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EASL Clinical Practice Guidelines: Management of cholestatic liver diseases

      Keywords

      Abbreviations:

      AIH (autoimmune hepatitis), AIP (autoimmune pancreatitis), AMA (antimitochondrial antibodies), AP (alkaline phosphatase in serum), ASMA (anti-smooth muscle antibodies), BRIC (benign recurrent intrahepatic cholestasis), CCA (cholangiocarcinoma), CF (cystic fibrosis), CFALD (cystic fibrosis-associated liver disease), CPG (Clinical Practice Guidelines), CT (computed tomography), DILI (drug-induced liver injury), EASL (European Association for the Study of the Liver), ERCP (endoscopic retrograde cholangiopancreatography), EUS (endoscopic ultrasound), FDG-PET ((18F)-fluoro-deoxy-d-glucose positron emission tomography), FXR (farnesoid X receptor), γGT (γ-glutamyltranspeptidase in serum), HCC (hepatocellular carcinoma), IAC (immunoglobulin G4-associated cholangitis), IAIHG (International Autoimmune Hepatitis Group), IBD (inflammatory bowel disease), IgG (immunoglobulin G in serum), IgG4 (immunoglobulin G4 in serum), MRCP (magnetic resonance cholangiopancreatography), NASH (non-alcoholic steatohepatitis), PBC (primary biliary cirrhosis), PDC-E2 (E2 subunit of the pyruvate dehydrogenase complex), PSC (primary sclerosing cholangitis), PIIINP (procollagen-3-aminoterminal propeptide), UC (ulcerative colitis), ULN (upper limit of normal), US (ultrasound)

      1. Introduction

      EASL Clinical Practice Guidelines (CPG) on the management of cholestatic liver diseases define the use of diagnostic, therapeutic and preventive modalities, including non-invasive and invasive procedures, in the management of patients with cholestatic liver diseases. They are intended to assist physicians and other healthcare providers as well as patients and interested individuals in the clinical decision-making process by describing a range of generally accepted approaches for the diagnosis, treatment and prevention of specific cholestatic liver diseases. The clinical care for patients with cholestatic liver diseases has advanced considerably during recent decades thanks to growing insight into pathophysiological mechanisms and remarkable methodological and technical developments in diagnostic procedures as well as therapeutic and preventive approaches. Still, various aspects in the care of patients with cholestatic disorders remain incompletely resolved. The EASL CPG on the management of cholestatic liver diseases aim to provide current recommendations on the following issues:
      • Diagnostic approach to the cholestatic patient.
      • Diagnosis and treatment of primary biliary cirrhosis (PBC).
      • Diagnosis and treatment of PBC–autoimmune hepatitis (AIH) overlap syndrome.
      • Diagnosis and treatment of primary sclerosing cholangitis (PSC).
      • Diagnosis and treatment of PSC–AIH overlap syndrome.
      • Diagnosis and treatment of immunoglobulin G4-associated cholangitis (IAC).
      • Diagnosis and treatment of drug-induced cholestatic liver diseases.
      • Diagnosis and treatment of genetic cholestatic liver diseases.
      • Diagnosis and treatment of cholestatic liver diseases in pregnancy.
      • Treatment of extrahepatic manifestations of cholestatic liver diseases.
      A panel of experts selected by the EASL Governing Board in May 2008 wrote and discussed these guidelines between June and November 2008. These guidelines have been produced using evidence from PubMed and Cochrane database searches before 1 October, 2008. Where possible, the level of evidence and recommendation are cited (Table 1a, Table 1b). The evidence and recommendations in these guidelines have been graded according to the Grading of Recommendations Assessment Development and Evaluation (GRADE system) [
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • Kunz R.
      • Falck-Ytter Y.
      • Alonso-Coello P.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      ]. The strength of recommendations thus reflects the quality of underlying evidence which has been classified in one of three levels: high [A], moderate [B] or low-quality evidence [C]. The GRADE system offers two grades of recommendation: strong [
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • Kunz R.
      • Falck-Ytter Y.
      • Alonso-Coello P.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      ] or weak [
      • Chazouillères O.
      • Housset C.
      Intrahepatic cholestasis.
      ] (Table 1b). The CPG thus consider the quality of evidence: the higher, the more likely a strong recommendation is warranted; the greater the variability in values and preferences, or the greater the uncertainty, the more likely a weaker recommendation is warranted. Where no clear evidence exists, guidance is based on the consensus advice of expert opinion in the literature and the writing committee.
      Table 1aCategories of evidence.
      GradeEvidence
      IRandomized controlled trials
      II-1Controlled trials without randomization
      II-2Cohort or case-control analytic studies
      II-3Multiple time series, dramatic uncontrolled experiments
      IIIOpinions of respected authorities, descriptive epidemiology
      Table 1bEvidence grading (adapted from the GRADE system
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • Kunz R.
      • Falck-Ytter Y.
      • Alonso-Coello P.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      ).
      EvidenceNotes
      High qualityFurther research is very unlikely to change our confidence in the estimate of effectA
      Moderate qualityFurther research is likely to have an important impact on our confidence in the estimate of effect and may change the estimateB
      Low qualityFurther research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Any change of estimate is uncertainC
      Recommendation
      StrongFactors influencing the strength of the recommendation included the quality of the evidence, presumed patient-important outcomes, and cost1
      WeakVariability in preferences and values, or more uncertainty. Recommendation is made with less certainty, higher cost or resource consumption2

      2. Diagnostic approach to cholestasis

      Cholestasis is an impairment of bile formation and/or bile flow which may clinically present with fatigue, pruritus and, in its most overt form, jaundice. Early biochemical markers in often asymptomatic patients include increases in serum alkaline phosphatase (AP) and γ-glutamyltranspeptidase (γGT) followed by conjugated hyperbilirubinemia at more advanced stages. Cholestasis may be classified as intrahepatic or extrahepatic. Intrahepatic cholestasis may result from hepatocellular functional defects or from obstructive lesions of the intrahepatic biliary tract distal from bile canaliculi. Cholestasis may also be related to mixed mechanisms in diseases such as lymphoma [
      • Chazouillères O.
      • Housset C.
      Intrahepatic cholestasis.
      ]. By convention, cholestasis is considered chronic if it lasts >6 months. Most chronic cholestatic diseases are purely intrahepatic, whereas sclerosing cholangitis may affect small and large intrahepatic and/or extrahepatic bile ducts. Asymptomatic patients are generally identified when routine laboratory tests are being performed or during work-up for another disease when an increase is noted in the serum level of AP and/or γGT. Isolated serum γGT elevation has little specificity for cholestasis, and may also result from enzyme induction in response to alcohol or drug intake. Isolated serum AP elevation is seen in cholestatic liver diseases including certain rare disorders (e.g., progressive familial intrahepatic cholestasis (PFIC) 1 & 2, bile acid synthesis defects), but may also result from rapid bone growth (e.g., in children), bone disease (e.g., Paget’s disease), or pregnancy. The cut-off levels of serum AP and γGT requiring diagnostic work-up are debated: AP levels higher than 1.5 times the upper limit of normal (ULN) and γGT levels >3× ULN have been proposed. The differential diagnosis of cholestatic disorders can be wide (Table 2a, Table 2b). Nevertheless, the first critical step is to differentiate intra- and extrahepatic cholestasis.
      Table 2aCauses of intrahepatic cholestasis in adulthood.
      Hepatocellular cholestasis
      Sepsis-, endotoxemia-induced cholestasis
      Cholestatic variety of viral hepatitis
      Alcoholic or non-alcoholic steatohepatitis
      Drug- or parenteral nutrition-induced cholestasis
      Genetic disorders: e.g., BRIC, PFIC, ABCB4 deficiency, intrahepatic cholestasis of pregnancy (ICP), erythropoietic protoporphyria
      Malignant infiltrating disorders: e.g., hematologic diseases, metastatic cancer
      Benign infiltrating disorders: e.g., amyloidosis, sarcoidosis hepatis and other granulomatoses, storage diseases
      Paraneoplastic syndromes: e.g., Hodgkin disease, renal carcinoma
      Ductal plate malformations: e.g., congenital hepatic fibrosis
      Nodular regenerative hyperplasia
      Vascular disorders: e.g., Budd–Chiari syndrome, veno-occlusive disease, congestive hepatopathy
      Cirrhosis (any cause)
      Cholangiocellular cholestasis
      Primary biliary cirrhosis (AMA+/AMA−)
      Primary sclerosing cholangitis
      Overlap syndromes of PBC and PSC with AIH
      IgG4-associated cholangitis
      Idiopathic adulthood ductopenia
      Ductal plate malformations: biliary hamartoma, Caroli syndrome Cystic fibrosis
      Drug-induced cholangiopathy
      Graft vs. host disease
      Secondary sclerosing cholangitis: e.g., due to various forms of cholangiolithiasis, ischemic choangiopathies (hereditary hemorragic telangiectasia, polyarteritis nodosa and other forms of vasculitis), infectious cholangitis related to AIDS and other forms of immunodepression, etc.
      Table 2bCauses of intrahepatic cholestasis in infancy and childhood
      • Chazouillères O.
      • Housset C.
      Intrahepatic cholestasis.
      .
      Metabolic disease
       – with biliary tract involvement: α1-antitrypsin storage disease, cystic fibrosis
       – without biliary tract involvement: galactosemia, tyrosinemia, fatty acid oxidation defects, lipid and glycogen storage disorders, peroxisomal disorders
       – specific defects in biliary function:
        disorders of bile acid biosynthesis and conjugation
        disorders of canalicular secretion (PFIC)
      Paucity of bile ducts
       – syndromic: Alagille syndrome (Jagged 1 defect)
       – non-syndromic
      Ductal plate malformations
      Infections: bacterial, viral
      Toxic: parenteral nutrition, drugs
      Idiopathic neonatal hepatitis
      Cirrhosis (any cause)
      Careful patient history and physical examination are essential in the diagnostic process and may provide valuable information so that an experienced clinician can predict the nature of cholestasis in many cases [
      • Heathcote E.J.
      Diagnosis and management of cholestatic liver disease.
      ]. Presence of extrahepatic diseases has to be recorded. A thorough occupational and drug history is imperative and any medications taken within 6 weeks of presentation may be incriminated (and discontinued); this includes herbal medicines, vitamins and other substances. A history of fever, especially when accompanied by rigors or right upper quadrant abdominal pain is suggestive of cholangitis due to obstructive diseases (particularly choledocholithiasis), but may be seen in alcoholic disease and rarely, viral hepatitis. A history of prior biliary surgery also increases the likelihood that biliary obstruction is present. Finally, a family history of cholestatic liver disease suggests a possibility of a hereditary disorder. Some cholestatic disorders are observed only under certain circumstances (e.g., pregnancy, childhood, liver transplantation, HIV-infection), and may require specific investigations that are not relevant in other populations.
      Abdominal ultrasonography is usually the first step to exclude dilated intra- and extrahepatic ducts and mass lesions because it is rather sensitive and specific, non-invasive, portable and relatively inexpensive. Its disadvantages are that its findings are operator-dependent and abnormalities of bile ducts such as those observed in sclerosing cholangitis may be missed. Furthermore, the lower common bile duct and pancreas are usually not well depicted. Computed tomography of the abdomen is less interpreter-dependent, but is associated with radiation exposure and may be not as good as ultrasound at delineating the biliary tree.
      If bile duct abnormalities are present, further work-up depends on the presumed cause. From a purely diagnostic perspective, magnetic resonance cholangiopancreatography (MRCP) is a safe option to explore the biliary tree. Its accuracy for detecting biliary tract obstruction approaches that of endoscopic retrograde cholangiopancreatography (ERCP) when performed in experienced centres with state-of-the-art technology. Endoscopic ultrasound (EUS) is equivalent to MRCP in the detection of bile duct stones and lesions causing extrahepatic obstruction and may be preferred to MRCP in endoscopic units.
      Extrahepatic biliary obstruction may be caused by stones, tumours, cysts, or strictures. The gold standard for visualizing the biliary tract and treating extrahepatic biliary obstruction is endoscopic retrograde cholangiopancreatography (ERCP), but even in experienced hands it carries a significant complication rate (pancreatitis in 3–5% of cases; when combined with sphincterotomy, bleeding 2%, cholangitis 1%, procedure-related mortality 0.4% [
      • Freeman M.L.
      • Nelson D.B.
      • Sherman S.
      • Haber G.B.
      • Herman M.E.
      • Dorsher P.J.
      • et al.
      Complications of endoscopic biliary sphincterotomy.
      ]). Thus, when extrahepatic obstruction is considered and the need for endoscopic intervention is unclear, MRCP or EUS should be performed in order to avoid ERCP if it is not needed [
      • Heathcote E.J.
      Diagnosis and management of cholestatic liver disease.
      ].
      If imaging studies do not demonstrate mechanical obstruction, a diagnosis of intrahepatic cholestasis can be reasonably made. However, in an individual whose history suggests an extrahepatic cause (like early pancreatic or ampullary carcinoma), clinical judgment should be pursued and repeat ultrasound or another imaging procedure should be performed [
      • Heathcote E.J.
      Diagnosis and management of cholestatic liver disease.
      ].
      When extrahepatic obstruction has been reasonably excluded, further work-up of intrahepatic cholestasis (Table 2a, Table 2b) depends on the clinical setting.
      In adult patients with chronic intrahepatic cholestasis, the next step is testing for serum antimitochondrial antibodies (AMA) since the diagnosis of PBC, which is the major cause of small-duct biliary diseases [
      • Ludwig J.
      Idiopathic adulthood ductopenia: an update.
      ], can be made with confidence in a patient with high-titer AMA (⩾1/40) and a cholestatic serum enzyme profile in the absence of an alternative explanation [
      • Heathcote E.J.
      Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines.
      ]. A liver biopsy may still be appropriate in selected patients. If AMA and PBC-specific antinuclear antibodies (ANA) are negative, MRCP (in a specialized centre) may be the next diagnostic step for most patients with chronic intrahepatic cholestasis of unknown cause.
      Subsequently, a liver biopsy should be performed when the diagnosis is still unclear. Particular attention to the condition of bile ducts is critical in the histologic evaluation and a biopsy of adequate quality should contain ⩾10 portal fields because of the high degree of sampling variability in patients with small bile duct disease. Biopsy findings should be classified under (i) disorders involving bile ducts (for typical biliary lesions, see Table 3) the main causes being AMA-negative PBC, isolated small duct PSC, ABCB4 deficiency, sarcoidosis, idiopathic ductopenia or prolonged drug-induced cholestasis; (ii) disorders not involving bile ducts, the main causes being a variety of storage or infiltrative liver diseases, hepatic granulomas (without cholangitis), nodular regenerative hyperplasia, peliosis, sinusoidal dilatation and cirrhosis; and (iii) hepatocellular cholestasis with only minimal histologic abnormalities as observed in benign recurrent intrahepatic cholestasis (BRIC), estrogen or anabolic steroid therapy, sepsis, total parenteral nutrition or as a paraneoplastic phenomenon.
      Table 3Typical biliary lesions and their main causes (liver transplant setting excluded)
      • Chazouillères O.
      • Housset C.
      Intrahepatic cholestasis.
      .
      1. Nonsuppurative destructive cholangitis
        Primary biliary cirrhosis
        Primary sclerosing cholangitis
        Autoimmune hepatitis
        Drug-induced cholangitis
        Sarcoidosis
        ABCB4 deficiency
        (Hepatitis C, B, E)
      2. Fibrous obliterative cholangitis
        Primary sclerosing cholangitis
        Secondary sclerosing cholangitis
        IgG4-associated cholangitis
        Sarcoidosis
      3. Other cholangitis (unusual)
        Malignant cholangitis
        Lymphoma (Hodgkin or non-Hodgkin)
        Systemic mastocytosis
        Langerhans cell histiocytosis
        Neutrophilic cholangitis: neutrophilic dermatosis
      4. Ductal plate malformations
        Biliary hamartomas (von Meyenburg complexes)
        Caroli syndrome
        Congenital hepatic fibrosis
      A general algorithm for evaluating the adult patient with cholestasis is presented in Fig. 1.
      Figure thumbnail gr1
      Fig. 1Diagnostic approach to cholestasis in adult patients. Abbreviations: US, ultrasound; CT, computed tomography; AMA, antimitochondrial antibodies; ANA, antinuclear antibodies; MRCP, magnetic resonance cholangiopancreatography; ERCP, endoscopic retrograde cholangiopancreatography; PBC, primary biliary cirrhosis; SC, sclerosing cholangitis.
      Recommendations
      • 1.
        A detailed history and physical examination are essential (III/C1).
      • 2.
        Ultrasound is the first-line non-invasive imaging procedure in order to differentiate intra- from extrahepatic cholestasis (III/C1).
      • 3.
        Testing for serum antimitochondrial antibodies (AMA) is mandatory in adults with chronic intrahepatic cholestasis (III/C1).
      • 4.
        Magnetic resonance cholangiopancreatography (MRCP) is the next step to be considered in patients with unexplained cholestasis (III/C1).
      • 5.
        Endoscopic ultrasound (EUS) is an alternative to MRCP for evaluation of distal biliary tract obstruction (II-2/B1).
      • 6.
        Diagnostic endoscopic retrograde cholangiopancreatography (ERCP) should be reserved for highly selected cases (II-2/A1). If the need for a therapeutic maneuver is not anticipated, MRCP or EUS should be preferred to ERCP because of the morbidity and mortality related to ERCP (II-2/A1).
      • 7.
        A liver biopsy should be considered in patients with otherwise unexplained intrahepatic cholestasis and a negative AMA test (III/C1).
      • 8.
        Genetic testing for ABCB4 (encoding the canalicular phospholipid export pump), when available, should be considered in patients with a negative AMA test and biopsy findings that might be compatible with PBC or PSC.

      3. Primary biliary cirrhosis (PBC)

      3.1 Diagnosis of PBC

      Patients with PBC may present with symptoms as fatigue, pruritus and/or jaundice, but the majority of them are asymptomatic at diagnosis. At first presentation, very few patients present in advanced stage of disease and with complications of portal hypertension (ascites, hepatic encephalopathy or esophageal variceal bleeding). Currently, a diagnosis of PBC is made with confidence on a combination of abnormal serum liver tests (elevation of AP of liver origin for at least 6 months) and presence of AMA (⩾1:40) in serum [
      • Heathcote E.J.
      Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines.
      ]. The diagnosis is confirmed by disclosing characteristic histological features of florid bile duct lesions. AMA-positive individuals with normal AP carry a high risk to develop PBC during follow-up [
      • Metcalf J.V.
      • Mitchison H.C.
      • Palmer J.M.
      • Jones D.E.
      • Bassendine M.F.
      • James O.F.
      Natural history of early primary biliary cirrhosis.
      ].

      3.1.1 Laboratory tests

      Biochemical markers: Serum AP and γGT are raised in PBC; serum aminotransferases (ALT, AST) and conjugated bilirubin can also be elevated, but are not diagnostic. Patients with normal AP and γGT, but with serological stigmata of PBC, should be reassessed clinically and biochemically at annual intervals. Patients with PBC typically present elevated levels of immunoglobulin M. Serum cholesterol is commonly elevated like in other cholestatic conditions. Alterations in prothrombin time, serum albumin and conjugated bilirubin are observed only in advanced disease.
      Immunological markers: The diagnostic hallmark of PBC is the presence of AMA, which are detected in serum of more than 90% of affected individuals; the specificity of AMA in PBC is greater than 95% [
      • Invernizzi P.
      • Lleo A.
      • Podda M.
      Interpreting serological tests in diagnosing autoimmune liver diseases.
      ]. AMA reactivity is classically studied by immunofluorescence and considered positive at a titre ⩾1/40 [
      • Vergani D.
      • Alvarez F.
      • Bianchi F.B.
      • Cancado E.L.
      • Mackay I.R.
      • Manns M.P.
      • et al.
      Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group.
      ]. The identification of the molecular mitochondrial target antigens has allowed the setting up of immunoenzymatic assays with recombinant proteins that raise the sensitivity and specificity of the test. If available, anti-AMA-M2 (anti-PDC-E2) may be a useful alternative. Non-specific antinuclear antibodies (ANA) are found in at least 30% of PBC sera. However, ANA directed against nuclear body or envelope proteins such as anti-Sp100 and anti-gp210 which present as multiple [
      • Heathcote E.J.
      Management of primary biliary cirrhosis. The American Association for the Study of Liver Diseases practice guidelines.
      ,
      • Metcalf J.V.
      • Mitchison H.C.
      • Palmer J.M.
      • Jones D.E.
      • Bassendine M.F.
      • James O.F.
      Natural history of early primary biliary cirrhosis.
      ,
      • Invernizzi P.
      • Lleo A.
      • Podda M.
      Interpreting serological tests in diagnosing autoimmune liver diseases.
      ,
      • Vergani D.
      • Alvarez F.
      • Bianchi F.B.
      • Cancado E.L.
      • Mackay I.R.
      • Manns M.P.
      • et al.
      Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group.
      ,
      • Ludwig J.
      • Dickson E.R.
      • McDonald G.S.
      Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis).
      ,
      • Scheuer P.J.
      Primary biliary cirrhosis: diagnosis, pathology and pathogenesis.
      ,
      • Beuers U.
      Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis.
      ] nuclear dots and perinuclear rims, respectively, at indirect immunofluorescence staining show a high specificity for PBC (>95%) and can be used as markers of PBC when AMA are absent. Their sensitivity, however, is low.

      3.1.2 Histology

      A liver biopsy is no longer regarded as mandatory to make a diagnosis of PBC in patients with a cholestatic serum enzyme pattern and serum AMA. It may, however, be useful for assessment of the activity and staging of the disease. Histological staging of PBC (stages 1–4) has been proposed by Ludwig et al.[
      • Ludwig J.
      • Dickson E.R.
      • McDonald G.S.
      Staging of chronic nonsuppurative destructive cholangitis (syndrome of primary biliary cirrhosis).
      ] and Scheuer [
      • Scheuer P.J.
      Primary biliary cirrhosis: diagnosis, pathology and pathogenesis.
      ] according to the degree of bile duct damage, inflammation and fibrosis. Focal duct obliteration with granuloma formation has been termed the florid duct lesion, and is judged almost pathognomonic for PBC when present. The liver is not uniformly involved, and features of all four stages of PBC can co-exist simultaneously in a single biopsy. The most advanced histological features should be used for histological staging.

      3.1.3 Imaging

      Abdominal ultrasound examination is indicated in all patients with elevation of serum AP and γGT to disclose intrahepatic or extrahepatic bile duct dilatation (see above) or focal liver lesions. There are no specific features of PBC on ultrasound; in particular the biliary tree appears normal. Ultrasound findings in advanced PBC resemble those seen in other forms of cirrhosis.
      Recommendations
      • 1.
        A diagnosis of PBC can be made with confidence in adult patients with otherwise unexplained elevation of AP and presence of AMA (⩾1:40) and/or AMA type M2. A liver biopsy is not essential for the diagnosis of PBC in these patients, but allows activity and stage of the disease to be assessed (III/A1).
      • 2.
        A liver biopsy is needed for the diagnosis of PBC in the absence of PBC specific antibodies. A liver biopsy may also be helpful in the presence of disproportionally elevated serum transaminases and/or serum IgG levels to identify additional or alternative processes (III/C1).
      • 3.
        AMA-positive individuals with normal serum liver tests should be followed with annual reassessment of biochemical markers of cholestasis (III/C2).

      3.2 Treatment of PBC

      3.2.1 Ursodeoxycholic acid (UDCA)

      Over the past two decades, increasing evidence has accumulated indicating that ursodeoxycholic acid (UDCA; 13–15 mg/kg/d) is the treatment of choice for patients with PBC based on placebo-controlled trials and more recent long-term case-control studies. UDCA has been demonstrated to exert anticholestatic effects in various cholestatic disorders. Several potential mechanisms and sites of action of UDCA have been unraveled in clinical and experimental studies which might explain its beneficial effects. Their relative contribution to the anticholestatic action of UDCA might depend on the type of the cholestatic injury. In early-stage PBC, protection of injured cholangiocytes against the toxic effects of bile acids might prevail, and stimulation of impaired hepatocellular secretion by mainly posttranscriptional mechanisms including stimulation of synthesis, targeting and apical membrane insertion of key transporters might be relevant in more advanced cholestasis [
      • Beuers U.
      Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis.
      ]. In addition, stimulation of ductular alkaline choleresis and inhibition of bile acid-induced hepatocyte and cholangiocyte apoptosis can have a certain role for the beneficial effect of UDCA in PBC [
      • Beuers U.
      Drug insight: mechanisms and sites of action of ursodeoxycholic acid in cholestasis.
      ].
      UDCA has been demonstrated to markedly decrease serum bilirubin, AP, γGT, cholesterol and immunoglobulin M levels, and to ameliorate histological features in patients with PBC in comparison to placebo treatment [
      • Poupon R.E.
      • Balkau B.
      • Eschwege E.
      • Poupon R.
      A multicenter, controlled trial of ursodiol for the treatment of primary biliary cirrhosis. UDCA-PBC Study Group.
      ,
      • Heathcote E.J.
      • Cauch-Dudek K.
      • Walker V.
      • Bailey R.J.
      • Blendis L.M.
      • Ghent C.N.
      • et al.
      The Canadian Multicenter Double-blind Randomized Controlled Trial of ursodeoxycholic acid in primary biliary cirrhosis.
      ,
      • Lindor K.D.
      • Dickson E.R.
      • Baldus W.P.
      • Jorgensen R.A.
      • Ludwig J.
      • Murtaugh P.A.
      • et al.
      Ursodeoxycholic acid in the treatment of primary biliary cirrhosis.
      ,
      • Combes B.
      • Carithers Jr., R.L.
      • Maddrey W.C.
      • Lin D.
      • McDonald M.F.
      • Wheeler D.E.
      • et al.
      A randomized, double-blind, placebo-controlled trial of ursodeoxycholic acid in primary biliary cirrhosis.
      ,
      • Pares A.
      • Caballeria L.
      • Rodes J.
      • Bruguera M.
      • Rodrigo L.
      • Garcia-Plaza A.
      • et al.
      Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver.
      ] although no significant effects on fatigue or pruritus were observed in these large trials. Moreover, long-term treatment with UDCA delayed the histological progression of the disease in patients in whom treatment was started at an early stage [
      • Pares A.
      • Caballeria L.
      • Rodes J.
      • Bruguera M.
      • Rodrigo L.
      • Garcia-Plaza A.
      • et al.
      Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial. UDCA-Cooperative Group from the Spanish Association for the Study of the Liver.
      ,
      • Corpechot C.
      • Carrat F.
      • Bonnand A.M.
      • Poupon R.E.
      • Poupon R.
      The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis.
      ]. Still, a clear-cut beneficial effect of UDCA on survival has not been shown in any of the studies mentioned above, probably due to the limited number of patients and the limited observation periods too short for a slowly progressing disease. A beneficial effect of UDCA on survival has only been demonstrated in a combined analysis of the raw data from the French, Canadian and Mayo cohorts followed up for 4 years [
      • Poupon R.E.
      • Lindor K.D.
      • Cauch-Dudek K.
      • Dickson E.R.
      • Poupon R.
      • Heathcote E.J.
      Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis.
      ]. In this analysis, UDCA treatment was associated with a significant reduction in the likelihood of liver transplantation or death. This benefit was seen in patients with moderate and severe disease but not in those with mild disease (serum bilirubin concentration <1.4 mg/dL (24 μmol/L), stage I or II histologic change) in whom progression to end-stage disease did not occur during the 4-year period of observation [
      • Poupon R.E.
      • Lindor K.D.
      • Cauch-Dudek K.
      • Dickson E.R.
      • Poupon R.
      • Heathcote E.J.
      Combined analysis of randomized controlled trials of ursodeoxycholic acid in primary biliary cirrhosis.
      ].
      The affirmative results on survival have been challenged by meta-analyses which included a majority of studies of up to two years’ duration and trials using UDCA doses which are today known to be ineffective [
      • Goulis J.
      • Leandro G.
      • Burroughs A.
      Randomised controlled trials of ursodeoxycholic-acid therapy for primary biliary cirrhosis: a meta-analysis.
      ,
      • Gong Y.
      • Huang Z.
      • Christensen E.
      • Gluud C.
      Ursodeoxycholic acid for patients with primary biliary cirrhosis: an updated systematic review and meta-analysis of randomized clinical trials using Bayesian approach as sensitivity analyses.
      ]. Inclusion of trials which have a duration of three months to two years for a disease with an estimated duration of one to two decades without intervention may be suited to analyze biochemical effects of medical treatment, but certainly carries a risk to dilute the information needed for a well-based survival analysis. Therefore, it was not surprising that meta-analyses which excluded studies of short duration (less than 24 months) and those that used an ineffective dose of UDCA (less than 10 mg/kg/d) concluded that long-term UDCA significantly improved transplant-free survival and delayed histologic progression in early-stage patients [
      • Shi J.
      • Wu C.
      • Lin Y.
      • Chen Y.X.
      • Zhu L.
      • Xie W.F.
      Long-term effects of mid-dose ursodeoxycholic acid in primary biliary cirrhosis: a meta-analysis of randomized controlled trials.
      ,
      • Lindor K.D.
      • Poupon R.
      • Heathcote E.J.
      • Therneau T.
      Ursodeoxycholic acid for primary biliary cirrhosis.
      ].
      Recent reports have demonstrated the favorable effects of UDCA on long-term survival in patients with PBC receiving standard doses (13–15 mg/kg/d) [
      • Angulo P.
      • Dickson E.R.
      • Therneau T.M.
      • Jorgensen R.A.
      • Smith C.
      • DeSotel C.K.
      • et al.
      Comparison of three doses of ursodeoxycholic acid in the treatment of primary biliary cirrhosis: a randomized trial.
      ] over 10–20 years. Treatment with UDCA led to a transplant-free survival similar to that of a healthy control population matched for age and gender in patients with early-stage disease [
      • Corpechot C.
      • Carrat F.
      • Bahr A.
      • Chretien Y.
      • Poupon R.E.
      • Poupon R.
      The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis.
      ,
      • ter Borg P.C.
      • Schalm S.W.
      • Hansen B.E.
      • van Buuren H.R.
      Prognosis of ursodeoxycholic acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients.
      ] and to improved survival in comparison to the estimated survival at the start of treatment as calculated by the Mayo risk score for PBC [
      • Corpechot C.
      • Carrat F.
      • Bahr A.
      • Chretien Y.
      • Poupon R.E.
      • Poupon R.
      The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis.
      ,
      • ter Borg P.C.
      • Schalm S.W.
      • Hansen B.E.
      • van Buuren H.R.
      Prognosis of ursodeoxycholic acid-treated patients with primary biliary cirrhosis. Results of a 10-yr cohort study involving 297 patients.
      ,
      • Pares A.
      • Caballeria L.
      • Rodes J.
      Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid.
      ]. Interestingly, a “good biochemical response” to UDCA defined as a decrease in AP >40% of pretreatment levels or normalization at one year (“Barcelona criteria”) was associated with an excellent 95% transplant-free survival at 14 years of follow-up, similar to that predicted for the standardized population [
      • Pares A.
      • Caballeria L.
      • Rodes J.
      Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic acid.
      ]. The prognostic impact of the “Barcelona criteria” was confirmed in a large independent cohort of PBC patients for which a serum bilirubin ⩽1 mg/dL (17 μmol/L), AP ⩽3× ULN, and AST ⩽2× ULN (“Paris criteria”) after one year of treatment even better identified those with a good long-term prognosis of a 90% (vs. 51%) ten year transplant-free survival [
      • Corpechot C.
      • Abenavoli L.
      • Rabahi N.
      • Chretien Y.
      • Andreani T.
      • Johanet C.
      • et al.
      Biochemical response to ursodeoxycholic acid and long-term prognosis in primary biliary cirrhosis.
      ]. Thus, additional therapeutic options for those patients failing to reach a “good biochemical response” under UDCA are warranted.

      3.2.2 Corticosteroids and other immunosuppressive agents

      Prednisolone improved serum liver tests and histological features, but markedly worsened bone mineral density in patients with PBC [
      • Mitchison H.C.
      • Bassendine M.F.
      • Malcolm A.J.
      • Watson A.J.
      • Record C.O.
      • James O.F.
      A pilot, double-blind, controlled 1-year trial of prednisolone treatment in primary biliary cirrhosis: hepatic improvement but greater bone loss.
      ] prohibiting its long-term use in PBC. In combination with UDCA (10 mg/kg/d), prednisolone (10 mg/d, 9 months) exerted beneficial effects on various features of liver histology in early-stage PBC in comparison to UDCA alone [
      • Leuschner M.
      • Guldutuna S.
      • You T.
      • Hubner K.
      • Bhatti S.
      • Leuschner U.
      Ursodeoxycholic acid and prednisolone versus ursodeoxycholic acid and placebo in the treatment of early stages of primary biliary cirrhosis.
      ].
      Budesonide in combination with UDCA showed favorable results on biochemical and histological parameters in early-stage disease [
      • Leuschner M.
      • Maier K.P.
      • Schlichting J.
      • Strahl S.
      • Herrmann G.
      • Dahm H.H.
      • et al.
      Oral budesonide and ursodeoxycholic acid for treatment of primary biliary cirrhosis: results of a prospective double-blind trial.
      ,
      • Rautiainen H.
      • Karkkainen P.
      • Karvonen A.L.
      • Nurmi H.
      • Pikkarainen P.
      • Nuutinen H.
      • et al.
      Budesonide combined with UDCA to improve liver histology in primary biliary cirrhosis: a three-year randomized trial.
      ], but not late-stage disease [
      • Angulo P.
      • Jorgensen R.A.
      • Keach J.C.
      • Dickson E.R.
      • Smith C.
      • Lindor K.D.
      Oral budesonide in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid.
      ,
      • Hempfling W.
      • Grunhage F.
      • Dilger K.
      • Reichel C.
      • Beuers U.
      • Sauerbruch T.
      Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis.
      ]. Studies with a longer follow-up using the combination of budesonide and UDCA in patients with early-stage disease not adequately responding to UDCA alone are warranted to confirm its safety and its effect on postponing or preventing the need for liver transplantation. Development of portal vein thrombosis probably related to short-term budesonide administration was reported in stage 4 patients with portal hypertension [
      • Hempfling W.
      • Grunhage F.
      • Dilger K.
      • Reichel C.
      • Beuers U.
      • Sauerbruch T.
      Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary biliary cirrhosis.
      ]. Thus, budesonide should not be administered to cirrhotic patients.
      Other immunosuppressive agents like azathioprine [
      • Christensen E.
      • Neuberger J.
      • Crowe J.
      • Altman D.G.
      • Popper H.
      • Portmann B.
      • et al.
      Beneficial effect of azathioprine and prediction of prognosis in primary biliary cirrhosis. Final results of an international trial.
      ], cyclosporine A [
      • Lombard M.
      • Portmann B.
      • Neuberger J.
      • Williams R.
      • Tygstrup N.
      • Ranek L.
      • et al.
      Cyclosporin A treatment in primary biliary cirrhosis: results of a long-term placebo controlled trial.
      ], methotrexate [
      • Hendrickse M.T.
      • Rigney E.
      • Giaffer M.H.
      • Soomro I.
      • Triger D.R.
      • Underwood J.C.
      • et al.
      Low-dose methotrexate is ineffective in primary biliary cirrhosis: long-term results of a placebo-controlled trial.
      ,
      • Gonzalez-Koch A.
      • Brahm J.
      • Antezana C.
      • Smok G.
      • Cumsille M.A.
      The combination of ursodeoxycholic acid and methotrexate for primary biliary cirrhosis is not better than ursodeoxycholic acid alone.
      ,
      • Combes B.
      • Emerson S.S.
      • Flye N.L.
      • Munoz S.J.
      • Luketic V.A.
      • Mayo M.J.
      • et al.
      Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis.
      ], chlorambucil [
      • Hoofnagle J.H.
      • Davis G.L.
      • Schafer D.F.
      • Peters M.
      • Avigan M.I.
      • Pappas S.C.
      • et al.
      Randomized trial of chlorambucil for primary biliary cirrhosis.
      ] and mycophenolate mofetil [
      • Talwalkar J.A.
      • Angulo P.
      • Keach J.C.
      • Petz J.L.
      • Jorgensen R.A.
      • Lindor K.D.
      Mycophenolate mofetil for the treatment of primary biliary cirrhosis in patients with an incomplete response to ursodeoxycholic acid.
      ] proved to be marginally effective, ineffective or potentially harmful during long-term administration and cannot be recommended for standard treatment in PBC.

      3.2.3 Anti-fibrotic agents

      Colchicine was inferior to UDCA in the treatment of PBC [
      • Vuoristo M.
      • Farkkila M.
      • Karvonen A.L.
      • Leino R.
      • Lehtola J.
      • Makinen J.
      • et al.
      A placebo-controlled trial of primary biliary cirrhosis treatment with colchicine and ursodeoxycholic acid.
      ] and did not, when combined with UDCA in comparison to UDCA alone [
      • Poupon R.E.
      • Huet P.M.
      • Poupon R.
      • Bonnand A.M.
      • Nhieu J.T.
      • Zafrani E.S.
      A randomized trial comparing colchicine and ursodeoxycholic acid combination to ursodeoxycholic acid in primary biliary cirrhosis. UDCA–PBC Study Group.
      ], significantly improve symptoms, serum liver tests, serum markers of fibrosis, or histological features. Thus, addition of colchicine to UDCA currently cannot be recommended in the treatment of PBC.
      d-Penicillamine is not effective in PBC and can be associated with severe side effects [
      • Neuberger J.
      • Christensen E.
      • Portmann B.
      • Caballeria J.
      • Rodes J.
      • Ranek L.
      • et al.
      Double blind controlled trial of d-penicillamine in patients with primary biliary cirrhosis.
      ,
      • Gong Y.
      • Klingenberg S.L.
      • Gluud C.
      Systematic review and meta-analysis: d-penicillamine vs. placebo/no intervention in patients with primary biliary cirrhosis–Cochrane Hepato-Biliary Group.
      ].

      3.2.4 Other drugs

      Malotilate [

      The results of a randomized double blind controlled trial evaluating malotilate in primary biliary cirrhosis. A European multicentre study group. J Hepatol 1993;17:227–35.

      ], thalidomide [
      • McCormick P.A.
      • Scott F.
      • Epstein O.
      • Burroughs A.K.
      • Scheuer P.J.
      • McIntyre N.
      Thalidomide as therapy for primary biliary cirrhosis: a double-blind placebo controlled pilot study.
      ], silymarin [
      • Angulo P.
      • Patel T.
      • Jorgensen R.A.
      • Therneau T.M.
      • Lindor K.D.
      Silymarin in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid.
      ] and atorvastatin [
      • Stojakovic T.
      • Putz-Bankuti C.
      • Fauler G.
      • Scharnagl H.
      • Wagner M.
      • Stadlbauer V.
      • et al.
      Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid.
      ] were not effective in the treatment of PBC. Sulindac [
      • Leuschner M.
      • Holtmeier J.
      • Ackermann H.
      • Leuschner U.
      The influence of sulindac on patients with primary biliary cirrhosis that responds incompletely to ursodeoxycholic acid: a pilot study.
      ] and the peroxisome proliferator-activated receptor α (PPARα) agonist, bezafibrate [
      • Iwasaki S.
      • Ohira H.
      • Nishiguchi S.
      • Zeniya M.
      • Kaneko S.
      • Onji M.
      • et al.
      The efficacy of ursodeoxycholic acid and bezafibrate combination therapy for primary biliary cirrhosis: a prospective, multicenter study.
      ] improved some serum liver tests in limited groups of patients with an incomplete response to UDCA, and bezafibrate deserves further studies. Tamoxifen [
      • Invernizzi P.
      • Alvaro D.
      • Crosignani A.
      • Gaudio E.
      • Podda M.
      Tamoxifen in treatment of primary biliary cirrhosis.
      ] decreased AP levels in two women who were taking it after surgery for breast cancer.
      Antiretroviral strategies have also been tested in PBC: Lamivudine alone or in combination with zidovudine (Combivir) was associated with minor clinical and biochemical effects. Combivir was also associated with improvement of some histological features, but this finding needs confirmation in randomized studies [
      • Mason A.L.
      • Farr G.H.
      • Xu L.
      • Hubscher S.G.
      • Neuberger J.M.
      Pilot studies of single and combination antiretroviral therapy in patients with primary biliary cirrhosis.
      ].

      3.2.5 Liver transplantation

      Liver transplantation has dramatically improved survival in patients with late-stage PBC. Indications are not different from those of patients with other etiologies of liver failure [
      • MacQuillan G.C.
      • Neuberger J.
      Liver transplantation for primary biliary cirrhosis.
      ]: decompensated cirrhosis with an unacceptable quality of life or anticipated death within a year due to treatment-resistant ascites and spontaneous bacterial peritonitis, recurrent variceal bleeding, encephalopathy or hepatocellular carcinoma. Severe, treatment-resistant pruritus may merit consideration for transplantation. Patients should be referred to a liver transplant center for assessment when their bilirubin approaches 6 mg/dL (103 μmol/L), the Mayo risk score is ⩾7,8, and the MELD score is >12 at the latest.
      Survival rates above 90% and 80–85% at one and five years, respectively, have been reported by many centers [
      • Milkiewicz P.
      Liver transplantation in primary biliary cirrhosis.
      ]. Most patients have no signs of liver disease after orthotopic liver transplantation, but their antimitochondrial antibody status does not change. The disease recurs with a calculated weighted disease recurrence of 18% [
      • Gautam M.
      • Cheruvattath R.
      • Balan V.
      Recurrence of autoimmune liver disease after liver transplantation: a systematic review.
      ], but rarely is associated with graft failure [
      • MacQuillan G.C.
      • Neuberger J.
      Liver transplantation for primary biliary cirrhosis.
      ].
      Recommendations
      • 1.
        Patients with PBC, including those with asymptomatic disease, should be treated with UDCA (13–15 mg/kg/d) (I/A1) on a long-term basis (II-2/B1).
      • 2.
        Favorable long-term effects of UDCA are observed in patients with early disease and in those with good biochemical response (II-2/B1), which should be assessed after one year. A good biochemical response after one year of UDCA treatment is currently defined by a serum bilirubin ⩽1 mg/dL (17 μmol/L), AP ⩽3× ULN and AST ⩽2× ULN (“Paris criteria”) or by a decrease of 40% or normalization of serum AP (“Barcelona criteria”) (II-2/B1).
      • 3.
        There is currently no consensus on how to treat patients with a suboptimal biochemical response to UDCA. One suggested approach is the combination of UDCA and budesonide (6–9 mg/d) in non-cirrhotic patients (stages 1–3) (III/C2). Further studies of this and other combination regimes should be a priority.
      • 4.
        Liver transplantation should be strongly considered in patients with advanced disease as reflected by serum bilirubin exceeding 6 mg/dL (103 μmol/L) or decompensated cirrhosis with an unacceptable quality of life or anticipated death within a year due to treatment-resistant ascites and spontaneous bacterial peritonitis, recurrent variceal bleeding, encephalopathy or hepatocellular carcinoma (II-2/A1).

      4. PBC–AIH overlap syndrome

      Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) are classically viewed as distinct liver diseases. However, patients presenting with clinical, biochemical, serological, and/or histological features reminiscent of both diseases, either simultaneously or consecutively have been repeatedly recognized. The ill-defined term “overlap syndrome” is used to describe these settings [
      • Chazouilleres O.
      • Wendum D.
      • Serfaty L.
      • Montembault S.
      • Rosmorduc O.
      • Poupon R.
      Primary biliary cirrhosis–autoimmune hepatitis overlap syndrome: clinical features and response to therapy.
      ,
      • Lohse A.W.
      • zum Buschenfelde K.H.
      • Franz B.
      • Kanzler S.
      • Gerken G.
      • Dienes H.P.
      Characterization of the overlap syndrome of primary biliary cirrhosis (PBC) and autoimmune hepatitis: evidence for it being a hepatitic form of PBC in genetically susceptible individuals.
      ,
      • Woodward J.
      • Neuberger J.
      Autoimmune overlap syndromes.
      ,
      • Beuers U.
      • Rust C.
      Overlap syndromes.
      ]. The pathogenesis of PBC–AIH overlap syndrome is debated and it remains unclear whether this syndrome forms a distinct entity or a variant of PBC or AIH. Different pathophysiological mechanisms have been discussed: (i) a pure coincidence of two independent autoimmune diseases; (ii) a different genetic background which determines the clinical, biochemical and histological appearance of one autoimmune disease entity; and (iii) a representation of the middle of a continuous spectrum of two autoimmune diseases [
      • Woodward J.
      • Neuberger J.
      Autoimmune overlap syndromes.
      ,
      • Beuers U.
      • Rust C.
      Overlap syndromes.
      ].

      4.1 Diagnosis

      Standardization of diagnostic criteria for PBC–AIH overlap syndrome has not been achieved so far, and “overlap syndrome” is a much overused descriptive term in hepatology [
      • Heathcote E.J.
      Overlap of autoimmune hepatitis and primary biliary cirrhosis: an evaluation of a modified scoring system.
      ]. Diagnosis of PBC and AIH is based on the combination of biochemical, serological and histological features. However, no individual test shows absolute specificity and much depends on the relative weighting of individual diagnostic criteria, and the cut-off levels of continuous variables considered representative for one or another condition [
      • Woodward J.
      • Neuberger J.
      Autoimmune overlap syndromes.
      ]. The 1999 scoring system, established by the International Autoimmune Hepatitis Group (IAIHG) for research purposes, comprises characteristic features of AIH and provides support for diagnosing AIH [
      • Alvarez F.
      • Berg P.A.
      • Bianchi F.B.
      • Bianchi L.
      • Burroughs A.K.
      • Cancado E.L.
      • et al.
      International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis.
      ]. However, applicability of this scoring system remains questionable in this specific setting since a score of “definite” AIH can be only observed in the very few patients with characteristic overlap syndrome whereas nearly 20% of PBC subjects will be classified with “probable” AIH overlap [
      • Heathcote E.J.
      Overlap of autoimmune hepatitis and primary biliary cirrhosis: an evaluation of a modified scoring system.
      ,
      • Talwalkar J.A.
      • Keach J.C.
      • Angulo P.
      • Lindor K.D.
      Overlap of autoimmune hepatitis and primary biliary cirrhosis: an evaluation of a modified scoring system.
      ,
      • Chazouilleres O.
      • Wendum D.
      • Serfaty L.
      • Rosmorduc O.
      • Poupon R.
      Long term outcome and response to therapy of primary biliary cirrhosis–autoimmune hepatitis overlap syndrome.
      ]. The simplified diagnostic score recently proposed by the IAIHG has not been validated yet in patients with suspected PBC–AIH overlap syndrome [
      • Hennes E.M.
      • Zeniya M.
      • Czaja A.J.
      • Pares A.
      • Dalekos G.N.
      • Krawitt E.L.
      • et al.
      Simplified criteria for the diagnosis of autoimmune hepatitis.
      ]. To differentiate PBC from PBC–AIH overlap syndrome, another diagnostic score has been established but the usefulness of this rather complex score needs confirmation by cross-evaluation prior to introduction to the clinic [
      • Yamamoto K.
      • Terada R.
      • Okamoto R.
      • Hiasa Y.
      • Abe M.
      • Onji M.
      • et al.
      A scoring system for primary biliary cirrhosis and its application for variant forms of autoimmune liver disease.
      ]. Because of the limited applicability of the different diagnostic scores, another approach based on the major characteristics of PBC and AIH has been proposed and requires the presence of at least 2 of the 3 accepted criteria of both diseases for diagnosing PBC–AIH overlap syndrome (Table 4) [
      • Chazouilleres O.
      • Wendum D.
      • Serfaty L.
      • Montembault S.
      • Rosmorduc O.
      • Poupon R.
      Primary biliary cirrhosis–autoimmune hepatitis overlap syndrome: clinical features and response to therapy.
      ] whereby histologic evidence of moderate to severe lymphocytic piecemeal necrosis (interface hepatitis) is mandatory.
      Table 4Diagnostic criteria of PBC–AIH overlap syndrome.
      PBC criteria
      1. AP >2× ULN or γGT >5× ULN
      2. AMA ⩾1:40
      3. Liver biopsy specimen showing florid bile duct lesions
      AIH criteria
      1. ALT >5× ULN
      2. IgG >2× ULN or a positive test for anti-smooth muscle antibodies (ASMA)
      3. Liver biopsy showing moderate or severe periportal or periseptal lymphocytic piecemeal necrosis
      Diagnostic criteria of PBC–AIH overlap syndrome of which at least 2 of 3 accepted criteria for PBC and AIH, respectively, should be present (proposed by Chazouilleres et al.
      • Chazouilleres O.
      • Wendum D.
      • Serfaty L.
      • Montembault S.
      • Rosmorduc O.
      • Poupon R.
      Primary biliary cirrhosis–autoimmune hepatitis overlap syndrome: clinical features and response to therapy.
      ). Histologic evidence of moderate to severe lymphocytic piecemeal necrosis (interface hepatitis) is mandatory for the diagnosis.
      In addition to cases with simultaneous characteristics of PBC and AIH, which is the most frequent mode of presentation, transitions from PBC to AIH or vice-versa have been described and termed “sequential syndromes” or consecutive forms [
      • Poupon R.
      • Chazouilleres O.
      • Corpechot C.
      • Chretien Y.
      Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis.
      ]. Occurrence of superimposed AIH cannot be predicted from baseline characteristics and initial response to UDCA therapy in PBC patients [
      • Poupon R.
      • Chazouilleres O.
      • Corpechot C.
      • Chretien Y.
      Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis.
      ]. Lastly, overlap of AMA-negative PBC with AIH has also been reported [
      • Chazouilleres O.
      • Wendum D.
      • Serfaty L.
      • Montembault S.
      • Rosmorduc O.
      • Poupon R.
      Primary biliary cirrhosis–autoimmune hepatitis overlap syndrome: clinical features and response to therapy.
      ].
      Precise prevalence of PBC–AIH overlap syndrome is unknown but approximately 10% of adults with AIH or PBC may belong in this overlap category [
      • Poupon R.
      • Chazouilleres O.
      • Corpechot C.
      • Chretien Y.
      Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis.
      ,
      • Czaja A.J.
      The variant forms of autoimmune hepatitis.
      ,
      • Rust C.
      • Beuers U.
      Overlap syndromes among autoimmune liver diseases.
      ]. Patients with PBC–AIH overlap syndrome might have a more severe disease with worse clinical outcomes compared to patients with PBC alone [
      • Silveira M.G.
      • Talwalkar J.A.
      • Angulo P.
      • Lindor K.D.
      Overlap of autoimmune hepatitis and primary biliary cirrhosis: long-term outcomes.
      ]. This emphasizes the notion that overlap syndrome should always be considered once PBC has been diagnosed [
      • Czaja A.J.
      The variant forms of autoimmune hepatitis.
      ].

      4.2 Treatment

      The low prevalence of PBC–AIH overlap syndrome has made controlled therapeutic trials impossible in these patients. Thus, therapeutic recommendations rely on the experience in the treatment of either PBC or AIH, and on retrospective, non-randomized studies. Whether PBC–AIH overlap syndrome requires immunosuppressive therapy in addition to UDCA is a debated issue. Under UDCA therapy, biochemical response at 24 months and survival in one cohort of 12 strictly defined PBC–AIH overlap syndrome patients were similar to 159 patients with “pure” PBC [
      • Joshi S.
      • Cauch-Dudek K.
      • Wanless I.R.
      • Lindor K.D.
      • Jorgensen R.
      • Batts K.
      • et al.
      Primary biliary cirrhosis with additional features of autoimmune hepatitis: response to therapy with ursodeoxycholic acid.
      ]. However, adjunction of immunosuppressive therapy was required in most patients of other cohorts to obtain a complete biochemical response [
      • Chazouilleres O.
      • Wendum D.
      • Serfaty L.
      • Montembault S.
      • Rosmorduc O.
      • Poupon R.
      Primary biliary cirrhosis–autoimmune hepatitis overlap syndrome: clinical features and response to therapy.
      ,
      • Lohse A.W.
      • zum Buschenfelde K.H.
      • Franz B.
      • Kanzler S.
      • Gerken G.
      • Dienes H.P.
      Characterization of the overlap syndrome of primary biliary cirrhosis (PBC) and autoimmune hepatitis: evidence for it being a hepatitic form of PBC in genetically susceptible individuals.
      ]. In the largest long-term follow-up study, 17 strictly defined patients [
      • Chazouilleres O.
      • Wendum D.
      • Serfaty L.
      • Rosmorduc O.
      • Poupon R.
      Long term outcome and response to therapy of primary biliary cirrhosis–autoimmune hepatitis overlap syndrome.
      ] received UDCA alone or UDCA in combination with immunosuppressors and were followed for 7.5 years. In the 11 patients treated with UDCA alone, biochemical response in terms of AIH features (ALT <2× ULN and IgG <16 g/L) was observed in only 3 patients whereas the 8 others were non-responders with increased fibrosis in 4. Overall, fibrosis progression in non-cirrhotic patients occurred more frequently under UDCA monotherapy (4/8) than under combined therapy (0/6) (p = 0.04). These results strongly suggest that combined therapy (UDCA and corticosteroids) is the best therapeutic option in most patients with strictly defined simultaneous PBC–AIH overlap syndrome. An alternative approach is to start with UDCA alone and to add corticosteroids if UDCA therapy does not induce an adequate biochemical response in an appropriate time span (e.g., 3 months) [
      • Rust C.
      • Beuers U.
      Overlap syndromes among autoimmune liver diseases.
      ]. Prednisone has been used at an initial dose of 0.5 mg/kg/d and should be progressively tapered once ALT levels show a response [
      • Chazouilleres O.
      • Wendum D.
      • Serfaty L.
      • Rosmorduc O.
      • Poupon R.
      Long term outcome and response to therapy of primary biliary cirrhosis–autoimmune hepatitis overlap syndrome.
      ]. Budesonide is a promising treatment option for patients with AIH and has also been used with success in some patients with PBC–AIH overlap syndrome [
      • Csepregi A.
      • Rocken C.
      • Treiber G.
      • Malfertheiner P.
      Budesonide induces complete remission in autoimmune hepatitis.
      ]. The role of other immunosuppressants, e.g., azathioprine, in the long-term management of these patients is unclear, but its successful use in AIH makes azathioprine an attractive alternative to corticosteroids for long-term immunosuppressive therapy. Interestingly, by comparison with typical AIH, it has been suggested that doses of immunosuppressants could be lower and rate of successful withdrawal higher [
      • Chazouilleres O.
      • Wendum D.
      • Serfaty L.
      • Rosmorduc O.
      • Poupon R.
      Long term outcome and response to therapy of primary biliary cirrhosis–autoimmune hepatitis overlap syndrome.
      ]. For corticosteroid-resistant patients, a beneficial effect of other immunosuppressants such as cyclosporine A has been reported [
      • Duclos-Vallee J.C.
      • Hadengue A.
      • Ganne-Carrie N.
      • Robin E.
      • Degott C.
      • Erlinger S.
      Primary biliary cirrhosis–autoimmune hepatitis overlap syndrome. Corticoresistance and effective treatment by cyclosporine A.
      ].
      In UDCA-treated PBC patients developing AIH (“sequential” overlap), use of immunosuppressive treatment is mandatory [
      • Poupon R.
      • Chazouilleres O.
      • Corpechot C.
      • Chretien Y.
      Development of autoimmune hepatitis in patients with typical primary biliary cirrhosis.
      ].
      Recommendations
      • 1.
        Standardization of diagnostic criteria for PBC–AIH overlap syndrome has not been achieved. Strict diagnostic criteria as shown in Table 4 provide a useful diagnostic template (III/C2).
      • 2.
        PBC–AIH overlap syndrome should always be considered once PBC has been diagnosed because of potential implications for therapy (III/C2).
      • 3.
        Combined therapy with UDCA and corticosteroids is the recommended therapeutic option in patients with PBC–AIH overlap syndrome (III/C2). An alternative approach is to start with UDCA only and to add corticosteroids if UDCA therapy has not induced an adequate biochemical response in an appropriate time span (3 months) (III/C2). Steroid sparing agents should be considered in patients requiring long-term immunosuppression (III/C2).

      5. Primary sclerosing cholangitis

      Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease that is characterized by an inflammatory and fibrotic process affecting both intra- and extrahepatic bile ducts [
      • Maggs J.R.
      • Chapman R.W.
      An update on primary sclerosing cholangitis.
      ]. The disease leads to irregular bile duct obliteration, including formation of multifocal bile duct strictures. PSC is a progressive disorder that eventually develops into liver cirrhosis and liver failure. The etiology of PSC is unknown, but there is evidence that genetic susceptibility factors are involved [
      • Karlsen T.H.
      • Schrumpf E.
      • Boberg K.M.
      Genetic epidemiology of primary sclerosing cholangitis.
      ]. The male to female ratio is approximately 2:1. PSC can be diagnosed in children as well as in the elderly, but mean age at diagnosis is around 40 years. Up to 80% of PSC patients have concomitant inflammatory bowel disease (IBD) that in the majority of cases is diagnosed as ulcerative colitis (UC). Thus, the “typical” PSC patient is a young to middle-aged man with IBD who presents with biochemical and/or clinical signs of a cholestatic liver disease.

      5.1 Diagnosis of PSC

      A diagnosis of PSC is made in patients with elevated serum markers of cholestasis (AP, γGT) not otherwise explained, when magnetic resonance cholangiopancreatography (MRCP) or endoscopic cholangiopancreatography (ERCP) show characteristic bile duct changes with multifocal strictures and segmental dilatations, and causes of secondary sclerosing cholangitis [
      • Abdalian R.
      • Heathcote E.J.
      Sclerosing cholangitis: a focus on secondary causes.
      ] and other cholestatic disorders are excluded. Patients who present with clinical, biochemical and histological features compatible with PSC, but have a normal cholangiogram, are classified as small duct PSC.

      5.1.1 Signs and symptoms

      About 50% of PSC patients are symptomatic at first presentation. Typical symptoms include pruritus, pain in the right upper abdominal quadrant, fatigue, weight loss, and episodes of fever and chills, which are reported in a variable number of patients [
      • Broome U.
      • Olsson R.
      • Loof L.
      • Bodemar G.
      • Hultcrantz R.
      • Danielsson A.
      • et al.
      Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis.
      ]. Symptoms of liver cirrhosis and portal hypertension with ascites and variceal hemorrhage are more rarely reported at diagnosis in PSC. Hepatomegaly and splenomegaly are the most frequent findings at clinical examination at the time of diagnosis in PSC. Osteopenic bone disease is a complication of advanced PSC, although less frequent than that reported in PBC. Fat malabsorption with steatorrhea and malabsorption of fat-soluble vitamins occur only with prolonged cholestasis.

      5.1.2 Biochemical tests

      Elevation of serum AP is the most common biochemical abnormality in PSC [
      • Broome U.
      • Olsson R.
      • Loof L.
      • Bodemar G.
      • Hultcrantz R.
      • Danielsson A.
      • et al.
      Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis.
      ,
      • Chapman R.W.
      • Arborgh B.A.
      • Rhodes J.M.
      • Summerfield J.A.
      • Dick R.
      • Scheuer P.J.
      • et al.
      Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology.
      ,
      • Tischendorf J.J.
      • Hecker H.
      • Kruger M.
      • Manns M.P.
      • Meier P.N.
      Characterization, outcome, and prognosis in 273 patients with primary sclerosing cholangitis: a single center study.
      ]. However, a normal AP activity should not preclude further steps to diagnose PSC if suspected on clinical basis. Serum aminotransferase levels are elevated at diagnosis in the majority of patients, typically to levels 2–3 times upper limits of normal, but normal levels are also observed. Serum bilirubin levels are normal at diagnosis in up to 70% of patients. Elevated levels of IgG have been noted in 61% of patients, most often to a level up to 1.5 times upper limit of normal [
      • Boberg K.M.
      • Fausa O.
      • Haaland T.
      • Holter E.
      • Mellbye O.J.
      • Spurkland A.
      • et al.
      Features of autoimmune hepatitis in primary sclerosing cholangitis: an evaluation of 114 primary sclerosing cholangitis patients according to a scoring system for the diagnosis of autoimmune hepatitis.
      ]. In one retrospectively studied cohort, 9% of PSC patients were reported with slightly elevated IgG4 levels, but total IgG was not reported in these patients. It remains unclear whether some of these patients suffered from IgG4-associated cholangitis (IAC) rather than PSC [
      • Mendes F.D.
      • Jorgensen R.
      • Keach J.
      • Katzmann J.A.
      • Smyrk T.
      • Donlinger J.
      • et al.
      Elevated serum IgG4 concentration in patients with primary sclerosing cholangitis.
      ]. Increased IgM levels have been reported in up to 45% of PSC cases [
      • Chapman R.W.
      • Arborgh B.A.
      • Rhodes J.M.
      • Summerfield J.A.
      • Dick R.
      • Scheuer P.J.
      • et al.
      Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology.
      ].

      5.1.3 Autoantibodies

      A variety of autoantibodies have been detected in PSC [
      • Hov J.R.
      • Boberg K.M.
      • Karlsen T.H.
      Autoantibodies in primary sclerosing cholangitis.
      ]. The autoantibodies most frequently reported are perinuclear antineutrophil cytoplasmic antibodies (pANCA) (26–94%), antinuclear antibodies (ANA) (8–77%), and smooth muscle antibodies (SMA) (0–83%) [
      • Hov J.R.
      • Boberg K.M.
      • Karlsen T.H.
      Autoantibodies in primary sclerosing cholangitis.
      ]. The pANCA pattern in PSC is “atypical”, as the putative antigen is located in the nucleus rather than in the cytoplasm. Atypical pANCA is frequently present in UC and AIH, and specificity in the diagnosis of PSC is low. Positive titres of ANA and SMA also are unspecific. A routine autoantibody screening is not required to establish a diagnosis of PSC. Analysis of ANA and SMA may be relevant in a subgroup of patients to support a suspicion of “autoimmune” features that may have therapeutic implications (see “PSC–AIH overlap syndrome”).

      5.1.4 Liver biopsy

      Liver histological findings may support a diagnosis of PSC, but they are non-specific and may show considerable variation. PSC has been described to progress through four stages. The initial changes (stage 1, portal stage) are limited to the portal tracts with features including portal oedema, mild portal hepatitis, a non-destructive cholangitis with infiltration of lymphocytes in the bile ducts, and ductular proliferation. Periductal fibrosis and fibrous-obliterative cholangitis may be present. In stage 2 (periportal stage), the lesion extends to involve periportal fibrosis, sometimes with interphase hepatitis. Portal tracts are often enlarged. In stage 3 (septal stage) there is development of bridging fibrous septa, while bile ducts degenerate and disappear. Stage 4 is characterized by cirrhosis [
      • Ludwig J.
      Surgical pathology of the syndrome of primary sclerosing cholangitis.
      ]. Periductal concentric fibrosis is considered highly suggestive of PSC, but this finding is relatively infrequent in needle biopsies in PSC and may also be associated with other conditions. Histological changes can be very subtle, and a liver biopsy may even appear normal because of sampling variability and since the liver is not uniformely involved. In PSC patients with relatively high serum aminotransferase levels, particularly in combination with positive ANA and/or SMA titres and markedly elevated IgG levels, a liver biopsy may be indicated to disclose features of a PSC–AIH overlap syndrome.

      5.1.5 Imaging

      Ultrasonography (US): In PSC, US is not diagnostic and often normal, but bile duct wall thickening and/or focal bile duct dilatations may be observed by experts. One or more gallbladder abnormalities, including wall thickening, gallbladder enlargement [
      • van de Meeberg P.C.
      • Portincasa P.
      • Wolfhagen F.H.
      • van Erpecum K.J.
      • VanBerge-Henegouwen G.P.
      Increased gall bladder volume in primary sclerosing cholangitis.
      ], gallstones, cholecystitis, and mass lesions, have been reported on the basis of US or cholangiography in up to 41% of PSC patients [
      • Said K.
      • Glaumann H.
      • Bergquist A.
      Gallbladder disease in patients with primary sclerosing cholangitis.
      ].
      Cholangiography: A detailed cholangiographic assessment of the biliary tree is essential in making a diagnosis of PSC [
      • Lee Y.M.
      • Kaplan M.M.
      Primary sclerosing cholangitis.
      ]. Efforts should be made to adequately visualize also the intrahepatic ducts to avoid false-negative results by overlooking subtle changes. The characteristic cholangiographic findings of PSC include mural irregularities and diffusely distributed multifocal, short, annular strictures alternating with normal or slightly dilated segments producing a “beaded” pattern [
      • MacCarty R.L.
      • LaRusso N.F.
      • Wiesner R.H.
      • Ludwig J.
      Primary sclerosing cholangitis: findings on cholangiography and pancreatography.
      ]. Sometimes outpouchings have a diverticular appearance [
      • MacCarty R.L.
      • LaRusso N.F.
      • Wiesner R.H.
      • Ludwig J.
      Primary sclerosing cholangitis: findings on cholangiography and pancreatography.
      ]. With more advanced disease, long, confluent strictures may be seen [
      • MacCarty R.L.
      • LaRusso N.F.
      • Wiesner R.H.
      • Ludwig J.
      Primary sclerosing cholangitis: findings on cholangiography and pancreatography.
      ]. In the majority of cases, both the intra- and extrahepatic bile ducts are involved. A variable proportion of patients (<25%) is described to have isolated intrahepatic disease, whereas lesions confined to the extrahepatic ducts are rarely observed (usually <5%) and should only be diagnosed in the presence of adequate filling of the intrahepatic ducts. Since intrahepatic bile duct abnormalities can also be seen in other chronic liver diseases, one must be cautious when diagnosing PSC in the presence of intrahepatic changes only. The gallbladder and cystic duct are involved in some cases, and abnormalities of the pancreatic duct resembling those of chronic pancreatitis have been noted in a variable number of PSC patients [
      • MacCarty R.L.
      • LaRusso N.F.
      • Wiesner R.H.
      • Ludwig J.
      Primary sclerosing cholangitis: findings on cholangiography and pancreatography.
      ].
      Endoscopic retrograde cholangiopancreatography (ERCP) has been the gold standard in diagnosing PSC [
      • Lee Y.M.
      • Kaplan M.M.
      Primary sclerosing cholangitis.
      ,
      • MacCarty R.L.
      • LaRusso N.F.
      • Wiesner R.H.
      • Ludwig J.
      Primary sclerosing cholangitis: findings on cholangiography and pancreatography.
      ], but ERCP is associated with complications such as pancreatitis and sepsis [
      • Bangarulingam S.Y.
      • Gossard A.A.
      • Petersen B.T.
      • Ott B.J.
      • Lindor K.D.
      Complications of endoscopic retrograde cholangiopancreatography in primary sclerosing cholangitis.
      ]. Clinicians may be reluctant to proceed with an ERCP in the assessment of cholestasis, and therefore, PSC most likely has been an underdiagnosed condition. Magnetic resonance cholangiopancreatography (MRCP) is a non-invasive method that in experienced centres is now generally accepted as a primary diagnostic modality in cases of suspected PSC. Studies comparing ERCP and MRCP have shown similar diagnostic accuracy, although the depiction of bile ducts may be poorer with MRCP than with ERCP [
      • Berstad A.E.
      • Aabakken L.
      • Smith H.J.
      • Aasen S.
      • Boberg K.M.
      • Schrumpf E.
      Diagnostic accuracy of magnetic resonance and endoscopic retrograde cholangiography in primary sclerosing cholangitis.
      ]. Sensitivity and specificity of MRCP has been ⩾80% and ⩾87%, respectively, for the diagnosis of PSC [
      • Berstad A.E.
      • Aabakken L.
      • Smith H.J.
      • Aasen S.
      • Boberg K.M.
      • Schrumpf E.
      Diagnostic accuracy of magnetic resonance and endoscopic retrograde cholangiography in primary sclerosing cholangitis.
      ,
      • Angulo P.
      • Pearce D.H.
      • Johnson C.D.
      • Henry J.J.
      • LaRusso N.F.
      • Petersen B.T.
      • et al.
      Magnetic resonance cholangiography in patients with biliary disease: its role in primary sclerosing cholangitis.
      ]. MRCP is superior in visualizing bile ducts proximal to duct obstructions. The method can also reveal changes within the bile duct walls and pathologies in the liver parenchyma as well as in other organs. However, cases with mild PSC changes without bile duct dilatation may be missed by MRCP and one should therefore be cautious to exclude early PSC on the basis of a normal MRCP. Thus, diagnostic ERCP still has a role in equivocal cases. The main role of ERCP, however, lies in therapeutic procedures and in diagnostic purposes like cytology sampling in PSC.

      5.1.6 Small duct PSC

      The term small duct PSC refers to a disease entity which is characterized by clinical, biochemical, and histological features compatible with PSC, but having a normal cholangiogram [
      • Bjornsson E.
      • Olsson R.
      • Bergquist A.
      • Lindgren S.
      • Braden B.
      • Chapman R.W.
      • et al.
      The natural history of small-duct primary sclerosing cholangitis.
      ]. One report has restricted the diagnosis of small duct PSC to patients with concomitant IBD [
      • Broome U.
      • Glaumann H.
      • Lindstom E.
      • Loof L.
      • Almer S.
      • Prytz H.
      • et al.
      Natural history and outcome in 32 Swedish patients with small duct primary sclerosing cholangitis (PSC).
      ], whereas IBD has only been present in a proportion (50–88%) of cases in other studies [
      • Angulo P.
      • Maor-Kendler Y.
      • Lindor K.D.
      Small-duct primary sclerosing cholangitis: a long-term follow-up study.
      ,
      • Bjornsson E.
      • Boberg K.M.
      • Cullen S.
      • Fleming K.
      • Clausen O.P.
      • Fausa O.
      • et al.
      Patients with small duct primary sclerosing cholangitis have a favourable long term prognosis.
      ]. These studies carry the risk to include patients with other cholangiopathies such as ABCB4 deficiency which cause histological features compatible with small duct PSC [
      • Gotthardt D.
      • Runz H.
      • Keitel V.
      • Fischer C.
      • Flechtenmacher C.
      • Wirtenberger M.
      • et al.
      A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults.
      ]. A high-quality cholangiogram is mandatory in order to exclude PSC with isolated intrahepatic distribution. One future approach for the diagnosis of small duct PSC is to accept a negative MRC in patients with concomitant IBD, but require a normal ERCP and a negative mutation analysis of ABCB4 in patients without IBD. Diagnostic criteria in small duct PSC are however still being discussed.

      5.1.7 PSC in children

      Criteria for diagnosis of PSC in adults also apply to children. Of note, levels of serum AP activity were observed within the normal range for the age group in up to 47% of cases [
      • Wilschanski M.
      • Chait P.
      • Wade J.A.
      • Davis L.
      • Corey M.
      • St. Louis P.
      • et al.
      Primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with survival analysis.
      ,
      • Feldstein A.E.
      • Perrault J.
      • El-Youssif M.
      • Lindor K.D.
      • Freese D.K.
      • Angulo P.
      Primary sclerosing cholangitis in children: a long-term follow-up study.
      ]. Patients with normal AP usually had elevated γGT activity [
      • Wilschanski M.
      • Chait P.
      • Wade J.A.
      • Davis L.
      • Corey M.
      • St. Louis P.
      • et al.
      Primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with survival analysis.
      ,
      • Feldstein A.E.
      • Perrault J.
      • El-Youssif M.
      • Lindor K.D.
      • Freese D.K.
      • Angulo P.
      Primary sclerosing cholangitis in children: a long-term follow-up study.
      ]. Presentation of PSC in children is frequently reported with features similar to those of autoimmune hepatitis, including high IgG concentrations, positive ANA and/or SMA titers and interphase hepatitis in the liver biopsy [
      • Wilschanski M.
      • Chait P.
      • Wade J.A.
      • Davis L.
      • Corey M.
      • St. Louis P.
      • et al.
      Primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with survival analysis.
      ,
      • Feldstein A.E.
      • Perrault J.
      • El-Youssif M.
      • Lindor K.D.
      • Freese D.K.
      • Angulo P.
      Primary sclerosing cholangitis in children: a long-term follow-up study.
      ,
      • Gregorio G.V.
      • Portmann B.
      • Karani J.
      • Harrison P.
      • Donaldson P.T.
      • Vergani D.
      • et al.
      Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study.
      ].

      5.1.8 Differential diagnosis of PSC versus secondary forms of sclerosing cholangitis

      Before the diagnosis of PSC can be settled, causes of secondary sclerosing cholangitis such as previous biliary surgery, cholangiolithiasis and disorders mimicking PSC such as carcinoma of the bile ducts have to be excluded although cholangiolithiasis and cholangiocarcinoma may also be the consequence of PSC [
      • Abdalian R.
      • Heathcote E.J.
      Sclerosing cholangitis: a focus on secondary causes.
      ]. Clinical and cholangiographic findings resembling those of PSC have most commonly been described in relation to intraductal stone disease, surgical trauma from cholecystectomy, abdominal injury, intra-arterial chemotherapy, and recurrent pancreatitis [
      • Abdalian R.
      • Heathcote E.J.
      Sclerosing cholangitis: a focus on secondary causes.
      ]. A variety of other conditions have also been associated with features imitating those of PSC, including IgG4-associated cholangitis/autoimmune pancreatitis (see below), hepatic inflammatory pseudotumor, eosinophilic cholangitis, mast cell cholangiopathy, portal hypertensive biliopathy, AIDS cholangiopathy, recurrent pyogenic cholangitis, ischemic cholangitis, as well as others [
      • Abdalian R.
      • Heathcote E.J.
      Sclerosing cholangitis: a focus on secondary causes.
      ]. Differentiating between primary and secondary sclerosing cholangitis may be particularly difficult since PSC patients themselves may have undergone bile duct surgery or have concomitant intraductal stone disease or even cholangiocarcinoma (CCA). Factors like clinical history, the distribution of the cholangiographic abnormalities, as well as the presence of concomitant IBD, have to be taken into account when determining whether a pathological cholangiogram is due to PSC or secondary to a benign or malignant bile duct stricture without PSC [
      • Abdalian R.
      • Heathcote E.J.
      Sclerosing cholangitis: a focus on secondary causes.
      ].
      Recommendations
      • 1.
        A diagnosis of PSC is made in patients with biochemical markers of cholestasis not otherwise explained, when MRCP shows typical findings and causes of secondary sclerosing cholangitis are excluded (II-2/B1). A liver biopsy is not essential for the diagnosis of PSC in these patients, but allows activity and staging of the disease to be assessed.
      • 2.
        A liver biopsy should be performed to diagnose small duct PSC if high-quality MRCP is normal, (III/C2). A liver biopsy may also be helpful in the presence of disproportionally elevated serum transaminases and/or serum IgG levels to identify additional or alternative processes (III/C1).
      • 3.
        ERCP can be considered
        • (i)
          If high-quality MRCP is uncertain (III/C2): the diagnosis of PSC is made in the case of typical ERCP findings.
        • (ii)
          In patients with IBD with normal high-quality MRCP but high suspicion for PSC (III/C2).

      5.2 Follow-up of PSC

      5.2.1 Inflammatory bowel disease and risk of colon cancer

      PSC is strongly associated with IBD, with a prevalence of IBD in Western countries commonly in the range of 60–80% [
      • Broome U.
      • Olsson R.
      • Loof L.
      • Bodemar G.
      • Hultcrantz R.
      • Danielsson A.
      • et al.
      Natural history and prognostic factors in 305 Swedish patients with primary sclerosing cholangitis.
      ,
      • Chapman R.W.
      • Arborgh B.A.
      • Rhodes J.M.
      • Summerfield J.A.
      • Dick R.
      • Scheuer P.J.
      • et al.
      Primary sclerosing cholangitis: a review of its clinical features, cholangiography, and hepatic histology.
      ] whereas in a recent report on 391 Japanese patients only 125 had a history of concomitant IBD [
      • Tanaka A.
      • Takamori Y.
      • Toda G.
      • Ohnishi S.
      • Takikawa H.
      Outcome and prognostic factors of 391 Japanese patients with primary sclerosing cholangitis.
      ]. UC accounts for the majority (80%) of IBD cases in PSC, while around 10% have Crohn‘s disease and another 10% are classified as indeterminate colitis [
      • Loftus Jr., E.V.
      • Harewood G.C.
      • Loftus C.G.
      • Tremaine W.J.
      • Harmsen W.S.
      • Zinsmeister A.R.
      • et al.
      PSC–IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis.
      ]. IBD can be diagnosed at any time during the course of PSC, but in a majority of cases IBD precedes PSC. Since the colitis in PSC characteristically is mild and sometimes even asymptomatic, colonoscopy with biopsies is recommended as part of the routine work-up in a patient diagnosed with PSC. A diagnosis of IBD has implications for follow-up and dysplasia/cancer surveillance as patients with UC and PSC have a higher risk of dysplasia and colon cancer than patients with UC only [
      • Soetikno R.M.
      • Lin O.S.
      • Heidenreich P.A.
      • Young H.S.
      • Blackstone M.O.
      Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis.
      ,
      • Broome U.
      • Bergquist A.
      Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer.
      ]. Compared to UC patients without PSC, the colitis in PSC more frequently is a pancolitis (87% vs. 54%), with backwash ileitis (51% vs. 7%), and rectal sparing (52% vs. 6%) [
      • Loftus Jr., E.V.
      • Harewood G.C.
      • Loftus C.G.
      • Tremaine W.J.
      • Harmsen W.S.
      • Zinsmeister A.R.
      • et al.
      PSC–IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis.
      ]. Patients with PSC and Crohn‘s disease characteristically only have colonic involvement. We recommend that PSC patients with colitis are enrolled in a surveillance program with annual colonoscopy with biopsies from the time of diagnosis of PSC [
      • Broome U.
      • Bergquist A.
      Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer.
      ].

      5.2.2 Hepatobiliary malignancies in PSC

      PSC is associated with an increased risk of hepatobiliary malignancies, in particular cholangiocarcinoma (CCA). In a large cohort of 604 Swedish PSC patients followed for (median) 5.7 years, hepatobiliary malignancies (CCA, hepatocellular carcinoma (HCC), and gallbladder carcinoma) were observed in 13.3%, corresponding to a risk 161 times that of the general population [
      • Bergquist A.
      • Ekbom A.
      • Olsson R.
      • Kornfeldt D.
      • Loof L.
      • Danielsson A.
      • et al.
      Hepatic and extrahepatic malignancies in primary sclerosing cholangitis.
      ]. CCA is by far the most common hepatobiliary malignancy in PSC, with a cumulative life-time incidence of 10–15% [
      • Lazaridis K.N.
      • Gores G.J.
      Primary sclerosing cholangitis and cholangiocarcinoma.
      ], whereas gallbladder carcinoma [
      • Said K.
      • Glaumann H.
      • Bergquist A.
      Gallbladder disease in patients with primary sclerosing cholangitis.
      ] and HCC [
      • Harnois D.M.
      • Gores G.J.
      • Ludwig J.
      • Steers J.L.
      • LaRusso N.F.
      • Wiesner R.H.
      Are patients with cirrhotic stage primary sclerosing cholangitis at risk for the development of hepatocellular cancer?.
      ] are observed in up to 2% of PSC patients, each. Up to 50% of CCA are diagnosed within the first year of diagnosis of PSC. After the first year, the yearly incidence rate is 0.5–1.5% [
      • Lazaridis K.N.
      • Gores G.J.
      Primary sclerosing cholangitis and cholangiocarcinoma.
      ]. Although factors like older age, alcohol consumption and smoking, long duration of IBD before diagnosis of PSC, and a history of colorectal malignancy, have been associated with an increased risk of CCA in PSC, no clinically useful prognostic variables have been identified so far. Possible genetic markers should be further explored [
      • Karlsen T.H.
      • Schrumpf E.
      • Boberg K.M.
      Genetic epidemiology of primary sclerosing cholangitis.
      ]. The symptoms of CCA complicating PSC may be very difficult to differentiate from those of PSC without concomitant malignancy, but awareness of CCA must in particular be raised in cases of rapid clinical deterioration.
      Median levels of the serum tumour marker carbohydrate antigen 19-9 (CA 19-9) are significantly higher in PSC patients with CCA than in those without [
      • Lazaridis K.N.
      • Gores G.J.
      Primary sclerosing cholangitis and cholangiocarcinoma.
      ], but in the individual case CA 19-9 cannot be relied upon in the differential diagnosis between PSC with and without CCA [
      • Lazaridis K.N.
      • Gores G.J.
      Primary sclerosing cholangitis and cholangiocarcinoma.
      ]. Distinguishing benign from malignant changes in PSC by imaging modalities like US, CT, MRCP/MRI as well as ERCP, is equally difficult [
      • Lazaridis K.N.
      • Gores G.J.
      Primary sclerosing cholangitis and cholangiocarcinoma.
      ,
      • Fevery J.
      • Verslype C.
      • Lai G.
      • Aerts R.
      • Van Steenbergen W.
      Incidence, diagnosis, and therapy of cholangiocarcinoma in patients with primary sclerosing cholangitis.
      ]. Serum CA 19-9 combined with cross-sectional liver imaging may be useful as a screening strategy [
      • Charatcharoenwitthaya P.
      • Enders F.B.
      • Halling K.C.
      • Lindor K.D.
      Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis.
      ], but further validation is needed. Whether dynamic (18F)-fluoro-deoxy-d-glucose positron emission tomography (FDG-PET) [
      • Prytz H.
      • Keiding S.
      • Bjornsson E.
      • Broome U.
      • Almer S.
      • Castedal M.
      • et al.
      Dynamic FDG-PET is useful for detection of cholangiocarcinoma in patients with PSC listed for liver transplantation.
      ] is more effective when combined with CT or MRI, needs to be shown. Brush cytology sampling, and biopsy when feasible, during ERCP adds to the diagnostic accuracy of CCA in PSC [
      • Lazaridis K.N.
      • Gores G.J.
      Primary sclerosing cholangitis and cholangiocarcinoma.
      ,
      • Charatcharoenwitthaya P.
      • Enders F.B.
      • Halling K.C.
      • Lindor K.D.
      Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis.
      ,
      • Boberg K.M.
      • Jebsen P.
      • Clausen O.P.
      • Foss A.
      • Aabakken L.
      • Schrumpf E.
      Diagnostic benefit of biliary brush cytology in cholangiocarcinoma in primary sclerosing cholangitis.
      ], but methodological refinement including validation of digital image analysis (DIA) and fluorescence in situ hybridization (FISH) of cell samples [
      • Charatcharoenwitthaya P.
      • Enders F.B.
      • Halling K.C.
      • Lindor K.D.
      Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis.
      ] is needed.
      Gallbladder mass lesions in PSC frequently (>50%) represent adenocarcinomas independently of their size [
      • Said K.
      • Glaumann H.
      • Bergquist A.
      Gallbladder disease in patients with primary sclerosing cholangitis.
      ]. Cholecystectomy is recommended in PSC patients with a gallbladder mass even <1 cm in diameter [
      • Said K.
      • Glaumann H.
      • Bergquist A.
      Gallbladder disease in patients with primary sclerosing cholangitis.
      ]. The risk for pancreatic carcinoma was 14-fold increased in a Swedish cohort of PSC patients in comparison to a matched-control population [
      • Bergquist A.
      • Ekbom A.
      • Olsson R.
      • Kornfeldt D.
      • Loof L.
      • Danielsson A.
      • et al.
      Hepatic and extrahepatic malignancies in primary sclerosing cholangitis.
      ], but its incidence in PSC is markedly lower than that of hepatobiliary malignancies, and regular screening strategies are, therefore, not recommended at present.
      Recommendations
      • 1.
        Total colonoscopy with biopsies should be performed in patients in whom the diagnosis of PSC has been established without known IBD (III/C1) and should be repeated annually (or every 1–2 years in individualized patients) in PSC patients with colitis from the time of diagnosis of PSC (III/C1).
      • 2.
        Annual abdominal ultrasonography should be considered for gallbladder abnormalities (III/C2).
      • 3.
        There is at present no biochemical marker or imaging modality which can be recommended for early detection of cholangiocarcinoma. ERCP with brush cytology (and/or biopsy) sampling should be carried out when clinically indicated (III/C2).

      5.3 Treatment of PSC

      5.3.1 Ursodeoxycholic acid (UDCA)

      UDCA and disease progression: UDCA is an effective treatment of primary biliary cirrhosis (PBC) as outlined above (2.2.1). UDCA has, therefore, also been investigated as a potential candidate for the treatment of PSC. Small pilot trials of UDCA in the early 1990’s demonstrated biochemical and in some cases histological improvement in PSC patients using doses of 10–15 mg/kg/day [
      • Chazouilleres O.
      • Poupon R.
      • Capron J.P.
      • Metman E.H.
      • Dhumeaux D.
      • Amouretti M.
      • et al.
      Ursodeoxycholic acid for primary sclerosing cholangitis.
      ,
      • O’Brien C.B.
      • Senior J.R.
      • Arora-Mirchandani R.
      • Batta A.K.
      • Salen G.
      Ursodeoxycholic acid for the treatment of primary sclerosing cholangitis: a 30-month pilot study.
      ,
      • Beuers U.
      • Spengler U.
      • Kruis W.
      • Aydemir U.
      • Wiebecke B.
      • Heldwein W.
      • et al.
      Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a placebo-controlled trial.
      ,
      • Stiehl A.
      Ursodeoxycholic acid therapy in treatment of primary sclerosing cholangitis.
      ]. A more substantial trial was published by Lindor in 1997 [
      • Lindor K.D.
      Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis–Ursodeoxycholic Acid Study Group.
      ], recruiting 105 patients in a double-blind placebo-controlled trial of 13–15 mg/kg of UDCA for 2 years. The results indicated improvement in serum liver tests but not in symptoms and, most importantly, no improvement in liver histology as evaluated by disease stage [
      • Lindor K.D.
      Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis–Ursodeoxycholic Acid Study Group.
      ]. Higher doses of UDCA were then studied on the grounds that larger doses might be necessary to provide sufficient enrichment of the bile acid pool in the context of cholestasis, and that these doses might also enhance the potential immunomodulatory effect of the drug. Studies using 20–25 mg/kg/day demonstrated significant improvements in the histological grade of liver fibrosis and the cholangiographic appearances of PSC, as well as the expected biochemical improvement [
      • Mitchell S.A.
      • Bansi D.S.
      • Hunt N.
      • Von Bergmann K.
      • Fleming K.A.
      • Chapman R.W.
      A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis.
      ]. A shorter, open-label trial using 25–30 mg/kg/day showed a significant improvement in projected survival using the Mayo risk score, but no direct measurement of the progression of the disease, such as liver biopsy or cholangiography was undertaken. Confirmatory results were obtained in a 2-year dose ranging pilot study of 30 patients in which the low dose (10 mg/kg/d) and the standard dose (20 mg/kg/d) tended to improve and the high dose (30 mg/kg/d) significantly improved projected survival [
      • Cullen S.N.
      • Rust C.
      • Fleming K.
      • Edwards C.
      • Beuers U.
      • Chapman R.
      High dose ursodeoxycholic acid for the treatment of primary sclerosig cholangitis is safe and effective.
      ].
      The Scandinavian UDCA trial deserves major credit for recruiting the largest group of PSC patients (n = 219) for the longest treatment period (5 years) ever studied using a dose of 17–23 mg/kg/day. It demonstrated a trend towards increased survival in the UDCA-treated group when compared with placebo [
      • Olsson R.
      • Boberg K.M.
      • de Muckadell O.S.
      • Lindgren S.
      • Hultcrantz R.
      • Folvik G.
      • et al.
      High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study.
      ]. But despite the relatively large number of patients recruited, it was still insufficiently powered to produce a statistically significant result. In comparison to other studies, the biochemical response was unexpectedly poor in this trial which prompted questions about adequate compliance in a part of the study population. Recently, a multicentre study using high doses of 28–30 mg/kg/d of UDCA in 150 PSC patients over 5 years has been aborted because of an enhanced risk in the UDCA treatment group to reach primary endpoints such as liver transplantation or development of varices in more advanced disease while biochemical features improved in the whole UDCA group [
      • Lindor K.D.
      • Enders F.B.
      • Schmoll J.A.
      • Hoskin T.L.
      • Jorgensen R.A.
      • Petz J.L.
      • et al.
      Randomized, double-blind controlled trial of high-dose ursodeoxycholic acid for primary sclerosing cholangitis.
      ]. Thus, the role for UDCA in slowing the progression of PSC-related liver disease is as yet unclear and high dose UDCA may be harmful in late-stage disease.
      UDCA and chemoprevention: Recent work has suggested that UDCA may have a role in the prevention of colonic neoplasia in patients with PSC associated with underlying IBD. Experimental studies in vitro and in vivo had suggested that UDCA might prevent development of colon carcinoma. A cross-sectional study of 59 PSC patients with ulcerative colitis (UC) undergoing colonoscopic surveillance found a significantly reduced risk of colonic dysplasia in patients taking UDCA although in comparison to an exceptionally high rate of dysplasia in the control group [
      • Tung B.Y.
      • Emond M.J.
      • Haggitt R.C.
      • Bronner M.P.
      • Kimmey M.B.
      • Kowdley K.V.
      • et al.
      Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis.
      ]. A historical cohort study compared 28 PSC patients under UDCA treatment with UC to 92 PSC patients with UC not treated with UDCA [
      • Wolf J.M.
      • Rybicki L.A.
      • Lashner B.A.
      The impact of ursodeoxycholic acid on cancer, dysplasia and mortality in ulcerative colitis patients with primary sclerosing cholangitis.
      ] and found a trend towards a lower risk of colonic dysplasia and neoplasia under UDCA treatment (adjusted relative risk 0.59, 95% CI 0.26–1.36, p = 0.17) and a lower mortality (adjusted relative risk 0.44, 95% CI 0.22–0.90, p = 0.02) [
      • Wolf J.M.
      • Rybicki L.A.
      • Lashner B.A.
      The impact of ursodeoxycholic acid on cancer, dysplasia and mortality in ulcerative colitis patients with primary sclerosing cholangitis.
      ]. A third study followed 52 patients with PSC and UC for 355 patient-years who participated in a randomized, placebo-controlled UDCA trial showing a significant reduction to 0.26 (95% CI 0.06–0.92, p = 003) in UDCA-treated patients in the relative risk of developing colorectal dysplasia or carcinoma [
      • Pardi D.S.
      • Loftus Jr., E.V.
      • Kremers W.K.
      • Keach J.
      • Lindor K.D.
      Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis.
      ].
      Limited evidence for a beneficial effect of UDCA on the risk to develop CCA comes from observational studies. The Scandinavian and American randomized, placebo-controlled UDCA trials with 219 and 150 PSC patients, respectively, did not observe a difference between UDCA- and placebo-treated patients regarding CCA development [
      • Olsson R.
      • Boberg K.M.
      • de Muckadell O.S.
      • Lindgren S.
      • Hultcrantz R.
      • Folvik G.
      • et al.
      High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study.
      ]. A German cohort study including 150 patients followed for a median of 6.4 years under UDCA treatment found CCA in 5 patients (3.3%), which represents about half the expected incidence of CCA in PSC [
      • Rudolph G.
      • Kloeters-Plachky P.
      • Rost D.
      • Stiehl A.
      The incidence of cholangiocarcinoma in primary sclerosing cholangitis after long-time treatment with ursodeoxycholic acid.
      ]. A Scandinavian study of 255 PSC patients listed for liver transplantation over a period of 11 years revealed lack of ursodeoxycholic acid treatment as an independent risk factor for the development of hepatobiliary malignancy [
      • Brandsaeter B.
      • Isoniemi H.
      • Broome U.
      • Olausson M.
      • Backman L.
      • Hansen B.
      • et al.
      Liver transplantation for primary sclerosing cholangitis; predictors and consequences of hepatobiliary malignancy.
      ].

      5.3.2 Immunosuppressive and other agents

      Corticosteroids and other immunosuppressants have not demonstrated improvement in disease activity or outcome of PSC. Small randomized, placebo-controlled or pilot trials have investigated the role of agents with immunosuppressive potency like prednisolone, budesonide, azathioprine, cyclosporine, methotrexate, mycophenolate, and tacrolimus, agents with TNFα antagonizing effects like pentoxifyllin, etanercept and anti-TNF monocolonal antibodies and anti-fibrotic agents like colchicine, penicillamine, or pirfenidone. There is no evidence that these drugs are effective and, therefore, none can be recommended for classic PSC. These drugs may well have a role in the context of a PSC–AIH overlap syndrome (see below) since pediatric patients and those with evidence of a PSC–AIH overlap syndrome are more likely to respond to immunosuppressive treatment [
      • Woodward J.
      • Neuberger J.
      Autoimmune overlap syndromes.
      ,
      • Beuers U.
      • Rust C.
      Overlap syndromes.
      ,
      • Gregorio G.V.
      • Portmann B.
      • Karani J.
      • Harrison P.
      • Donaldson P.T.
      • Vergani D.
      • et al.
      Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study.
      ]. A retrospective study in adults also suggested a beneficial role of steroids in a subgroup with AIH overlap features [
      • Boberg K.M.
      • Egeland T.
      • Schrumpf E.
      Long-term effect of corticosteroid treatment in primary sclerosing cholangitis patients.
      ].

      5.3.3 ERCP and endoscopic therapy

      Diagnostic ERCP has been the procedure of choice for suspected PSC in the past, but is associated with significant risks including pancreatitis and cholangitis [
      • Etzel J.P.
      • Eng S.C.
      • Ko C.W.
      • Lee S.D.
      • Saunders M.D.
      • Tung B.Y.
      • et al.
      Complications after ERCP in patients with primary sclerosing cholangitis.
      ,
      • Andriulli A.
      • Loperfido S.
      • Napolitano G.
      • Niro G.
      • Valvano M.R.
      • Spirito F.
      • et al.
      Incidence rates of post-ERCP complications: a systematic survey of prospective studies.
      ]. Whilst a low complication rate was found in patients undergoing ‘diagnostic’ ERCP, the complication rate increased up to 14% when interventions such as balloon dilatation, endoscopic sphincterotomy and stenting were performed [
      • Freeman M.L.
      • Nelson D.B.
      • Sherman S.
      • Haber G.B.
      • Herman M.E.
      • Dorsher P.J.
      • et al.
      Complications of endoscopic biliary sphincterotomy.
      ,
      • van den Hazel S.J.
      • Wolfhagen E.H.
      • van Buuren H.R.
      • van de Meeberg P.C.
      • Van Leeuwen D.J.
      Prospective risk assessment of endoscopic retrograde cholangiography in patients with primary sclerosing cholangitis. Dutch PSC Study Group.
      ].
      Dominant bile duct strictures have been defined as stenoses <1.5 mm in diameter in the common bile duct and <1 mm in the right and left hepatic duct [
      • Bjornsson E.
      • Lindqvist-Ottosson J.
      • Asztely M.
      • Olsson R.
      Dominant strictures in patients with primary sclerosing cholangitis.
      ]. The prevalence of dominant bile duct strictures in large duct PSC is variously reported as being 10–50%. Studies in animals and humans have suggested that decompression of biliary obstruction may prevent further damage and can reverse fibrotic liver disease [
      • Hammel P.
      • Couvelard A.
      • O’Toole D.
      • Ratouis A.
      • Sauvanet A.
      • Flejou J.F.
      • et al.
      Regression of liver fibrosis after biliary drainage in patients with chronic pancreatitis and stenosis of the common bile duct.
      ]. Endoscopic treatment of biliary strictures often improves liver biochemistry and pruritus and may reduce the risk of recurrent cholangitis. Therefore, repeated endoscopic dilatation of dominant biliary strictures has been carried out in symptomatic patients [
      • Stiehl A.
      • Rudolph G.
      • Klo-ters-Plachky P.
      • Sauer P.
      • Walker S.
      Development of dominant bile duct stenoses in patients with primary sclerosing cholangitis treated with ursodeoxycholic acid: outcome after endoscopic treatment.
      ,
      • Baluyut A.R.
      • Sherman S.
      • Lehman G.A.
      • Hoen H.
      • Chalasani N.
      Impact of endoscopic therapy on the survival of patients with primary sclerosing cholangitis.
      ,
      • Johnson G.K.
      • Geenen J.E.
      • Venu R.P.
      • Schmalz M.J.
      • Hogan W.J.
      Endoscopic treatment of biliary tract strictures in sclerosing cholangitis: a larger series and recommendations for treatment.
      ]. Non-randomized studies comparing jaundice, cholangitis, transplantation and actuarial survival rates with estimates from prognostic models have suggested a trend towards a benefit of endoscopic intervention for dominant biliary strictures although patients also received UDCA [
      • Baluyut A.R.
      • Sherman S.
      • Lehman G.A.
      • Hoen H.
      • Chalasani N.
      Impact of endoscopic therapy on the survival of patients with primary sclerosing cholangitis.
      ,
      • Stiehl A.
      • Rudolph G.
      • Sauer P.
      • Benz C.
      • Stremmel W.
      • Walker S.
      • et al.
      Efficacy of ursodeoxycholic acid treatment and endoscopic dilation of major duct stenoses in primary sclerosing cholangitis. An 8-year prospective study.
      ]. In contrast, a Swedish study which compared liver biochemistry in those with and without dominant strictures suggested that variations in cholestasis and jaundice are a feature of PSC liver disease and not related to dilatation of dominant strictures [
      • Bjornsson E.
      • Lindqvist-Ottosson J.
      • Asztely M.
      • Olsson R.
      Dominant strictures in patients with primary sclerosing cholangitis.
      ]. The optimum method and frequency of dilatation of dominant strictures is unclear. The most widely used technique to facilitate biliary drainage has been plastic stent insertion with or without prior dilatation. The problem with this approach is that further ERCP’s are required to remove or replace the stent and there is a high rate of stent occlusion and/or cholangitis within 3 months of insertion. One study assessed the effectiveness and safety of short-term stenting (mean 9 days) resulting in improved outcome, particularly with regard to cholangitis and stent occlusion rates [
      • van Milligen de Wit A.W.
      • Rauws E.A.
      • van Bracht J.
      • Mulder C.J.
      • Jones E.A.
      • Tytgat G.N.
      • et al.
      Lack of complications following short-term stent therapy for extrahepatic bile duct strictures in primary sclerosing cholangitis.
      ]. The strategy of short-term stenting for 2–3 weeks is followed by some experienced centers. Other studies have compared the role of stenting with balloon dilatation, with similar efficacy and lower rates of complications such as cholangitis (18% vs. 50%) associated with balloon dilatation alone [
      • Kaya M.
      • Petersen B.T.
      • Angulo P.
      • Baron T.H.
      • Andrews J.C.
      • Gostout C.J.
      • et al.
      Balloon dilation compared to stenting of dominant strictures in primary sclerosing cholangitis.
      ]. Multiple dilatations are usually required over months or years in order to maintain patency once dominant strictures are identified and treated, and not all strictures are amenable to endoscopic intervention. In these patients, careful consideration should be made regarding a conservative, radiological or surgical (including liver transplantation) approach to treatment.

      5.3.4 Liver transplantation

      Liver transplantation is the only therapy of late-stage PSC that can cure advanced disease. One and ten-year survival after liver transplantation has lately been above 90% and 80%, respectively, in experienced centers. Resection of the extrahepatic biliary tree and Roux-en Y choledochojejunostomy are widely regarded as the method of choice for biliary reconstruction after liver transplantation in PSC [
      • Welsh F.K.
      • Wigmore S.J.
      Roux-en-Y choledochojejunostomy is the method of choice for biliary reconstruction in liver transplantation for primary sclerosing cholangitis.
      ]. Recurrence of PSC after liver transplantation has been reported at various rates up to a third of patients transplanted, but is difficult to define due to similarities in bile duct damage with ischemic type biliary lesions, infections, medication-induced injury, preservation injury, or chronic rejection [
      • Gordon F.
      Recurrent primary sclerosing cholangitis: clinical diagnosis and long-term management issues.
      ]. In different cohorts, PSC recurrence was associated with steroid-resistant rejection, OKT3 use, preservation injury, ABO incompatibility, cytomegalovirus infection, male sex, or donor-recipient gender mismatch [
      • LaRusso N.F.
      • Shneider B.L.
      • Black D.
      • Gores G.J.
      • James S.P.
      • Doo E.
      • et al.
      Primary sclerosing cholangitis: summary of a workshop.
      ]. Colectomy prior to liver transplantation for advanced colitis or colon dysplasia protected against PSC recurrence as did the absence of ulcerative colitis [
      • Cholongitas E.
      • Shusang V.
      • Papatheodoridis G.V.
      • Marelli L.
      • Manousou P.
      • Rolando N.
      • et al.
      Risk factors for recurrence of primary sclerosing cholangitis after liver transplantation.
      ].
      Recommendations
      • 1.
        The available data base shows that UDCA (15–20 mg/d) improves serum liver tests and surrogate markers of prognosis (I/B1), but does not reveal a proven benefit on survival (III/C2). The limited data base does not yet allow a specific recommendation for the general use of UDCA in PSC.
      • 2.
        Currently there is suggestive but limited evidence for the use of UDCA for chemoprevention of colorectal cancer in PSC (II-2/C2). UDCA may be particularly considered in high-risk groups such as those with a strong family history of colorectal cancer, previous colorectal neoplasia or longstanding extensive colitis (III/C2).
      • 3.
        Corticosteroids and other immunosuppressants are not indicated for treatment of PSC in adults unless there is evidence of an overlap syndrome (III/C2).
      • 4.
        Dominant bile duct strictures with significant cholestasis should be treated with biliary dilatation (II-2/B1). Biliary stent insertion should be reserved for cases where stricture dilatation and biliary drainage are unsatisfactory (III/C2). Prophylactic antibiotic coverage is recommended in this setting (III/C1).
      • 5.
        Liver transplantation is recommended in patients with late-stage PSC (II-2/A1) and may be considered in patients with evidence of cholangiocyte dysplasia or severe recurrent bacterial cholangitis (III/C2).

      6. PSC–AIH overlap syndrome

      6.1 Diagnosis

      PSC–AIH overlap syndrome is an ill-defined immune-mediated disorder which is predominantly found in children, adolescents and young adults [
      • Gregorio G.V.
      • Portmann B.
      • Karani J.
      • Harrison P.
      • Donaldson P.T.
      • Vergani D.
      • et al.
      Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study.
      ,
      • el-Shabrawi M.
      • Wilkinson M.L.
      • Portmann B.
      • Mieli-Vergani G.
      • Chong S.K.
      • Williams R.
      • et al.
      Primary sclerosing cholangitis in childhood.
      ,
      • Minuk G.Y.
      • Sutherland L.R.
      • Pappas G.
      • Kelly J.K.
      • Martin S.E.
      Autoimmune chronic active hepatitis (lupoid hepatitis) and primary sclerosing cholangitis in two young adult females.
      ,
      • Rabinovitz M.
      • Demetris A.J.
      • Bou-Abboud C.F.
      • Van Thiel D.H.
      Simultaneous occurrence of primary sclerosing cholangitis and autoimmune chronic active hepatitis in a patient with ulcerative colitis.
      ,
      • Lawrence S.P.
      • Sherman K.E.
      • Lawson J.M.
      • Goodman Z.D.
      A 39 year old man with chronic hepatitis.
      ,
      • Debray D.
      • Pariente D.
      • Urvoas E.
      • Hadchouel M.
      • Bernard O.
      Sclerosing cholangitis in children.
      ,
      • Wilschanski M.
      • Chait P.
      • Wade J.A.
      • Davis L.
      • Corey M.
      • St. Louis P.
      • et al.
      Primary sclerosing cholangitis in 32 children: clinical, laboratory, and radiographic features, with survival analysis.
      ,
      • Gohlke F.
      • Lohse A.W.
      • Dienes H.P.
      • Lohr H.
      • Marker-Hermann E.
      • Gerken G.
      • et al.
      Evidence for an overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis.
      ,
      • McNair A.N.
      • Moloney M.
      • Portmann B.C.
      • Williams R.
      • McFarlane I.G.
      Autoimmune hepatitis overlapping with primary sclerosing cholangitis in five cases.
      ,
      • Al-Chalabi T.
      • Portmann B.C.
      • Bernal W.
      • McFarlane I.G.
      • Heneghan M.A.
      Autoimmune hepatitis overlap syndromes: an evaluation of treatment response, long-term outcome and survival.
      ]. Its characteristics include clinical, biochemical, and histologic features of AIH as summarized in the modified AIH score defined by an international group of experts for study purposes [
      • Alvarez F.
      • Berg P.A.
      • Bianchi F.B.
      • Bianchi L.
      • Burroughs A.K.
      • Cancado E.L.
      • et al.
      International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis.
      ] and cholangiographic features typical of PSC [
      • Beuers U.
      • Rust C.
      Overlap syndromes.
      ]. Retrospective diagnosis of an overlap syndrome by use of the modified AIH score was established in 8% of 113 PSC patients from The Netherlands [
      • van Buuren H.R.
      • van Hoogstraten H.J.E.
      • Terkivatan T.
      • Schalm S.W.
      • Vleggaar F.P.
      High prevalence of autoimmune hepatitis among patients with primary sclerosing cholangitis.
      ], and in 1.4% of 211 PSC patients from the U.S. (with somewhat incomplete data available for retrospective analysis) [
      • Kaya M.
      • Angulo P.
      • Lindor K.D.
      Overlap of autoimmune hepatitis and primary sclerosing cholangitis: an evaluation of a modified scoring system.
      ]. Prospective analysis of 41 consecutive PSC patients from Italy for the presence of: (i) a revised AIH score >15; (ii) ANA or ASMA antibodies present in a titre of at least 1:40; and (iii) liver histology with piecemeal necrosis, lymphocyte rosetting, and moderate or severe periportal or periseptal inflammation revealed a PSC–AIH overlap syndrome as defined by these criteria in 17% [
      • Floreani A.
      • Rizzotto E.R.
      • Ferrara F.
      • Carderi I.
      • Caroli D.
      • Blasone L.
      • et al.
      Clinical course and outcome of autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome.
      ]. These patients were treated with UDCA (15–20 mg/kg daily), prednisolone (0.5 mg/kg daily, tapered to 10–15 mg/d) and 50–75 mg azathioprine with good biochemical response.
      The largest case series reported so far consisted of 27 children with PSC–AIH overlap syndromes from England [
      • Gregorio G.V.
      • Portmann B.
      • Karani J.
      • Harrison P.
      • Donaldson P.T.
      • Vergani D.
      • et al.
      Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study.
      ] out of 55 children with clinical, biochemical, and histological signs of AIH, followed prospectively for 16 years. Children and adolescents with PSC–AIH overlap syndrome more commonly suffered from IBD and more often were positive for atypical pANCA in serum than those with AIH only. Otherwise, they presented with similar signs and symptoms. Serum transaminases tend to be higher in AIH, but serum AP although mostly elevated in PSC, may be normal both in PSC–AIH overlap syndrome and AIH. Increasing awareness for the PSC–AIH overlap syndrome has led to the observation that AIH and PSC may be sequential in their occurrence, and this has been described in children [
      • Gregorio G.V.
      • Portmann B.
      • Karani J.
      • Harrison P.
      • Donaldson P.T.
      • Vergani D.
      • et al.
      Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study.
      ] and adults [
      • Abdo A.A.
      • Bain V.G.
      • Kichian K.
      • Lee S.S.
      Evolution of autoimmune hepatitis to primary sclerosing cholangitis: a sequential syndrome.
      ]. Thus, in patients with AIH who become cholestatic and/or resistant to immunosuppression, PSC should be ruled out.

      6.2 Therapy

      UDCA is widely used in the treatment of PSC although long-term efficacy remains unproven so far [
      • Beuers U.
      • Spengler U.
      • Kruis W.
      • Aydemir U.
      • Wiebecke B.
      • Heldwein W.
      • et al.
      Ursodeoxycholic acid for treatment of primary sclerosing cholangitis: a placebo-controlled trial.
      ,
      • Stiehl A.
      Ursodeoxycholic acid therapy in treatment of primary sclerosing cholangitis.
      ,
      • Lindor K.D.
      Ursodiol for primary sclerosing cholangitis. Mayo Primary Sclerosing Cholangitis–Ursodeoxycholic Acid Study Group.
      ,
      • Mitchell S.A.
      • Bansi D.S.
      • Hunt N.
      • Von Bergmann K.
      • Fleming K.A.
      • Chapman R.W.
      A preliminary trial of high-dose ursodeoxycholic acid in primary sclerosing cholangitis.
      ,
      • Cullen S.N.
      • Rust C.
      • Fleming K.
      • Edwards C.
      • Beuers U.
      • Chapman R.
      High dose ursodeoxycholic acid for the treatment of primary sclerosig cholangitis is safe and effective.
      ,
      • Olsson R.
      • Boberg K.M.
      • de Muckadell O.S.
      • Lindgren S.
      • Hultcrantz R.
      • Folvik G.
      • et al.
      High-dose ursodeoxycholic acid in primary sclerosing cholangitis: a 5-year multicenter, randomized, controlled study.
      ]. UDCA has been used in combination with immunosuppressive regimens in PSC–AIH overlap syndrome [
      • Gregorio G.V.
      • Portmann B.
      • Karani J.
      • Harrison P.
      • Donaldson P.T.
      • Vergani D.
      • et al.
      Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study.
      ,
      • Floreani A.
      • Rizzotto E.R.
      • Ferrara F.
      • Carderi I.
      • Caroli D.
      • Blasone L.
      • et al.
      Clinical course and outcome of autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome.
      ]. A response to immunosuppressive therapy has been documented in children [
      • Gregorio G.V.
      • Portmann B.
      • Karani J.
      • Harrison P.
      • Donaldson P.T.
      • Vergani D.
      • et al.
      Autoimmune hepatitis/sclerosing cholangitis overlap syndrome in childhood: a 16-year prospective study.
      ]. UDCA in combination with an immunosuppressive regimen might, therefore, be an adequate medical treatment for most patients with PSC–AIH overlap syndrome [
      • Floreani A.
      • Rizzotto E.R.
      • Ferrara F.
      • Carderi I.
      • Caroli D.
      • Blasone L.
      • et al.
      Clinical course and outcome of autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome.
      ], although no data of controlled trials exist. Prognosis of PSC–AIH overlap syndrome was reported to be better than that of PSC [
      • Floreani A.
      • Rizzotto E.R.
      • Ferrara F.
      • Carderi I.
      • Caroli D.
      • Blasone L.
      • et al.
      Clinical course and outcome of autoimmune hepatitis/primary sclerosing cholangitis overlap syndrome.
      ], but worse than that of AIH [
      • Al-Chalabi T.
      • Portmann B.C.
      • Bernal W.
      • McFarlane I.G.
      • Heneghan M.A.
      Autoimmune hepatitis overlap syndromes: an evaluation of treatment response, long-term outcome and survival.
      ]. Liver transplantation is indicated in end-stage disease.
      Recommendations
      • 1.
        PSC–AIH overlap syndrome is an ill-defined immune-mediated disorder characterized by histological features of AIH and cholangiographic findings typical of PSC (III/C2).
      • 2.
        Medical treatment of AIH–PSC overlap syndrome with UDCA and immunosuppressive therapy is recommended, but is not evidence-based due to lack of adequate studies (III/C2). Liver transplantation is the treatment of choice for end-stage disease (III/A1).

      7. Immunoglobulin G4-associated cholangitis

      7.1 Diagnosis

      Immunoglobulin G4-associated cholangitis (IAC) is a recently described biliary disease of unknown etiology that presents with biochemical and cholangiographic features indistinguishable from PSC, frequently involves the extrahepatic bile ducts, responds to anti-inflammatory therapy, is often associated with autoimmune pancreatitis and other fibrosing conditions, and is characterized by elevated serum IgG4 and infiltration of IgG4-positive plasma cells in bile ducts and liver tissue [
      • Stathopoulos G.
      • Nourmand A.D.
      • Blackstone M.
      • Andersen D.
      • Baker A.L.
      Rapidly progressive sclerosing cholangitis following surgical treatment of pancreatic pseudotumor.
      ,
      • Erkelens G.W.
      • Vleggaar F.P.
      • Lesterhuis W.
      • van Buuren H.R.
      • van der Werf S.D.
      Sclerosing pancreato-cholangitis responsive to steroid therapy.
      ,
      • van Buuren H.R.
      • Vleggaar F.P.
      • Willemien Erkelens G.
      • Zondervan P.E.
      • Lesterhuis W.
      • Van Eijck C.H.
      • et al.
      Autoimmune pancreatocholangitis: a series of ten patients.
      ,
      • Bjornsson E.
      • Chari S.T.
      • Smyrk T.C.
      • Lindor K.
      Immunoglobulin G4 associated cholangitis: description of an emerging clinical entity based on review of the literature.
      ,
      • Umemura T.
      • Zen Y.
      • Hamano H.
      • Kawa S.
      • Nakanuma Y.
      • Kiyosawa K.
      Immunoglobin G4-hepatopathy: association of immunoglobin G4-bearing plasma cells in liver with autoimmune pancreatitis.
      ,
      • Zen Y.
      • Fujii T.
      • Harada K.
      • Kawano M.
      • Yamada K.
      • Takahira M.
      • et al.
      Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis.
      ,
      • Ghazale A.
      • Chari S.T.
      • Zhang L.
      • Smyrk T.C.
      • Takahashi N.
      • Levy M.J.
      • et al.
      Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy.
      ]. In contrast to PSC, IAC is not associated with IBD. Preliminary data suggest that immunopathogenesis of IAC strikingly differs from other immune-mediated cholestatic liver diseases like PSC and PBC in that T helper 2 (Th2) and T regulatory (Treg) cytokines were markedly overexpressed in IAC patients [
      • Zen Y.
      • Fujii T.
      • Harada K.
      • Kawano M.
      • Yamada K.
      • Takahira M.
      • et al.
      Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis.
      ]. In the largest cohorts of 53 and 17 IAC patients, respectively [
      • Ghazale A.
      • Chari S.T.
      • Zhang L.
      • Smyrk T.C.
      • Takahashi N.
      • Levy M.J.
      • et al.
      Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy.
      ,
      • Umemura T.
      • Zen Y.
      • Hamano H.
      • Kawa S.
      • Nakanuma Y.
      • Kiyosawa K.
      Immunoglobin G4-hepatopathy: association of immunoglobin G4-bearing plasma cells in liver with autoimmune pancreatitis.
      ], median age at diagnosis of the mostly male patients (7/8) was around 60 years.
      The diagnosis of IAC was recently proposed to be definitive if a patient with biliary stricture(s) in the intrahepatic, proximal extrahepatic and/or intrapancreatic bile ducts
      • (i)
        has recently undergone pancreatic/biliary surgery or core biopsy of the pancreas showing diagnostic features of autoimmune pancreatitis (AIP)/IAC; or
      • (ii)
        shows classical imaging findings of AIP and elevated IgG4; or
      • (iii)
        fulfils two of the following criteria (elevated serum IgG4; suggestive pancreatic imaging findings; other organ manifestations including sclerosing sialadenitis, retroperitoneal fibrosis, or gastrointestinal involvement and abdominal lymphadenopathy with infiltration of IgG4-positive plasma cells; >10 IgG4-pos. plasma cells per high power field in bile duct biopsies) and shows an adequate response to a 4-week course of corticosteroid treatment to allow stent removal without relapse of obstructive cholestasis, to reach serum liver tests <2× ULN, and to present decreasing IgG4 and CA 19-9 [
        • Ghazale A.
        • Chari S.T.
        • Zhang L.
        • Smyrk T.C.
        • Takahashi N.
        • Levy M.J.
        • et al.
        Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy.
        ].
      Although not yet cross-validated in an independent cohort of IAC patients, this diagnostic recommendation may temporarily serve as a guideline for diagnosis of IAC.

      7.2 Treatment

      Immunosuppressive treatment has been shown to exert a marked effect on inflammatory activity of IAC, and complete long-term remission after three months of treatment has been reported. However, the extent of disease may affect the long-term response, and a retrospective analysis showed that patients with alterations of proximal extrahepatic and intrahepatic bile ducts are prone to a higher risk of relapse after stop of treatment than patients with distal bile duct strictures only [
      • Ghazale A.
      • Chari S.T.
      • Zhang L.
      • Smyrk T.C.
      • Takahashi N.
      • Levy M.J.
      • et al.
      Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy.
      ]. Thus, corticosteroids are regarded as the initial treatment of choice in this disease, and azathioprine at doses up to 2 mg/kg/d should be considered in those with proximal and intrahepatic stenoses and those after relapse during/after corticosteroid therapy. Treatment duration of 3 months may be sufficient for some patients, but long-term maintenance therapy at low doses may be required when disease activity has not completely come to a standstill or has relapsed.
      Recommendations
      • 1.
        IAC is a corticosteroid-responsive (II-2/C2) sclerosing cholangitis of unknown immunopathogenesis which, unlike PSC, affects mostly older patients and has a good long-term prognosis after adequate response to immunosuppressive treatment (II-2/C2).
      • 2.
        The diagnosis of IAC is proposed to be made in patients with cholangiographic findings typical of sclerosing cholangitis on the basis of (i) histological features of autoimmune pancreatitis (AIP)/IAC or (ii) classical imaging findings of AIP and elevated IgG4; or (iii) two diagnostic biochemical, histological and imaging criteria and an adequate response to a 4-week course of corticosteroid treatment to allow biliary stent removal without relapse of obstructive cholestasis, and to reach serum liver tests <2× ULN (III/C2).
      • 3.
        Long-term treatment of IAC with corticosteroids and/or azathioprine may be needed after relapse or for inadequate response (III/C2).

      8. Genetic cholestatic liver diseases

      8.1 Cystic fibrosis-associated liver disease

      Cystic fibrosis-associated liver disease (CFALD) was observed in up to 27% of patients with CF during long-term follow-up as defined by hepatomegaly, persistent elevation of at least two serum liver tests and abnormal findings on ultrasound [
      • Colombo C.
      • Battezzati P.M.
      • Crosignani A.
      • Morabito A.
      • Costantini D.
      • Padoan R.
      • et al.
      Liver disease in cystic fibrosis: a prospective study on incidence, risk factors, and outcome.
      ] and may manifest as neonatal cholestasis, hepatic steatosis, focal or multilobular cirrhosis. Complications of CFALD represent today the second most frequent cause of disease-related death in patients with CF.

      8.1.1 Diagnosis

      Diagnostic criteria for CFALD are not well defined. CF-related hepatomegaly is found in a third of CF patients and may be caused by CFALD or as a consequence of cor pulmonale with liver congestion. Serum liver tests (AP, ALT, AST, bilirubin) are recommended at yearly intervals in CF patients [
      • Sokol R.J.
      • Durie P.R.
      Recommendations for management of liver and biliary tract disease in cystic fibrosis. Cystic Fibrosis Foundation Hepatobiliary Disease Consensus Group.
      ]. Elevation above 1.5× ULN of serum liver tests should induce control after 3–6 months and when persisting should prompt further investigations to more closely evaluate liver damage (prothrombin time, albumin) and exclude other causes of liver disease (e.g., drugs, toxins, infections, biliary atresia, gallstones, antitrypsine deficiency, autoimmune hepatitis, PSC or other causes of bile duct obstruction). Ultrasound may reveal signs of CFALD such as hepatomegaly or bile duct alterations [
      • Sokol R.J.
      • Durie P.R.
      Recommendations for management of liver and biliary tract disease in cystic fibrosis. Cystic Fibrosis Foundation Hepatobiliary Disease Consensus Group.
      ]. Liver biopsy is controversially discussed due to the focal nature of fibrosis/cirrhosis in many cases.

      8.1.2 Therapy

      No therapy of proven benefit for the long-term prognosis of CFALD exists. Optimization of nutritional state in cholestatic patients to avoid vitamin deficiency and malnutrition is recommended, but not of proven efficacy.
      UDCA at doses of 20–30 mg/kg/d has been shown to consistently improve serum liver tests [
      • Colombo C.
      • Battezzati P.M.
      • Podda M.
      • Bettinardi N.
      • Giunta A.
      Ursodeoxycholic acid for liver disease associated with cystic fibrosis: a double-blind multicenter trial. The Italian Group for the Study of Ursodeoxycholic Acid in Cystic Fibrosis.
      ,
      • van de Meeberg P.C.
      • Houwen R.H.
      • Sinaasappel M.
      • Heijerman H.G.
      • Bijleveld C.M.
      • Vanberge-Henegouwen G.P.
      Low-dose versus high-dose ursodeoxycholic acid in cystic fibrosis-related cholestatic liver disease. Results of a randomized study with 1-year follow-up.
      ], to stimulate impaired biliary secretion, to improve histological appearance (over 2 years) [
      • Lindblad A.
      • Glaumann H.
      • Strandvik B.
      A two-year prospective study of the effect of ursodeoxycholic acid on urinary bile acid excretion and liver morphology in cystic fibrosis-associated liver disease.
      ] and nutritional status. The optimal dose of UDCA and its impact on survival in CF remain to be established.
      Treatment of complications of cirrhosis is not different from other liver diseases. Medical treatment of portal hypertension with beta blockers and/or endoscopic treatment of varices has not been adequately evaluated in CFALD whereas elective shunt surgery in portal hypertensive patients has allowed long-term survival in a case series [
      • Debray D.
      • Lykavieris P.
      • Gauthier F.
      • Dousset B.
      • Sardet A.
      • Munck A.
      • et al.
      Outcome of cystic fibrosis-associated liver cirrhosis: management of portal hypertension.
      ]. Outcome of liver transplantation is comparable to that for other end-stage liver diseases.
      Recommendations
      • 1.
        CFALD affects a third of patients with CF during long-term follow-up, but is not well defined. It may be disclosed by detection of hepatomegaly (III/C2), annual performance of serum liver tests (III/C2), and, if abnormal, ultrasound of the liver (III/C2).
      • 2.
        UDCA (20–30 mg/kg/d) improves serum liver tests (I/C1) and histological parameters (III/C1) in CFALD. No medical therapy of proven long-term benefit exists in CFALD (III/C2). Liver transplantation is the treatment of choice in end-stage CFALD (III/B1).

      8.2 Progressive familial intrahepatic cholestasis

      8.2.1 Classification

      Progressive familial intrahepatic cholestasis (PFIC) summarizes a group of three inherited cholestatic diseases which may start early after birth or at young age and may rapidly progress to end-stage disease [
      • Oude Elferink R.P.
      • Paulusma C.C.
      • Groen A.K.
      Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases.
      ]. Mutations in canalicular transporter genes of the ATP-binding cassette (ABC) transporters are responsible for these rare disorders.
      PFIC type 1 (formerly “Byler disease”) typically presents in the neonatal period with signs and symptoms (pruritus!) of liver disease. Elevation of serum transaminases, bilirubin and bile acids is contrasted by low levels of γGT (in contrast to biliary atresia and Alagille syndrome). Liver histology reveals fibrosis, but no bile duct proliferation. Most patients develop end-stage liver disease before the end of the first decade of life. Diarrhea, pancreatitis, failure to thrive, and hearing deficits are extrahepatic manifestations of this genetic defect caused by mutations in the ATP8B1 gene which encodes a phospholipid (phosphatidylserine?) flippase, FIC1 [
      • de Vree J.M.
      • Jacquemin E.
      • Sturm E.
      • Cresteil D.
      • Bosma P.J.
      • Aten J.
      • et al.
      Mutations in the MDR3 gene cause progressive familial intrahepatic cholestasis.
      ,
      • Paulusma C.C.
      • Groen A.
      • Kunne C.
      • Ho-Mok K.S.
      • Spijkerboer A.L.
      • Rudi de Waart D.
      • et al.
      Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport.
      ].
      PFIC type 2 (formerly “Byler syndrome”) presents like PFIC type 1 in early childhood with clinical and biochemical signs and symptoms of progressive liver disease, but low levels of γGT. Histology reveals portal inflammation and giant cell hepatitis. Electron microscopic studies show coarse granular bile in PFIC1 and amorphous bile in PFIC2. PFIC2 is caused by mutations in the ABCB11 gene which encodes the canalicular bile salt export pump, ABCB11/BSEP [
      • Strautnieks S.S.
      • Bull L.N.
      • Knisely A.S.
      • Kocoshis S.A.
      • Dahl N.
      • Arnell H.
      • et al.
      A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis.
      ]. The course of PFIC2 is complicated by development of hepatocellular carcinoma at considerable rates [
      • Knisely A.S.
      • Strautnieks S.S.
      • Meier Y.
      • Stieger B.
      • Byrne J.A.
      • Portmann B.C.
      • et al.
      Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency.
      ] making liver transplantation an attractive treatment option.
      PFIC type 3 typically presents in the first years of childhood with progressive cholestasis [
      • Trauner M.
      • Fickert P.
      • Wagner M.
      MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes.
      ], although disease manifestation and cirrhosis in adulthood has also been described most recently [
      • Gotthardt D.
      • Runz H.
      • Keitel V.
      • Fischer C.
      • Flechtenmacher C.
      • Wirtenberger M.
      • et al.
      A mutation in the canalicular phospholipid transporter gene, ABCB4, is associated with cholestasis, ductopenia, and cirrhosis in adults.
      ]. In contrast to PFIC1 and PFIC2, γGT is usually markedly elevated in PFIC3 and histology reveals, in addition to portal inflammation and fibrosis/cirrhosis, massive bile duct proliferation. PFIC3 may be associated with intrahepatic gallstone disease. PFIC3 is caused by mutations in the ABCB4 gene which encodes the canalicular phospholipid transporter, ABCB4/MDR3 [
      • Trauner M.
      • Fickert P.
      • Wagner M.
      MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes.
      ].

      8.2.2 Therapy

      No medical therapy of proven benefit for the long-term prognosis of PFIC exists. Supplementation with medium chain triglycerides and fat-soluble vitamins is generally recommended in children. UDCA has been reported to improve biochemical tests in almost 50% of patients with PFIC3 [
      • Jacquemin E.
      Role of multidrug resistance 3 deficiency in pediatric and adult liver disease: one gene for three diseases.
      ], but generally does not affect PFIC1 and PFIC2. Rifampicin may alleviate pruritus. Partial biliary diversion and ileal exclusion have been reported in case series to improve signs and symptoms of particularly PFIC1 and also PFIC2 [
      • Whitington P.F.
      • Whitington G.L.
      Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis.
      ,
      • Arnell H.
      • Bergdahl S.
      • Papadogiannakis N.
      • Nemeth A.
      • Fischler B.
      Preoperative observations and short-term outcome after partial external biliary diversion in 13 patients with progressive familial intrahepatic cholestasis.
      ]. Liver transplantation is the recommended treatment of end-stage disease in PFIC.
      Recommendations
      • 1.
        PFIC type 1, 2 and 3 are rare chronic progressive cholestatic disorders of early childhood and adolescence. PFIC type 1 and 2 are characterized by low γGT, severe pruritus and various extrahepatic manifestations.
      • 2.
        No medical therapy of proven benefit for the long-term prognosis of PFIC exists (III/C2). UDCA improves serum liver tests in a part of PFIC3 patients (III/C2). Rifampicin may alleviate pruritus (III/C2). Partial biliary diversion has shown beneficial clinical and biochemical effects in PFIC1 and PFIC2 (III/C2). Liver transplantation is recommended for end-stage disease (III/B1).

      8.3 Benign recurrent intrahepatic cholestasis

      Benign recurrent intrahepatic cholestasis (BRIC) type 1 and 2 are acute cholestatic disorders of adolescence and adulthood and represent the benign forms of PFIC1 and PFIC2 mainly caused by missense mutations in the ATP8B1 and ABCB11 genes [
      • Oude Elferink R.P.
      • Paulusma C.C.
      • Groen A.K.
      Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases.
      ,
      • Trauner M.
      • Fickert P.
      • Wagner M.
      MDR3 (ABCB4) defects: a paradigm for the genetics of adult cholestatic syndromes.
      ]. BRIC is characterized by acute episodes of cholestasis, jaundice and severe pruritus caused by unknown factors which after weeks or months completely resolve to start again after an asymptomatic period of months to years. BRIC1 like PFIC1 may be accompanied by pancreatitis, whereas BRIC2 may be accompanied by gallstone disease [
      • Oude Elferink R.P.
      • Paulusma C.C.
      • Groen A.K.
      Hepatocanalicular transport defects: pathophysiologic mechanisms of rare diseases.
      ]. Liver fibrosis has been described in cases of BRIC indicating a continuum between BRIC and PFIC in some cases [
      • van Ooteghem N.A.
      • Klomp L.W.
      • van Berge-Henegouwen G.P.
      • Houwen R.H.
      Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum.
      ].
      No effective medical therapy of BRIC exists. UDCA and rifampicin have been anecdotally reported to affect the course of BRIC as has nasobiliary drainage [
      • Stapelbroek J.M.
      • van Erpecum K.J.
      • Klomp L.W.
      • Venneman N.G.
      • Schwartz T.P.
      • van Berge Henegouwen G.P.
      • et al.
      Nasobiliary drainage induces long-lasting remission in benign recurrent intrahepatic cholestasis.
      ].
      Recommendations
      • 1.
        BRIC is characterized by acute episodes of cholestasis, jaundice and severe pruritus which after weeks to months completely resolve (III/C1).
      • 2.
        No evidence-based treatment of BRIC is known. Treatment attempts with UDCA, rifampicin or nasobiliary drainage are still experimental (III/C2).

      8.4 Alagille syndrome

      Alagille syndrome is an autosomal dominant multiorgan disease of children and adolescents which is characterized by chronic progressive cholestasis with ductopenia without relevant inflammatory changes in liver histology [
      • Piccoli D.A.
      • Spinner N.B.
      Alagille syndrome and the Jagged1 gene.
      ]. The extrahepatic signs and symptoms with involvement of nearly every organ system including heart, kidney, skeleton, central nervous system and a typical facies with hypertelorism, deep-set eyes and a flat nasal bridge may lead to the diagnosis of Alagille syndrome in young cholestatic patients suffering from often severe itch. The disease is caused by mutations in the JAG1 gene in 70% of patients. No effective medical treatment exists. Anecdotally, partial biliary diversion has been reported to cause relief from severe pruritus.
      Recommendations
      • 1.
        Alagille syndrome is characterized by cholestasis with pruritus and ductopenia at early age in combination with various extrahepatic stigmata and symptoms indicating multiorgan involvement as a consequence of JAG1 mutations (III/C2).
      • 2.
        No effective medical treatment is known (III/C2).

      9. Drug-induced cholestatic liver disease

      Acute drug-induced cholestatic injury represents one of three major forms of drug-induced liver injury (DILI) and has been defined by an international consensus panel by an isolated elevation of serum alkaline phosphatase (AP) >2× ULN or an alanine aminotransferase (ALT)/AP ratio (both elevated above ULN) <2 [
      • Benichou C.
      Criteria of drug-induced liver disorders. Report of an international consensus meeting.
      ]. In comparison, drug-induced hepatocellular injury as the predominant form of DILI is defined by isolated ALT >2× ULN or an ALT/AP ratio (both elevated above ULN) >5, whereas mixed type injury is defined by an ALT/AP ratio of 2–5. Drug-induced cholestatic injury has a better prognosis than hepatocellular injury [
      • Andrade R.J.
      • Lucena M.I.
      • Fernandez M.C.
      • Pelaez G.
      • Pachkoria K.
      • Garcia-Ruiz E.
      • et al.
      Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.
      ]. Several hundred drugs, herbal remedies, and illegal compounds have been reported to trigger drug-induced cholestatic injury. Adverse liver reactions are predictable and dose dependent only in a very few cases, whereas the vast majority is caused by unpredictable idiosyncratic or hypersensitive mechanisms. For many drugs, the reported prevalence of DILI is between 1 in 10,000 and 1 in 100,000 patients, and about 30% of cases with DILI are cholestatic. However, these estimates are weakened by considerable underreporting of DILI. Both environmental and genetic factors may determine susceptibility [
      • Kaplowitz N.
      Idiosyncratic drug hepatotoxicity.
      ]. Genetically determined variations of hepatobiliary transporter and biotransformation enzyme expression and function may be important risk factors for an individual’s susceptibility to cholestasis under conditions of xenobiotic stress by drugs.

      9.1 Diagnosis

      Because there are no specific diagnostic tests, diagnosis requires clinical suspicion, a careful drug history, consideration of the temporal relationship between drug intake and liver disease and exclusion of other disorders. Rechallenge could confirm the diagnosis, but is potentially harmful, unethical and not indicated in clinical practice; inadvertent re-challenge nevertheless may sometimes lead to diagnosis. When drug-induced cholestatic injury is assumed, liver biopsy is usually not required, and the natural course after stopping of drug administration is carefully followed until normalization of serum liver tests within 3 months in most cases. A severe, progressive or prolonged course may require liver biopsy to get additional information on the type of liver injury and to exclude other causes of liver cholestasis. Abdominal ultrasound is indicated to exclude other liver diseases (see Introduction 1).

      9.2 Pathogenetic mechanisms and most frequent drugs

      Drug-induced cholestasis may be based on two major mechanisms and sites of action, [
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • Kunz R.
      • Falck-Ytter Y.
      • Alonso-Coello P.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      ] inhibition of hepatocellular transporter expression and/or function with alteration of bile secretion at the hepatocellular level (Table 5) and [
      • Chazouillères O.
      • Housset C.
      Intrahepatic cholestasis.
      ] induction of an idiosyncratic inflammatory or hypersensitive reaction at the bile ductular/cholangiocellular level with ductular/ductal cholestasis, which can also interfere with hepatocyte bile secretion (Table 5). Rarely, drugs induce a vanishing bile duct syndrome (VBDS) that can progress to biliary cirrhosis [
      • Marschall H.U.
      • Wagner M.
      • Zollner G.
      • Trauner M.
      Clinical hepatotoxicity. Regulation and treatment with inducers of transport and cofactors.
      ,
      • Maddrey W.C.
      Drug-induced hepatotoxicity: 2005.
      ]. Various factors such as age, gender, dose, or co-administered medications may affect the risk to develop drug-induced hepatic injury [
      • Erlinger S.
      Drug-induced cholestasis.
      ].
      Table 5Most frequent drugs causing hepatocellular or ductular/ductal cholestasis.
      Hepatocellular cholestasisDuctular/ductal cholestasis
      Sex hormonesAllopurinol
      CarbamazepineAmoxicillin-clavulanic acid
      ChlorpromazineAzathioprine
      Amoxicillin-clavulanic acidBarbiturates
      Trimethroprim-sulfamethoxazoleCaptopril
      Erytromicin, ClarithromycinCarbamazepine
      NitrofurantoinChlorpropamide
      ChlorpropamideClindamycin
      AzathioprinePhenytoin
      CyclosporineSulpiride
      PropafenoneTrimethroprim-sulfamethoxazole
      NifedipineMedicinal herbs
      Medicinal herbs
      NSAIDS, nimesulide

      9.3 Treatment

      There is no effective treatment for drug-induced cholestasis except for withdrawal of the drug [
      • Navarro V.J.
      • Senior J.R.
      Drug-related hepatotoxicity.
      ]. Prevention and early detection of abnormal serum liver tests, together with prompt withdrawal of the suspected drug are crucial to avoid serious liver injury. In some cases, hepatotoxicity is severe, disabling or life-threatening and liver transplantation may be required. Some studies have reported that ursodeoxycholic acid (UDCA) may beneficially affect cholestasis in two-thirds of cases [
      • Nathwani R.A.
      • Kaplowitz N.
      Drug hepatotoxicity.
      ]. A potential benefit of corticosteroid therapy in cases of drug-induced cholestasis has been reported occasionally and may be particularly expected in hypersensitivity-induced cholestasis, but no relevant controlled trials are available on this subject [
      • Maddrey W.C.
      Drug-induced hepatotoxicity: 2005.
      ]. The outcome of drug-induced cholestatic injury, after withdrawal of the drug, is generally good [
      • Aithal P.G.
      • Day C.P.
      The natural history of histologically proved drug induced liver disease.
      ]. Occasionally it is followed by prolonged cholestasis. The prototype drug causing cholestasis longer than 6 months is chlorpromazine; it can cause the “vanishing bile duct syndrome in drug-induced liver disease”, leading to permanent liver damage [
      • Desmet V.J.
      Vanishing bile duct syndrome in drug-induced liver disease.
      ]. A minority of the patients who had a drug-related liver injury shows, during follow-up, abnormal liver test and persistent liver damage at histology [
      • Aithal P.G.
      • Day C.P.
      The natural history of histologically proved drug induced liver disease.
      ].
      Recommendations
      • 1.
        Diagnosis of drug-induced cholestatic liver disease (AP >2× ULN or ALT (×ULN)/AP (×ULN) ratio <2) is mainly supported by a temporal relationship between drug intake and onset of clinical picture and exclusion of other causes (III/C1). A liver biopsy is not mandatory (III/C2).
      • 2.
        Acute withdrawal of the suspected drug and careful clinical and biochemical monitoring are recommended (III/C2). Therapeutic attempts with UDCA or corticosteroids are regarded as experimental due to lack of adequate controlled trials (III/C2).

      10. Cholestatic disorders in pregnancy

      10.1 Intrahepatic cholestasis of pregnancy (ICP)

      Intrahepatic cholestasis of pregnancy (ICP, also known as obstetric cholestasis) is a reversible form of cholestasis characterized by (i) intense pruritus in pregnancy (starting in the second or third trimester of pregnancy in most patients), (ii) elevated serum ALT activities and fasting serum bile acid levels, and (iii) spontaneous relief of signs and symptoms after delivery (within 4–6 weeks) [
      • Lammert F.
      • Marschall H.U.
      • Glantz A.
      • Matern S.
      Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management.
      ,
      • Pusl T.
      • Beuers U.
      Intrahepatic cholestasis of pregnancy.
      ]. In Europe, about 0.4–2.0% of pregnancies are affected [
      • Lammert F.
      • Marschall H.U.
      • Glantz A.
      • Matern S.
      Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management.
      ,
      • Glantz A.
      • Marschall H.U.
      • Mattsson L.A.
      Intrahepatic cholestasis of pregnancy: relationships between bile acid levels and fetal complication rates.
      ]. The clinical importance of ICP lies in the potential fetal risks (spontaneous or iatrogenic prematurity, asphyxial events during delivery, intrauterine death), albeit perinatal mortality rates from recent studies (9/1000) are comparable to whole population figures, most likely due to improvements in obstetric and neonatal care [

      Royal College of Obstetricians and Gynaecologists. Obstetric cholestasis. RCOG Guideline No. 43, 2006:1–10.

      ]. Pruritus (typically worse at night) impairs the mother’s quality of life. Only infrequently, ICP is associated with steatorrhea and postpartum haemorrhage due to vitamin K deficiency.
      The pathogenesis of ICP is multifactorial, with genetic, hormonal and environmental factors playing important roles. During ICP, there is an increased flux of bile acids from the mother to the fetus, as indicated by elevated bile acid levels in amniotic fluid, cord blood and meconium [
      • Brites D.
      Intrahepatic cholestasis of pregnancy: changes in maternal-fetal bile acid balance and improvement by ursodeoxycholic acid.
      ]. The central role of hormonal factors is supported by the higher ICP incidence in twin pregnancies and the observation that high-dose oral contraceptives and progesterone can trigger ICP [
      • Lammert F.
      • Marschall H.U.
      • Glantz A.
      • Matern S.
      Intrahepatic cholestasis of pregnancy: molecular pathogenesis, diagnosis and management.
      ]. An increased ICP incidence in family members and ethnic differences point to genetic factors. Recent genetic studies have identified gene variants of hepatocanalicular transport proteins (ATP-binding cassette [ABC] transporter B4 = phosphatidylcholine floppase, ABC transporter B11 = bile salt export pump, ABC transporter C2 = conjugated organic anion transporter, ATP8B1 = FIC1) and their regulators (e.g., the bile acid sensor farnesoid X receptor, FXR) in some ICP patients [