear if ART is associated with improvement in outcomes [20,28]. A more detailed discussion of the benefits of ART in patients with opportunistic infections is found elsewhere. (See "When to initiate antiretroviral therapy in persons with HIV", section on 'Patients with opportunistic infections'.)

PROGNOSIS — The survival of patients is not affected by cholangiopathy, since the mortality rate is primarily determined by the natural history of AIDS [2,7,13]. As AIDS cholangiopathy typically occurs in patients with advanced AIDS (CD4 cell count below 100/mm3), the mean survival has been only 7 to 12 months. As an example, in one series of 45 patients, one- and two-year survival rates were 41 and 8 percent, respectively [2]. In a retrospective study of 82 AIDS patients who developed cryptosporidiosis, those who had biliary symptoms were significantly more likely to die than HIV-infected patients without these symptoms during the following year (83 versus 48 percent) [6]. However, these studies were performed prior to the availability of potent antiretroviral therapy. (See "Microsporidiosis" and "Cryptosporidiosis: Epidemiology, clinical manifestations, and diagnosis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Biliary infection and obstruction".)

SUMMARY AND RECOMMENDATIONS

AIDS cholangiopathy is a syndrome of biliary obstruction resulting from infection-associated strictures of the biliary tract, usually seen in patients with a CD4 count well below 100/mm3. The incidence is not known precisely but has declined since the introduction of potent antiretroviral therapy. (See 'Epidemiology' above.)

C. parvum is the most common pathogen associated with AIDS cholangiopathy. Other pathogens include cytomegalovirus, Microsporidium, Cyclospora, and Histoplasma. However, in approximately 20 to 40 percent of cases, no infectious etiology is identified. (See 'Etiology and pathogenesis' above.)

Patients typically have right upper quadrant and epigastric pain, and diarrhea; fever and jaundice are less common. The severity of the abdominal pain varies with the biliary tract lesion. Severe abdominal pain is indicative of papillary stenosis, while milder abdominal pain is usually associated with intrahepatic and extrahepatic sclerosing cholangitis without papillary stenosis (image 1). (See 'Clinical manifestations' above.)

The diagnosis is made by endoscopic retrograde cholangiopancreatography (ERCP). However, other studies (particularly ultrasound and magnetic resonance cholangiopancreatography) can be helpful in early evaluation and in selecting patients for ERCP. (See 'Clinical suspicion and diagnosis' above.)

Treatment of the cholangiographic abnormalities is primarily endoscopic, and the approach varies with the anatomic abnormality. In patients with AIDS cholangiopathy and acute cholangitis (fever, abdominal pain, and jaundice), management includes monitoring for and treating sepsis, providing antibiotic coverage, and establishing biliary drainage with endoscopic decompression. (See 'Endoscopic therapy' above.)

In patients who have symptomatic (abdominal pain, cholangitis, or jaundice) papillary stenosis, we suggest sphincterotomy (Grade 2C). Sphincterotomy does not help patients with sclerosing cholangitis in the absence of papillary stenosis. (See 'Symptomatic papillary stenosis' above.)

In patients with an isolated or dominant common bile duct stricture we suggest endoscopic stenting (Grade 2C). (See 'Biliary stricture' above.)

Treatment options for patients with intrahepatic or extrahepatic sclerosing cholangitis are limited. We suggest ursodeoxycholic acid in a dose 300 mg three times daily (Grade 2C). (See 'Management' above.)

Although infection is the most common cause of AIDS cholangiopathy, medical treatment directed against common pathogens (C. parvum, Microsporidium, or cytomegalovirus) may not improve cholangiographic abnormalities. Nevertheless, when a specific etiology is diagnosed, pathogen-specific therapy should be given to prevent progression of the underlying opportunistic infection. (See 'Treatment of the underlying infection' above.)

Patients with advanced immunosuppression should be started on antiretroviral therapy. In most patients, we initiate treatment as soon as possible (and within two weeks). (See 'Antiretroviral therapy' above.)

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