Version May 2024
INTRODUCTION — Vanishing bile duct syndrome (VBDS) is an uncommon, acquired, but potentially serious form of chronic cholestatic liver disease. Hepatic ductopenia (a pathologic description; also designated as bile duct paucity) refers to a reduction in the number of intrahepatic bile ducts, a process that may ultimately lead to cholestatic liver disease and can progress to biliary cirrhosis. VBDS is manifested histologically by severe bile duct destruction, defined as a loss of the intralobular bile ducts in >50 percent of portal areas. This topic will discuss the etiology, clinical features, diagnosis, and management of acquired hepatic ductopenia and VBDS.
Genetic and congenital diseases that are associated with disorders of the bile ducts are discussed separately:
●Syndromic (ie, Alagille syndrome) and nonsyndromic varieties of paucity of interlobular bile ducts (see "Inherited disorders associated with conjugated hyperbilirubinemia")
●Cystic fibrosis (see "Cystic fibrosis: Clinical manifestations and diagnosis")
●Alpha-1 antitrypsin deficiency (see "Extrapulmonary manifestations of alpha-1 antitrypsin deficiency")
●Trihydroxycoprostanic acidemia; trisomies 17, 18, 21 (see "Congenital cytogenetic abnormalities")
●Extrahepatic bile duct atresia and paucity of interlobular bile ducts (see "Causes of cholestasis in neonates and young infants")
Causes of cholestasis in neonates and young infants are discussed separately (see "Causes of cholestasis in neonates and young infants")
NORMAL BILIARY TREE ANATOMY — The biliary tree is the tubular system of ducts that transports bile from the liver to the small intestine. It is divided into intra- and extrahepatic systems. Few disease states involve both systems, thus allowing for a natural taxonomic separation between the intra- and extrahepatic biliary tree [1].
●The extrahepatic system includes the right and left hepatic ducts, cystic duct, and common bile duct.
●The intrahepatic biliary tree contains ducts proximal to the right and left hepatic ducts [2]. The intrahepatic system is further divided into intrahepatic large bile ducts (segmental and area ducts) that are grossly visible, and the intrahepatic small bile ducts (interlobular bile ducts and periportal bile ductules [canals of Hering]).
The diameter of the bile ducts steadily decreases from the liver hilum toward the periphery. The bile ducts, as well as branches of the hepatic artery and portal vein, form a triad in the portal tract. Interlobular bile ducts are identified in portal tracts near arterial branches of similar size.
PATHOGENESIS — The pathogenesis of VBDS is not well understood; however, immunologic injury has been implicated in bile duct loss, and T-cell mediated immunologic reaction may lead to epithelial cell apoptosis [3]. Biliary apoptosis is implicated in the pathogenesis of multiple cholangiopathies and may actually be underappreciated due to the difficulty in accurately identifying apoptotic biliary cells in hematoxylin and eosin-stained specimens.
Biliary homeostasis exists as a balance between apoptosis and regeneration. Liver stem cells from the canals of Hering are likely the source of new biliary cells, a process regulated via B cell lymphoma (BCL)-2 proteins [2,4]. BAX (BCL-2 associated X protein), an apoptosis promoter, and BCL-2, which regulates apoptosis, are both expressed on bile duct cells. However, BAX is expressed along the entire biliary tree, whereas BCL-2 appears to be limited to bile ductules and interlobular bile ducts.
CAUSES OF DUCTOPENIA
Drug-induced liver injury — Drug-induced liver injury can lead to cholestasis (defined as elevated alkaline phosphatase ≥2 times the upper limit of normal) (table 1), and some patients with DILI may progress to VBDS despite discontinuing the offending agent. Drugs that have been implicated in causing VBDS include: amoxicillin/clavulanate, other penicillins, macrolide antibiotics, fluoroquinolones, sulfonamides, antifungal agents, nonsteroidal anti-inflammatory agents, phenothiazines, tricyclic antidepressants, and anticonvulsants [5-9]. The National Institutes of Health maintains a database of drugs and herbal medicines that have been associated with VBDS. (See "Drugs and the liver: Metabolism and mechanisms of injury" and "Drug-induced liver injury".)
Patients with DILI typically present with jaundice and pruritus one to six months after the onset of bile duct injury [9]. Symptoms and liver biochemical and function tests may ultimately improve; however, progressive bile duct loss can lead to cirrhosis, liver failure, and death or liver transplantation [10].
Immune-mediated disorders — Immune-mediated disorders that have been associated with bile duct inflammation and loss include:
●Primary biliary cholangitis – Primary biliary cholangitis (PBC) is a known cause of destruction of the interlobular bile ducts; however, this pathognomonic biopsy finding for PBC is seen infrequently. Periductular granulomas with bile duct injury and subsequent loss are more commonly seen on liver biopsy in patients with PBC. (See "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis".)
Progressive bile duct loss can also be found in patients with autoimmune cholangitis, a disorder that has similar clinical, biochemical, and histologic features of PBC but without antimitochondrial antibodies. Other autoimmune markers (eg, antinuclear and antismooth muscle antibodies) are frequently present. (See "Autoimmune hepatitis variants: Definitions and treatment", section on 'Autoimmune hepatitis-PBC overlaps' and "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis", section on 'IgG4-associated cholangitis'.)
●Primary sclerosing cholangitis – Primary sclerosing cholangitis (PSC) typically involves both the intra- and extrahepatic biliary systems, resulting in fibrosis and stricturing. The diagnosis is established by cholangiography. Findings on liver biopsy are usually nonspecific, although a classic (but uncommonly seen) finding is fibrous obliteration of small bile ducts in an "onion skin" pattern. (See "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis".)
●T-cell-mediated (cellular) rejection of the liver allograft – The pathologic changes in acute T-cell-mediated (cellular) rejection of the liver allograft include bile duct damage that is characterized by nonsuppurative cholangitis of the bile duct epithelium. (See "Liver transplantation in adults: Clinical manifestations and diagnosis of acute T-cell mediated (cellular) rejection of the liver allograft".)
●Chronic graft-versus-host disease – Chronic graft-versus-host disease is typically seen after allogenic bone marrow transplantation [11]. Bile duct injury occurs when minor histocompatibility antigens expressed on the biliary epithelium are mismatched. Mononuclear cells react and ultimately obstruct small interlobular bile ducts. Patients may present with signs and symptoms of cholestasis (eg, jaundice, elevated liver biochemical tests). (See "Clinical manifestations and diagnosis of chronic graft-versus-host disease".)
●Sarcoidosis – Sarcoidosis is a systemic disease characterized by noncaseating granulomas, and most patients have liver involvement. When granulomas are present in the portal tract, adjacent bile ducts may be injured, which may result in ductopenia [12]. (See "Gastrointestinal, hepatic, pancreatic, and peritoneal sarcoidosis", section on 'Hepatic'.)
Infectious causes — Infectious causes that have been linked to bile duct loss and VBDS include viral and bacterial infections [2]:
●Cytomegalovirus – Cases of VBDS in the setting of cytomegalovirus infection have been reported in immunocompromised patients [13,14].
●Chronic viral hepatitis – Bile duct injury and loss have been reported in patients with chronic viral hepatitis (hepatitis B virus [HBV] or hepatitis C virus infection [HCV]) [15-17]. Fibrosing cholestatic hepatitis with severe bile duct loss has also been reported after liver and kidney transplantation in such patients [15-17]. Recurrence of HBV or HCV following transplantation is discussed separately. (See "Liver transplantation in adults: Preventing hepatitis B virus infection in liver transplant recipients" and "Hepatitis C virus infection in liver transplant candidates and recipients".)
●Epstein-Barr virus infection – Epstein-Barr virus infection has rarely been associated with bile duct loss [18]. (See "Clinical manifestations and treatment of Epstein-Barr virus infection".)
Infections may also play a role in triggering or progression of immune-mediated biliary disease [2]. (See 'Immune-mediated disorders' above.)
Malignancy — Malignancies that have been associated with VBDS include:
●Hodgkin lymphoma – Cholestasis with bile duct loss is a well-established but rare presentation of Hodgkin lymphoma [19-23]. (See "Clinical presentation and diagnosis of classic Hodgkin lymphoma in adults".)
Liver infiltration by lymphoma cells in Hodgkin lymphoma has been seen in up to 50 percent of patients; however, progression to VBDS is rare [23,24]. Management includes treatment of Hodgkin lymphoma, while patients with persistent cholestasis may be evaluated for liver transplantation.
●Macrophage activation syndrome – Macrophage activation syndrome is a form of hemophagocytic lymphohistiocytosis that occurs in patients with autoimmune diseases and that can rarely present with marked cholestasis, destructive small bile duct injury, and secondary biliary cholangitis. Histologically, the inflammatory changes and bile duct lesions are dominated by the presence of activated macrophages and T-cells, in particular CD8+ lymphocytes [25,26]. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis".)
Idiopathic adulthood ductopenia — Idiopathic adulthood ductopenia is an uncommon disorder in adults who have unexplained cholestatic liver disease and ductopenia despite evaluation with laboratory testing, imaging, and liver biopsy [27-29]. In a single-center study including 2082 adult patients with intrahepatic bile duct injury, an underlying cause could not be identified in 25 patients (1 percent); thus, bile duct loss was regarded as idiopathic [30].
Idiopathic adulthood ductopenia can be categorized as nonsevere or severe (the latter of which is also referred to as vanishing bile duct syndrome) [9,31-33]. Determining the severity of hepatic ductopenia is discussed below. (See 'Defining severity of ductopenia' below.)
Data limited to case reports and small case series have suggested that patients with nonsevere idiopathic bile duct loss are likely to recover, while some patients with extensive bile duct destruction may require liver transplantation [31]. (See 'Prognosis' below.)
It has been suggested that patients with idiopathic adulthood ductopenia may have several disorders with atypical features, including [30]:
●Late-onset nonsyndromic paucity of intrahepatic bile ducts (see "Inherited disorders associated with conjugated hyperbilirubinemia").
●Small duct PSC without large duct involvement and without evidence of inflammatory bowel disease (see "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis", section on 'Small duct PSC').
●Nonsuppurative viral cholangitis.
●Autoimmune cholangitis in the absence of the typical autoantibodies (eg, lack of antimitochondrial antibody) (see "Clinical manifestations, diagnosis, and prognosis of primary biliary cholangitis").
In addition, familial clustering of idiopathic adulthood ductopenia has been described, suggesting that genetic factors may play a role for some patients [34].
CLINICAL FEATURES
Patterns of clinical presentation — The timing of clinical presentation for patients with hepatic ductopenia and VBDS is variable and may depend on the underlying etiology. As an example, for patients with drug-induced liver injury (DILI), VBDS typically presents in one to six months after the offending drug was initiated [9]. (See 'Causes of ductopenia' above.)
Some patients may be asymptomatic and are initially identified based on laboratory abnormalities (eg, elevated alkaline phosphatase), while other patients may have symptoms of cholestasis such a jaundice, pruritus, and fatigue. For patients with chronic cholestasis, additional clinical features may include gallstone formation, hyperlipidemia, malabsorption, cutaneous xanthomas, and fat-soluble vitamin deficiencies [35]. (See "Nutritional issues in adult patients with cirrhosis".)
In addition, patients with progressive disease leading to cirrhosis may develop complications related to portal hypertension such as ascites and esophageal varices. (See "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis".)
Laboratory studies — Laboratory abnormalities generally reflect cholestasis with elevations in alkaline phosphatase (often >3 times the upper limit of normal), total serum bilirubin, and gamma-glutamyl transpeptidase. Moderate elevations in serum aminotransferases (alanine aminotransferase and aspartate aminotransferase) may also be present, but are rarely >10 times the upper limit of normal. (See "Laboratory test reference ranges in adults".)
EVALUATION — For patients with cholestasis and suspected VBDS, goals of the evaluation are to identify an underlying cause of intrahepatic cholestasis, exclude extrahepatic biliary obstruction, establish the diagnosis of VBDS, and determine the severity of bile duct loss.
History and physical examination — The history includes a description of symptoms and use of prescription and nonprescription drugs.
The physical examination should include an assessment for jaundice, hepatomegaly, skin excoriations from scratching, and stigmata of chronic liver disease (eg, ascites). (See "Overview of the evaluation of hepatomegaly in adults", section on 'Examining the liver'.)
Approach to testing
Laboratory evaluation — Laboratory testing is performed to look for abnormalities in liver biochemistries and function and to identify possible causes of bile duct loss. For most patients, we obtain the following tests (see "Cirrhosis in adults: Etiologies, clinical manifestations, and diagnosis", section on 'Hematologic abnormalities'):
●Serum aminotransferases – Alanine aminotransferase (ALT) and aspartate aminotransferase (AST).
●Alkaline phosphatase.
●Total bilirubin.
●Gamma-glutamyl transpeptidase.
●Serum albumin.
●Prothrombin time/international normalized ratio.
●Complete blood count, with a focus on evaluating for thrombocytopenia.
●Antimitochondrial antibody.
●Autoimmune markers – Antismooth muscle antibody, antinuclear antibody.
●Serologies to exclude hepatitis B virus (HBV) and hepatitis C virus (HCV) infection – Hepatitis B surface antigen, hepatitis B surface antibody, hepatitis B core antibody, and anti-HCV antibody.
●Cytomegalovirus assay. (See "Overview of diagnostic tests for cytomegalovirus infection".).
●Anti-Epstein-Barr virus (EBV) IgG and IgM antibodies. (See "Infectious mononucleosis", section on 'Diagnosis'.)
The evaluation of patients with suspected extrapulmonary sarcoidosis is discussed separately. (See "Clinical manifestations and diagnosis of sarcoidosis".)
Imaging — Extrahepatic biliary obstruction should be excluded with imaging (eg, magnetic resonance cholangiopancreatography). Because VBDS is characterized by small duct injury, imaging tests are generally less helpful than liver biopsy for establishing the diagnosis. The cholangiogram is usually normal until extensive fibrosis from secondary biliary cirrhosis develops, in which the peripheral biliary tree may appeared "pruned" in areas of stenosis and ectasia. (See "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis", section on 'Small duct PSC'.)
Liver biopsy — A liver biopsy is performed to establish the diagnosis and evaluate severity of liver disease. (See 'Diagnosis' below and 'Defining severity of ductopenia' below.)
DIAGNOSIS — The diagnosis of VBDS may be suspected in a patient with liver biochemical abnormalities consistent with cholestasis (alkaline phosphatase ≥2 times the upper limit of normal) in the absence of other conditions associated with cholestasis (eg, primary biliary cholangitis, primary sclerosing cholangitis, viral infections). (See 'Causes of ductopenia' above.)
The diagnosis of VBDS is established by histologic examination acquired through liver biopsy and by excluding other conditions (eg, extrahepatic biliary obstruction) with imaging tests. VBDS is defined as loss of interlobular bile ducts in >50 percent of portal areas, provided that the histologic specimen contains ≥10 portal tracts (picture 1) [27].
Diagnostic yield can be increased by immunostaining the liver biopsy specimen with cytokeratin 7 and 19, both of which identify biliary elements (picture 2 and picture 3) [2]. Ductular proliferation may coexist with interlobular duct loss, and thus bile ductules must be distinguished from bile ducts. Bile ducts parallel hepatic artery branches of similar size, whereas ductular proliferation tends to appear near the limiting plate or within lobules [30].
DIFFERENTIAL DIAGNOSIS — The differential diagnosis of VBDS on microscopic examination of the liver includes ischemic hepatic necrosis with resultant bile duct injury and loss, acute T-cell mediated rejection, and primary sclerosing cholangitis. The clinical setting (ie, liver transplant recipient), findings on imaging studies (ie, biliary strictures) can help distinguish among these entities. (See "Liver transplantation in adults: Endoscopic management of biliary adverse events" and "Primary sclerosing cholangitis in adults: Clinical manifestations and diagnosis", section on 'Diagnosis'.)
MANAGEMENT
Measures for all patients — For patients with cholestasis and hepatic ductopenia (loss of ≥25 percent of intrahepatic small bile ducts on liver biopsy) without a clear cause identified on laboratory testing, imaging, or liver histology, general measures include (algorithm 1):
●Avoid drugs associated with liver injury – Drugs that have been associated with liver injury are avoided. (See "Drug-induced liver injury".)
The National Institutes of Health maintains a searchable database of drugs and dietary supplements that have been associated with drug-induced liver injury (DILI).
●Abstain from alcohol – We advise patients with hepatic ductopenia to abstain from alcohol.
●Manage symptoms – Pruritus is a characteristic cholestatic symptom in patients with bile duct loss, and the approach to management is discussed separately. (See "Pruritus associated with cholestasis".)
●Lifestyle modifications – We advise patients to maintain an ideal body weight through dietary therapy and exercise. Lifestyle interventions to promote weight loss and maintain ideal body weight are discussed separately. (See "Obesity in adults: Overview of management".)
●Immunizations – Vaccinations for hepatitis A virus and hepatitis B virus are given to patients without serologic evidence of immunity. Additional vaccines for patients with chronic liver disease include pneumococcal vaccination and immunizations that are given to the general population (eg, influenza) (figure 1 and figure 2). Immunization schedules are described separately. (See "Immunizations for adults with chronic liver disease", section on 'Vaccines in chronic liver disease'.)
●Hepatology consultation – We suggest that patients with hepatic ductopenia and VBDS are referred to a hepatologist for long-term management.
Defining severity of ductopenia — The management of patients with histologic evidence of hepatic ductopenia is guided by the severity of bile duct loss, provided that the pathologic specimen contained at least 10 portal tracts [9]:
●Nonsevere hepatic ductopenia – Loss of interlobular bile ducts in 25 to 50 percent of portal tracts
●Severe hepatic ductopenia (also referred to as VBDS) – Loss of interlobular bile ducts in >50 percent of portal tracts
Patients with nonsevere ductopenia — Patients with nonsevere idiopathic ductopenia are initially managed with supportive measures only, based mainly on clinical experience as published data have been limited. (See 'Measures for all patients' above and 'Patients with severe ductopenia (vanishing bile duct syndrome)' below.)
Patients are monitored with liver biochemical tests (ie, alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, total bilirubin) every one to three months until alkaline phosphatase is <2 times the upper limit of normal. For patients with nonsevere ductopenia who do not have improvement in alkaline phosphatase within one to three months, ursodeoxycholic acid (UDCA) is typically initiated, similar to treatment for severe ductopenia (vanishing bile duct syndrome). (See 'Patients with severe ductopenia (vanishing bile duct syndrome)' below.)
Patients with severe ductopenia (vanishing bile duct syndrome)
Initial therapy — For patients with severe ductopenia without a clear etiology, initial therapy is UDCA at a total daily dose of 13 to 15 mg/kg orally and usually administered twice daily. Improvement in symptoms (eg, pruritus) is typically observed shortly after starting UDCA, while liver biochemical tests (ie, alkaline phosphatase) may remain chronically elevated.
After initiating therapy, liver biochemical testing (ie, ALT, AST, alkaline phosphatase and total bilirubin) is performed at one to three-month intervals. UDCA should be continued until alkaline phosphatase is <2 times the upper limit of normal. When cholestasis has resolved, we gradually taper UDCA over two to three months. After UDCA is discontinued, we monitor liver biochemical tests for an additional three to six months.
Patients without improvement in alkaline phosphatase despite UDCA therapy are monitored for long-term complications of cholestasis (eg, fat-soluble vitamin deficiency, metabolic bone disease) and for progression to biliary cirrhosis. (See 'Subsequent management' below.)
UDCA is generally well-tolerated with few adverse effects (eg, modest weight gain [approximately 3 kg]) [36].
Data supporting UDCA as pharmacologic therapy for VBDS are limited to few case reports that have described improvement in symptoms and liver biochemical tests for patients with severe ductopenia associated with DILI [3,37,38]. However, the impact of UDCA on disease progression is unknown. Cholestyramine, a drug that is commonly used for pruritus, may decrease the bioavailability of UDCA secondary to intraluminal binding; thus, these drugs should be given at separate intervals. (See "Pruritus associated with cholestasis".)
UDCA, a hydrophilic bile acid, is thought to exert its beneficial effects in cholestatic liver disorders through several mechanisms of action including [39-41]:
●Increased hydrophilic index of the circulating bile acid pool
●Stimulation of hepatocellular and ductular secretions
●Cytoprotection against hydrophobic bile acid- and cytokine-induced injury
●Immunomodulation and anti-inflammatory effects
Subsequent management — Patients who do not have liver biochemical improvement with UDCA or who develop progressive debilitating symptoms (eg, pruritus) are monitored by a hepatologist with a focus on symptomatic relief and anticipating complications. (See "Pruritus associated with cholestasis".)
Patients are monitored for signs of disease progression (eg, jaundice, complications of portal hypertension such as ascites, variceal bleeding) and for complications of chronic cholestasis (eg, fat soluble vitamin deficiency, metabolic bone disease). For patients with idiopathic ductopenia, management of cholestasis-related complications is similar to the approach for patients with cholestasis related to primary biliary cholangitis, and this is discussed separately. (See "Overview of the management of primary biliary cholangitis", section on 'Complications'.)
Patients with chronic cholestasis who progress to decompensated cirrhosis should be referred for liver transplantation evaluation. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Decompensated cirrhosis'.)
Successful liver transplantation without disease recurrence has been described in adult patients with idiopathic ductopenia [42]. The selection of patients for liver transplantation and the pretransplant evaluation are discussed separately. (See "Liver transplantation in adults: Patient selection and pretransplantation evaluation".)
Investigational therapies — The use of immunosuppressive agents (eg, glucocorticoids, tacrolimus) for treating VBDS and chronic cholestasis has been reported [35,43]. The rationale for using immunosuppression has been that several etiologies of ductopenia appear to be related to an immune-mediated cause. (See 'Immune-mediated disorders' above.)
However, we do not typically use immunosuppressive agents because the benefit remains uncertain, while there may be exceptions to this approach (eg, patients with intractable pruritus who have not responded to UDCA, patients with histologic features suggestive of immune-mediated pathology).
PROGNOSIS — The natural history of acquired bile duct loss resulting in hepatic ductopenia has often been unpredictable and has been described as two potential outcomes [23]:
●Gradual recovery – Biliary epithelial regeneration and resolution of symptoms typically occurs gradually over a period of months to years. Bile duct loss may be reversible and is preceded by a ductular proliferation, followed by reappearance of bile ducts [28,31].
●Irreversible bile duct loss – Progressive, irreversible bile duct loss leads to extensive ductopenia, biliary obstruction, and cirrhosis.
For some patients, idiopathic ductopenia has been associated with a poor prognosis. Small case series have suggested that up to 50 percent of patients with idiopathic severe ductopenia progress to liver failure requiring liver transplantation [27,30,34]. However, some patients appear to progress slowly (eg, over >10 years) [32]. The development of decompensated cirrhosis reflects progressive biliary obstruction and the development of secondary biliary cirrhosis. (See "Cirrhosis in adults: Overview of complications, general management, and prognosis", section on 'Decompensated cirrhosis'.)
Limited data have suggested that the prognosis may be more favorable for patients with nonsevere hepatic ductopenia on liver biopsy or who are diagnosed after age 40 years [30,44]. (See 'Defining severity of ductopenia' above.)
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: Drug-induced liver injury".)
SUMMARY AND RECOMMENDATIONS
●Background – Vanishing bile duct syndrome (VBDS) is an uncommon, acquired, but potentially serious form of cholestatic liver disease. Hepatic ductopenia (a pathologic description; also designated as bile duct paucity) refers to a reduction in the number of intrahepatic bile ducts, a process that may lead to cholestasis. VBDS is manifested histologically by severe hepatic ductopenia, defined as a loss of the intralobular bile ducts in >50 percent of small portal tracts. (See 'Introduction' above.)
●Clinical features – Some patients with hepatic ductopenia may be asymptomatic, while others may have symptoms of cholestasis such a jaundice, pruritus, and fatigue. Laboratory abnormalities generally reflect cholestasis with elevations in alkaline phosphatase (often >3 times the upper limit of normal), total bilirubin, and gamma-glutamyl transpeptidase. Moderate elevations in serum aminotransferases (alanine aminotransferase and aspartate aminotransferase) may also be present, but are rarely >10 times the upper limit of normal. (See 'Clinical features' above.)
●Evaluation – For patients with suspected VBDS, the evaluation includes history and physical examination, laboratory studies, imaging to exclude extrahepatic biliary obstruction, and liver biopsy. Goals of the diagnostic evaluation are to identify an underlying cause of intrahepatic cholestasis, exclude extrahepatic biliary obstruction, establish the diagnosis of VBDS, and determine the severity of bile duct loss. (See 'Evaluation' above.)
●Diagnosis – The diagnosis of VBDS is established by histologic examination acquired through liver biopsy and by excluding other conditions (eg, extrahepatic biliary obstruction) with imaging tests. VBDS is defined as loss of interlobular bile ducts in >50 percent of portal tracts, provided that the histologic specimen contained at least 10 portal tracts. (See 'Diagnosis' above.)
●Management – For patients with evidence of cholestasis and hepatic ductopenia (loss of ≥25 percent of intrahepatic small bile ducts on liver biopsy) without a clear cause identified on laboratory testing, imaging, or liver histology, general measures include (algorithm 1) (see 'Measures for all patients' above):
•Manage symptoms that are associated with cholestasis (eg, pruritus) (see "Pruritus associated with cholestasis").
•Avoid drugs associated with liver injury.
•Abstain from alcohol.
•Maintain ideal body weight through dietary therapy and exercise.
•Vaccinations for hepatitis A virus and hepatitis B virus are given to patients without serologic evidence of immunity. (See "Immunizations for adults with chronic liver disease", section on 'Vaccines in chronic liver disease'.)
•Hepatology consultation for long-term management.
For patients with severe idiopathic ductopenia (ie, VBDS), we suggest ursodeoxycholic acid (UDCA) as first-line therapy rather than supportive measures alone (Grade 2C). UDCA has been associated with improvement in liver biochemistries and symptoms. UDCA at a total daily dose of 13 to 15 mg/kg is typically administered in two divided doses and is continued until alkaline phosphatase is <2 times the upper limit of normal. (See 'Initial therapy' above.)
●Prognosis – The natural history of hepatic ductopenia has been described as two potential outcomes: gradual recovery that typically occurs over months to years, or progressive, irreversible bile duct loss that may lead to biliary obstruction and cirrhosis. (See 'Prognosis' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Donald Jensen, MD, who contributed to an earlier version of this topic review.
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