Easl clinical practice guidelines: management of cholestatic liver diseases

Journal of Hepatology 51 (2009) 237–267 EASL Clinical Practice Guidelines: Management of cholestatic liver diseases European Association for the Study of the Liver* Keywords: Primary biliary cirrhosis; Primary sclerosing cholangitis; Overlap syndrome; Immunoglobulin G4-associatedcholangitis; Drug-induced cholestatic liver disease; Genetic cholestatic liver disease; Cholestatic liver diseases inpregnancy; Intrahepatic cholestasis of pregnancy; Fatigue; Pruritus cholestatic liver diseases. The clinical care for patientswith cholestatic liver diseases has advanced considerably EASL Clinical Practice Guidelines (CPG) on the during recent decades thanks to growing insight into management of cholestatic liver diseases define the use pathophysiological mechanisms and remarkable meth- of diagnostic, therapeutic and preventive modalities, odological and technical developments in diagnostic including non-invasive and invasive procedures, in the procedures as well as therapeutic and preventive management of patients with cholestatic liver diseases.
approaches. Still, various aspects in the care of patients They are intended to assist physicians and other health- with cholestatic disorders remain incompletely resolved.
care providers as well as patients and interested individ- The EASL CPG on the management of cholestatic liver diseases aim to provide current recommendations on the describing a range of generally accepted approaches following issues: for the diagnosis, treatment and prevention of specific  Diagnostic approach to the cholestatic patient.
 Diagnosis and treatment of primary biliary cirrhosis EASL Office, 7 rue des Battoirs, 1205 Geneva, Switzerland.
Tel.: +41 22 8070360; fax: +41 22 3280724.
Abbreviations: AIH, autoimmune hepatitis; AIP, autoimmune pancreatitis; AMA, antimitochondrial antibodies; AP, hepatitis (AIH) overlap syndrome.
phosphatase in serum; ASMA, anti-smooth muscle antibodies; BRIC,  Diagnosis and treatment of primary sclerosing cho- benign recurrent intrahepatic cholestasis; CCA, cholangiocarcinoma; CF, cystic fibrosis; CFALD, cystic fibrosis-associated liver disease; langitis (PSC).
CPG, Clinical Practice Guidelines; CT, computed tomography; DILI,  Diagnosis and treatment of PSC–AIH overlap drug-induced liver injury; EASL, European Association for the Studyof the Liver; ERCP, endoscopic retrograde cholangiopancreatography; EUS, endoscopic ultrasound; FDG-PET, (18F)-fluoro-deoxy-D-glucose  Diagnosis and treatment of immunoglobulin G4- cGT, c-glutamyltranspeptidase in serum; HCC, hepatocellular carci- associated cholangitis (IAC).
noma; IAC, immunoglobulin G4-associated cholangitis; IAIHG,International Autoimmune Hepatitis Group; IBD, inflammatory bo-wel disease; IgG, immunoglobulin G in serum; IgG4, immunoglobulinG4 in serum; MRCP, magnetic resonance cholangiopancreatography; Contributors: Clinical Practice Guidelines Panel: Ulrich Beuers, NASH, non-alcoholic steatohepatitis; PBC, primary biliary cirrhosis; Kirsten M. Boberg, Roger W. Chapman, Olivier Chazouille res, Pietro PDC-E2, E2 subunit of the pyruvate dehydrogenase complex; PSC, Invernizzi, David E.J. Jones, Frank Lammert, Albert Pare s, Michael primary sclerosing cholangitis; PIIINP, procollagen-3-aminoterminal Trauner; Reviewers: Antonio Benedetti, Peter L.M. Jansen, Hanns- propeptide; UC, ulcerative colitis; ULN, upper limit of normal; US, Ulrich Marschall, James Neuberger, Gustav Paumgartner, Raoul Poupon, Jesu´s Prieto.
0168-8278/$36.00 Ó 2009 Published by Elsevier B.V. on behalf of the European Association for the Study of the Liver.
doi:10.1016/j.jhep.2009.04.009 European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267  Diagnosis and treatment of drug-induced cholestatic Where no clear evidence exists, guidance is based on the liver diseases.
consensus advice of expert opinion in the literature andthe writing committee.
 Diagnosis and treatment of genetic cholestatic liver 2. Diagnostic approach to cholestasis  Diagnosis and treatment of cholestatic liver diseases in pregnancy.
Cholestasis is an impairment of bile formation and/or bile flow which may clinically present with fatigue, pru-  Treatment of extrahepatic manifestations of chole- ritus and, in its most overt form, jaundice. Early bio- static liver diseases.
chemical markers in often asymptomatic patients include increases in serum alkaline phosphatase (AP) Categories of evidence.
and c-glutamyltranspeptidase (cGT) followed by conju- gated hyperbilirubinemia at more advanced stages. Cho- Randomized controlled trials lestasis may be classified as intrahepatic or extrahepatic.
Controlled trials without randomization Intrahepatic cholestasis may result from hepatocellular Cohort or case-control analytic studies functional defects or from obstructive lesions of the Multiple time series, dramatic uncontrolled experiments intrahepatic biliary tract distal from bile canaliculi. Cho- Opinions of respected authorities, descriptive epidemiology lestasis may also be related to mixed mechanisms in dis-eases such as lymphoma By convention, cholestasisis considered chronic if it lasts >6 months. Most chronic A panel of experts selected by the EASL Governing cholestatic diseases are purely intrahepatic, whereas Board in May 2008 wrote and discussed these guidelines sclerosing cholangitis may affect small and large intrahe- between June and November 2008. These guidelines have patic and/or extrahepatic bile ducts. Asymptomatic been produced using evidence from PubMed and Cochra- patients are generally identified when routine laboratory ne database searches before 1 October, 2008. Where pos- tests are being performed or during work-up for another sible, the level of evidence and recommendation are cited disease when an increase is noted in the serum level of (The evidence and recommendations in AP and/or cGT. Isolated serum cGT elevation has little these guidelines have been graded according to the Grad- specificity for cholestasis, and may also result from ing of Recommendations Assessment Development and enzyme induction in response to alcohol or drug intake.
Evaluation (GRADE system) The strength of recom- Isolated serum AP elevation is seen in cholestatic liver mendations thus reflects the quality of underlying evi- diseases including certain rare disorders (e.g., progres- dence which has been classified in one of three levels: sive familial intrahepatic cholestasis (PFIC) 1 & 2, bile high [A], moderate [B] or low-quality evidence [C]. The acid synthesis defects), but may also result from rapid GRADE system offers two grades of recommendation: bone growth (e.g., in children), bone disease (e.g., strong or weak (). The CPG thus consider Paget's disease), or pregnancy. The cut-off levels of the quality of evidence: the higher, the more likely a strong serum AP and cGT requiring diagnostic work-up are recommendation is warranted; the greater the variability debated: AP levels higher than 1.5 times the upper limit in values and preferences, or the greater the uncertainty, of normal (ULN) and cGT levels >3 ULN have been the more likely a weaker recommendation is warranted.
proposed. The differential diagnosis of cholestatic disor- Table 1bEvidence grading (adapted from the GRADE system Further research is very unlikely to change our confidence in the estimate of effect Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change theestimate. Any change of estimate is uncertain Factors influencing the strength of the recommendation included the quality of the evidence, presumed patient-important outcomes,and cost Variability in preferences and values, or more uncertainty.
Recommendation is made with less certainty, higher cost orresource consumption European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 ders can be wide ). Nevertheless, the first critical mass lesions because it is rather sensitive and specific, step is to differentiate intra- and extrahepatic cholestasis.
non-invasive, portable and relatively inexpensive. Its Careful patient history and physical examination are disadvantages are that its findings are operator-depen- essential in the diagnostic process and may provide valu- dent and abnormalities of bile ducts such as those able information so that an experienced clinician can pre- observed in sclerosing cholangitis may be missed. Fur- dict the nature of cholestasis in many cases . Presence of thermore, the lower common bile duct and pancreas extrahepatic diseases has to be recorded. A thorough are usually not well depicted. Computed tomography occupational and drug history is imperative and any med- of the abdomen is less interpreter-dependent, but is asso- ications taken within 6 weeks of presentation may be ciated with radiation exposure and may be not as good incriminated (and discontinued); this includes herbal as ultrasound at delineating the biliary tree.
medicines, vitamins and other substances. A history of If bile duct abnormalities are present, further work-up fever, especially when accompanied by rigors or right depends on the presumed cause. From a purely diagnostic upper quadrant abdominal pain is suggestive of cholangi- perspective, magnetic resonance cholangiopancreatogra- tis due to obstructive diseases (particularly choledocholi- phy (MRCP) is a safe option to explore the biliary tree. Its thiasis), but may be seen in alcoholic disease and rarely, accuracy for detecting biliary tract obstruction approa- viral hepatitis. A history of prior biliary surgery also ches that of endoscopic retrograde cholangiopancreatog- increases the likelihood that biliary obstruction is present.
raphy (ERCP) when performed in experienced centres Finally, a family history of cholestatic liver disease sug- with state-of-the-art technology. Endoscopic ultrasound gests a possibility of a hereditary disorder. Some chole- (EUS) is equivalent to MRCP in the detection of bile duct static disorders are observed only under certain stones and lesions causing extrahepatic obstruction and circumstances (e.g., pregnancy, childhood, liver trans- may be preferred to MRCP in endoscopic units.
plantation, HIV-infection), and may require specific Extrahepatic biliary obstruction may be caused by investigations that are not relevant in other populations.
stones, tumours, cysts, or strictures. The gold standard Abdominal ultrasonography is usually the first step for visualizing the biliary tract and treating extrahepatic to exclude dilated intra- and extrahepatic ducts and biliary obstruction is endoscopic retrograde cholangio-pancreatography (ERCP), but even in experiencedhands it carries a significant complication rate (pancrea- titis in 3–5% of cases; when combined with sphincterot- Causes of intrahepatic cholestasis in adulthood.
omy, bleeding 2%, cholangitis 1%, procedure-related mortality 0.4% Thus, when extrahepatic obstruction Sepsis-, endotoxemia-induced cholestasisCholestatic variety of viral hepatitis is considered and the need for endoscopic intervention is Alcoholic or non-alcoholic steatohepatitis unclear, MRCP or EUS should be performed in order to Drug- or parenteral nutrition-induced cholestasis avoid ERCP if it is not needed Genetic disorders: e.g., BRIC, PFIC, ABCB4 deficiency, intrahepatic If imaging studies do not demonstrate mechanical cholestasis of pregnancy (ICP), erythropoietic protoporphyria obstruction, a diagnosis of intrahepatic cholestasis can Malignant infiltrating disorders: e.g., hematologic diseases, metastatic be reasonably made. However, in an individual whose Benign infiltrating disorders: e.g., amyloidosis, sarcoidosis hepatis and history suggests an extrahepatic cause (like early pancre- other granulomatoses, storage diseases atic or ampullary carcinoma), clinical judgment should Paraneoplastic syndromes: e.g., Hodgkin disease, renal carcinomaDuctal plate malformations: e.g., congenital hepatic fibrosisNodular regenerative hyperplasia Vascular disorders: e.g., Budd–Chiari syndrome, veno-occlusive Causes of intrahepatic cholestasis in infancy and childhood disease, congestive hepatopathy Metabolic disease Cirrhosis (any cause) – with biliary tract involvement: a1-antitrypsin storage disease, Primary biliary cirrhosis (AMA+/AMA ) – without biliary tract involvement: galactosemia, tyrosinemia, fatty Primary sclerosing cholangitis acid oxidation defects, lipid and glycogen storage disorders, Overlap syndromes of PBC and PSC with AIH peroxisomal disorders – specific defects in biliary function: Idiopathic adulthood ductopenia disorders of bile acid biosynthesis and conjugation Ductal plate malformations: biliary hamartoma, Caroli syndrome disorders of canalicular secretion (PFIC) Paucity of bile ducts – syndromic: Alagille syndrome (Jagged 1 defect) Graft vs. host disease – non-syndromic Secondary sclerosing cholangitis: e.g., due to various forms of Ductal plate malformations cholangiolithiasis, ischemic choangiopathies (hereditary hemorragic Infections: bacterial, viral telangiectasia, polyarteritis nodosa and other forms of vasculitis), Toxic: parenteral nutrition, drugs infectious cholangitis related to AIDS and other forms of Idiopathic neonatal hepatitis Cirrhosis (any cause) European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 be pursued and repeat ultrasound or another imaging procedure should be performed .
Typical biliary lesions and their main causes (liver transplant settingexcluded) .
When extrahepatic obstruction has been reasonably excluded, further work-up of intrahepatic cholestasis 1. Nonsuppurative destructive cholangitis Primary biliary cirrhosis (depends on the clinical setting.
Primary sclerosing cholangitis In adult patients with chronic intrahepatic cholesta- Autoimmune hepatitis sis, the next step is testing for serum antimitochondrial Drug-induced cholangitis antibodies (AMA) since the diagnosis of PBC, which is the major cause of small-duct biliary diseases ABCB4 deficiency(Hepatitis C, B, E) can be made with confidence in a patient with high-titerAMA (P1/40) and a cholestatic serum enzyme profile in 2. Fibrous obliterative cholangitis the absence of an alternative explanation . A liver Primary sclerosing cholangitisSecondary sclerosing cholangitis 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 3. Other cholangitis (unusual) the next diagnostic step for most patients with chronic Malignant cholangitis intrahepatic cholestasis of unknown cause.
Lymphoma (Hodgkin or non-Hodgkin) Subsequently, a liver biopsy should be performed Systemic mastocytosis when the diagnosis is still unclear. Particular attention Langerhans cell histiocytosis to the condition of bile ducts is critical in the histologic Neutrophilic cholangitis: neutrophilic dermatosis evaluation and a biopsy of adequate quality should con- 4. Ductal plate malformations tain P10 portal fields because of the high degree of sam- Biliary hamartomas (von Meyenburg complexes)Caroli syndrome pling variability in patients with small bile duct disease.
Congenital hepatic fibrosis Biopsy findings should be classified under (i) disordersinvolving bile ducts (for typical biliary lesions, see ) the main causes being AMA-negative PBC, isolated 6. Diagnostic endoscopic retrograde cholangiopancrea- small duct PSC, ABCB4 deficiency, sarcoidosis, idio- tography (ERCP) should be reserved for highly pathic ductopenia or prolonged drug-induced cholesta- selected cases (II-2/A1). If the need for a therapeutic sis; (ii) disorders not involving bile ducts, the main maneuver is not anticipated, MRCP or EUS should causes being a variety of storage or infiltrative liver dis- be preferred to ERCP because of the morbidity and eases, hepatic granulomas (without cholangitis), nodular mortality related to ERCP (II-2/A1).
regenerative hyperplasia, peliosis, sinusoidal dilatation 7. A liver biopsy should be considered in patients with and cirrhosis; and (iii) hepatocellular cholestasis with otherwise unexplained intrahepatic cholestasis and a only minimal histologic abnormalities as observed in negative AMA test (III/C1).
benign recurrent intrahepatic cholestasis (BRIC), estro- 8. Genetic testing for ABCB4 (encoding the canalicular gen or anabolic steroid therapy, sepsis, total parenteral phospholipid export pump), when available, should nutrition or as a paraneoplastic phenomenon.
be considered in patients with a negative AMA test A general algorithm for evaluating the adult patient and biopsy findings that might be compatible with with cholestasis is presented in 3. Primary biliary cirrhosis (PBC) 1. A detailed history and physical examination are 3.1. Diagnosis of PBC essential (III/C1).
2. Ultrasound is the first-line non-invasive imaging pro- Patients with PBC may present with symptoms as cedure in order to differentiate intra- from extrahe- fatigue, pruritus and/or jaundice, but the majority of patic cholestasis (III/C1).
them are asymptomatic at diagnosis. At first presenta- tion, very few patients present in advanced stage of dis- (AMA) is mandatory in adults with chronic intrahe- ease and with complications of portal hypertension patic cholestasis (III/C1).
(ascites, hepatic encephalopathy or esophageal variceal bleeding). Currently, a diagnosis of PBC is made with (MRCP) is the next step to be considered in patients confidence on a combination of abnormal serum liver with unexplained cholestasis (III/C1).
tests (elevation of AP of liver origin for at least 6 5. Endoscopic ultrasound (EUS) is an alternative to months) and presence of AMA (P1:40) in serum .
MRCP for evaluation of distal biliary tract obstruc- The diagnosis is confirmed by disclosing characteristic tion (II-2/B1).

European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 Fig. 1. Diagnostic approach to cholestasis in adult patients. Abbreviations: US, ultrasound; CT, computed tomography; AMA, antimitochondrialantibodies; ANA, antinuclear antibodies; MRCP, magnetic resonance cholangiopancreatography; ERCP, endoscopic retrograde cholangiopancreatog-raphy; PBC, primary biliary cirrhosis; SC, sclerosing cholangitis.
AMA-positive individuals with normal AP carry a high with PBC typically present elevated levels of immuno- risk to develop PBC during follow-up globulin M. Serum cholesterol is commonly elevated likein other cholestatic conditions. Alterations in prothrom- 3.1.1. Laboratory tests bin time, serum albumin and conjugated bilirubin are Biochemical markers: Serum AP and cGT are raised observed only in advanced disease.
in PBC; serum aminotransferases (ALT, AST) and con- Immunological markers: The diagnostic hallmark of jugated bilirubin can also be elevated, but are not diag- PBC is the presence of AMA, which are detected in nostic. Patients with normal AP and cGT, but with serum of more than 90% of affected individuals; the spec- serological stigmata of PBC, should be reassessed clini- ificity of AMA in PBC is greater than 95% AMA cally and biochemically at annual intervals. Patients reactivity is classically studied by immunofluorescence European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 and considered positive at a titre P1/40 The identifi- 3. AMA-positive individuals with normal serum liver cation of the molecular mitochondrial target antigens tests should be followed with annual reassessment has allowed the setting up of immunoenzymatic assays of biochemical markers of cholestasis (III/C2).
with recombinant proteins that raise the sensitivity andspecificity of the test. If available, anti-AMA-M2 (anti- 3.2. Treatment of PBC PDC-E2) may be a useful alternative. Non-specific anti-nuclear antibodies (ANA) are found in at least 30% of 3.2.1. Ursodeoxycholic acid (UDCA) PBC sera. However, ANA directed against nuclear body Over the past two decades, increasing evidence has or envelope proteins such as anti-Sp100 and anti-gp210 which present as multiple nuclear dots and perinu- (UDCA; 13–15 mg/kg/d) is the treatment of choice for clear rims, respectively, at indirect immunofluorescence patients with PBC based on placebo-controlled trials staining show a high specificity for PBC (>95%) and and more recent long-term case-control studies. UDCA can be used as markers of PBC when AMA are absent.
has been demonstrated to exert anticholestatic effects in Their sensitivity, however, is low.
various cholestatic disorders. Several potential mecha-nisms and sites of action of UDCA have been unraveled in clinical and experimental studies which might explain A liver biopsy is no longer regarded as mandatory to its beneficial effects. Their relative contribution to the make a diagnosis of PBC in patients with a cholestatic anticholestatic action of UDCA might depend on the serum enzyme pattern and serum AMA. It may, how- type of the cholestatic injury. In early-stage PBC, pro- ever, be useful for assessment of the activity and staging tection of injured cholangiocytes against the toxic effects of the disease. Histological staging of PBC (stages 1–4) of bile acids might prevail, and stimulation of impaired has been proposed by Ludwig et al.and Scheuer hepatocellular secretion by mainly posttranscriptional according to the degree of bile duct damage, inflam- mechanisms including stimulation of synthesis, targeting mation and fibrosis. Focal duct obliteration with granu- and apical membrane insertion of key transporters loma formation has been termed the florid duct lesion, might be relevant in more advanced cholestasis In and is judged almost pathognomonic for PBC when addition, stimulation of ductular alkaline choleresis present. The liver is not uniformly involved, and features and inhibition of bile acid-induced hepatocyte and cho- of all four stages of PBC can co-exist simultaneously in a langiocyte apoptosis can have a certain role for the ben- single biopsy. The most advanced histological features eficial effect of UDCA in PBC should be used for histological staging.
UDCA has been demonstrated to markedly decrease serum bilirubin, AP, cGT, cholesterol and immunoglob-ulin M levels, and to ameliorate histological features in patients with PBC in comparison to placebo treatment Abdominal ultrasound examination is indicated in all although no significant effects on fatigue or pru- patients with elevation of serum AP and cGT to disclose ritus were observed in these large trials. Moreover, long- intrahepatic or extrahepatic bile duct dilatation (see term treatment with UDCA delayed the histological above) or focal liver lesions. There are no specific fea- progression of the disease in patients in whom treatment tures of PBC on ultrasound; in particular the biliary tree was started at an early stage Still, a clear-cut appears normal. Ultrasound findings in advanced PBC beneficial effect of UDCA on survival has not been resemble those seen in other forms of cirrhosis.
shown in any of the studies mentioned above, probablydue to the limited number of patients and the limited observation periods too short for a slowly progressingdisease. A beneficial effect of UDCA on survival has 1. A diagnosis of PBC can be made with confidence in only been demonstrated in a combined analysis of the adult patients with otherwise unexplained elevation raw data from the French, Canadian and Mayo cohorts of AP and presence of AMA (P1:40) and/or followed up for 4 years . In this analysis, UDCA AMA type M2. A liver biopsy is not essential for treatment was associated with a significant reduction the diagnosis of PBC in these patients, but allows in the likelihood of liver transplantation or death. This activity and stage of the disease to be assessed benefit was seen in patients with moderate and severe disease but not in those with mild disease (serum biliru- 2. A liver biopsy is needed for the diagnosis of PBC in bin concentration <1.4 mg/dL (24 lmol/L), stage I or II the absence of PBC specific antibodies. A liver biopsy histologic change) in whom progression to end-stage may also be helpful in the presence of disproportion- disease did not occur during the 4-year period of obser- ally elevated serum transaminases and/or serum IgG levels to identify additional or alternative processes The affirmative results on survival have been chal- lenged by meta-analyses which included a majority of European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 studies of up to two years' duration and trials using tion. Development of portal vein thrombosis probably UDCA doses which are today known to be ineffective related to short-term budesonide administration was Inclusion of trials which have a duration of three reported in stage 4 patients with portal hypertension months to two years for a disease with an estimated . Thus, budesonide should not be administered to cir- duration of one to two decades without intervention rhotic patients.
may be suited to analyze biochemical effects of medical Other immunosuppressive agents like azathioprine treatment, but certainly carries a risk to dilute the infor- , cyclosporine A methotrexate chloram- mation needed for a well-based survival analysis. There- bucil and mycophenolate mofetil proved to be fore, it was not surprising that meta-analyses which marginally effective, ineffective or potentially harmful excluded studies of short duration (less than 24 months) during long-term administration and cannot be recom- and those that used an ineffective dose of UDCA (less mended for standard treatment in PBC.
than 10 mg/kg/d) concluded that long-term UDCA sig-nificantly improved transplant-free survival and delayed 3.2.3. Anti-fibrotic agents histologic progression in early-stage patients .
Colchicine was inferior to UDCA in the treatment of Recent reports have demonstrated the favorable effects PBC and did not, when combined with UDCA in of UDCA on long-term survival in patients with PBC comparison to UDCA alone significantly improve receiving standard doses (13–15 mg/kg/d) over 10– symptoms, serum liver tests, serum markers of fibrosis, 20 years. Treatment with UDCA led to a transplant-free or histological features. Thus, addition of colchicine to survival similar to that of a healthy control population UDCA currently cannot be recommended in the treat- matched for age and gender in patients with early-stage ment of PBC.
disease and to improved survival in comparison D-Penicillamine is not effective in PBC and can be to the estimated survival at the start of treatment as calcu- associated with severe side effects lated by the Mayo risk score for PBC Interest-ingly, a ‘‘good biochemical response" to UDCA defined 3.2.4. Other drugs as a decrease in AP >40% of pretreatment levels or nor- Malotilate , thalidomide , silymarin and malization at one year (‘‘Barcelona criteria") was associ- atorvastatin were not effective in the treatment of ated with an excellent 95% transplant-free survival at 14 PBC. Sulindac and the peroxisome proliferator-acti- years of follow-up, similar to that predicted for the stan- vated receptor a (PPARa) agonist, bezafibrate dardized population The prognostic impact of the improved some serum liver tests in limited groups of ‘‘Barcelona criteria" was confirmed in a large indepen- patients with an incomplete response to UDCA, and dent cohort of PBC patients for which a serum bilirubin bezafibrate deserves further studies. Tamoxifen 61 mg/dL (17 lmol/L), AP 63 ULN, and AST 62 decreased AP levels in two women who were taking it ULN (‘‘Paris criteria") after one year of treatment even after surgery for breast cancer.
better identified those with a good long-term prognosis Antiretroviral strategies have also been tested in of a 90% (vs. 51%) ten year transplant-free survival .
PBC: Lamivudine alone or in combination with zidovu- Thus, additional therapeutic options for those patients dine (Combivir) was associated with minor clinical and failing to reach a ‘‘good biochemical response" under biochemical effects. Combivir was also associated with UDCA are warranted.
improvement of some histological features, but this find-ing needs confirmation in randomized studies 3.2.2. Corticosteroids and other immunosuppressiveagents 3.2.5. Liver transplantation Prednisolone improved serum liver tests and histolog- Liver transplantation has dramatically improved sur- ical features, but markedly worsened bone mineral den- vival in patients with late-stage PBC. Indications are not sity in patients with PBC prohibiting its long-term different from those of patients with other etiologies of use in PBC. In combination with UDCA (10 mg/kg/ liver failure : decompensated cirrhosis with an unac- d), prednisolone (10 mg/d, 9 months) exerted beneficial ceptable quality of life or anticipated death within a year effects on various features of liver histology in early- due to treatment-resistant ascites and spontaneous stage PBC in comparison to UDCA alone .
bacterial peritonitis, recurrent variceal bleeding, enceph- Budesonide in combination with UDCA showed alopathy or hepatocellular carcinoma. Severe, treat- favorable results on biochemical and histological param- ment-resistant pruritus may merit consideration for eters in early-stage disease , but not late-stage dis- transplantation. Patients should be referred to a liver ease . Studies with a longer follow-up using the transplant center for assessment when their bilirubin combination of budesonide and UDCA in patients with approaches 6 mg/dL (103 lmol/L), the Mayo risk score early-stage disease not adequately responding to UDCA is P7,8, and the MELD score is >12 at the latest.
alone are warranted to confirm its safety and its effect on Survival rates above 90% and 80–85% at one and five postponing or preventing the need for liver transplanta- years, respectively, have been reported by many centers European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 . Most patients have no signs of liver disease after orthotopic liver transplantation, but their antimitoc-hondrial antibody status does not change. The disease Standardization of diagnostic criteria for PBC–AIH recurs with a calculated weighted disease recurrence of overlap syndrome has not been achieved so far, and 18% , but rarely is associated with graft failure ‘‘overlap syndrome" is a much overused descriptive termin hepatology . Diagnosis of PBC and AIH is based on the combination of biochemical, serological and his-tological features. However, no individual test shows 1. Patients with PBC, including those with asymptom- absolute specificity and much depends on the relative atic disease, should be treated with UDCA (13– weighting of individual diagnostic criteria, and the cut- 15 mg/kg/d) (I/A1) on a long-term basis (II-2/B1).
off levels of continuous variables considered representa- 2. Favorable long-term effects of UDCA are observed in tive for one or another condition The 1999 scoring patients with early disease and in those with good bio- system, established by the International Autoimmune chemical response (II-2/B1), which should be assessed Hepatitis Group (IAIHG) for research purposes, com- after one year. A good biochemical response after one prises characteristic features of AIH and provides sup- year of UDCA treatment is currently defined by a port for diagnosing AIH . However, applicability serum bilirubin 61 mg/dL (17 lmol/L), AP 63 of this scoring system remains questionable in this spe- ULN and AST 62 ULN (‘‘Paris criteria") or by a cific setting since a score of ‘‘definite" AIH can be only decrease of 40% or normalization of serum AP (‘‘Bar- observed in the very few patients with characteristic celona criteria") (II-2/B1).
overlap syndrome whereas nearly 20% of PBC subjects 3. There is currently no consensus on how to treat patients with a suboptimal biochemical response to The simplified diagnostic score recently pro- UDCA. One suggested approach is the combination posed by the IAIHG has not been validated yet in of UDCA and budesonide (6–9 mg/d) in non-cir- patients with suspected PBC–AIH overlap syndrome rhotic patients (stages 1–3) (III/C2). Further studies To differentiate PBC from PBC–AIH overlap syn- of this and other combination regimes should be a drome, another diagnostic score has been established but the usefulness of this rather complex score needs 4. Liver transplantation should be strongly considered confirmation by cross-evaluation prior to introduction in patients with advanced disease as reflected by to the clinic Because of the limited applicability serum bilirubin exceeding 6 mg/dL (103 lmol/L) or of the different diagnostic scores, another approach decompensated cirrhosis with an unacceptable quality based on the major characteristics of PBC and AIH of life or anticipated death within a year due to treat- has been proposed and requires the presence of at least ment-resistant ascites and spontaneous bacterial peri- 2 of the 3 accepted criteria of both diseases for diagnos- tonitis, recurrent variceal bleeding, encephalopathy ing PBC–AIH overlap syndrome whereby or hepatocellular carcinoma (II-2/A1).
histologic evidence of moderate to severe lymphocyticpiecemeal necrosis (interface hepatitis) is mandatory.
In addition to cases with simultaneous characteristics 4. PBC–AIH overlap syndrome of PBC and AIH, which is the most frequent mode ofpresentation, transitions from PBC to AIH or vice-versa Primary biliary cirrhosis (PBC) and autoimmune hep- have been described and termed ‘‘sequential syndromes" atitis (AIH) are classically viewed as distinct liver dis-eases. However, patients presenting with clinical, Table 4Diagnostic criteria of PBC–AIH overlap syndrome.
biochemical, serological, and/or histological features reminiscent of both diseases, either simultaneously or 1. AP >2 ULN or cGT >5 ULN consecutively have been repeatedly recognized. The ill- defined term ‘‘overlap syndrome" is used to describe these 3. Liver biopsy specimen showing florid bile duct lesions settings The pathogenesis of PBC–AIH overlap syndrome is debated and it remains unclear whether this 1. ALT >5 ULN syndrome forms a distinct entity or a variant of PBC or 2. IgG >2 ULN or a positive test for anti-smooth muscle antibodies AIH. Different pathophysiological mechanisms have been discussed: (i) a pure coincidence of two independent 3. Liver biopsy showing moderate or severe periportal or periseptallymphocytic piecemeal necrosis autoimmune diseases; (ii) a different genetic backgroundwhich determines the clinical, biochemical and histologi- Diagnostic criteria of PBC–AIH overlap syndrome of which at least 2of 3 accepted criteria for PBC and AIH, respectively, should be present cal appearance of one autoimmune disease entity; and (iii) (proposed by Chazouilleres et al. ). Histologic evidence of moder- a representation of the middle of a continuous spectrum ate to severe lymphocytic piecemeal necrosis (interface hepatitis) is of two autoimmune diseases mandatory for the diagnosis.
European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 or consecutive forms Occurrence of superimposed tive alternative to corticosteroids for long-term immu- AIH cannot be predicted from baseline characteristics nosuppressive therapy. Interestingly, by comparison and initial response to UDCA therapy in PBC patients with typical AIH, it has been suggested that doses of Lastly, overlap of AMA-negative PBC with AIH immunosuppressants could be lower and rate of success- has also been reported ful withdrawal higher For corticosteroid-resistant Precise prevalence of PBC–AIH overlap syndrome is patients, a beneficial effect of other immunosuppressants unknown but approximately 10% of adults with AIH or such as cyclosporine A has been reported .
PBC may belong in this overlap category .
In UDCA-treated PBC patients developing AIH Patients with PBC–AIH overlap syndrome might have (‘‘sequential" overlap), use of immunosuppressive treat- a more severe disease with worse clinical outcomes com- ment is mandatory pared to patients with PBC alone This emphasizesthe notion that overlap syndrome should always be con- sidered once PBC has been diagnosed 1. Standardization of diagnostic criteria for PBC–AIH overlap syndrome has not been achieved. Strict diag-nostic criteria as shown in provide a useful The low prevalence of PBC–AIH overlap syndrome diagnostic template (III/C2).
has made controlled therapeutic trials impossible in 2. PBC–AIH overlap syndrome should always be con- these patients. Thus, therapeutic recommendations rely sidered once PBC has been diagnosed because of on the experience in the treatment of either PBC or potential implications for therapy (III/C2).
AIH, and on retrospective, non-randomized studies.
3. Combined therapy with UDCA and corticosteroids is Whether PBC–AIH overlap syndrome requires immu- the recommended therapeutic option in patients with nosuppressive therapy in addition to UDCA is a PBC–AIH overlap syndrome (III/C2). An alternative debated issue. Under UDCA therapy, biochemical approach is to start with UDCA only and to add cor- response at 24 months and survival in one cohort of ticosteroids if UDCA therapy has not induced an 12 strictly defined PBC–AIH overlap syndrome patients adequate biochemical response in an appropriate time were similar to 159 patients with ‘‘pure" PBC . How- span (3 months) (III/C2). Steroid sparing agents ever, adjunction of immunosuppressive therapy was should be considered in patients requiring long-term required in most patients of other cohorts to obtain a complete biochemical response In the largestlong-term follow-up study, 17 strictly defined patientsreceived UDCA alone or UDCA in combination 5. Primary sclerosing cholangitis with immunosuppressors and were followed for 7.5years. In the 11 patients treated with UDCA alone, bio- Primary sclerosing cholangitis (PSC) is a chronic, chemical response in terms of AIH features (ALT <2 cholestatic liver disease that is characterized by an ULN and IgG <16 g/L) was observed in only 3 patients inflammatory and fibrotic process affecting both intra- whereas the 8 others were non-responders with increased and extrahepatic bile ducts . The disease leads to fibrosis in 4. Overall, fibrosis progression in non-cir- irregular bile duct obliteration, including formation of rhotic patients occurred more frequently under UDCA multifocal bile duct strictures. PSC is a progressive dis- monotherapy (4/8) than under combined therapy (0/6) order that eventually develops into liver cirrhosis and (p = 0.04). These results strongly suggest that combined liver failure. The etiology of PSC is unknown, but there therapy (UDCA and corticosteroids) is the best thera- is evidence that genetic susceptibility factors are peutic option in most patients with strictly defined involved The male to female ratio is approximately simultaneous PBC–AIH overlap syndrome. An alterna- 2:1. PSC can be diagnosed in children as well as in the tive approach is to start with UDCA alone and to add elderly, but mean age at diagnosis is around 40 years.
corticosteroids if UDCA therapy does not induce an Up to 80% of PSC patients have concomitant inflamma- adequate biochemical response in an appropriate time tory bowel disease (IBD) that in the majority of cases is span (e.g., 3 months) Prednisone has been used at diagnosed as ulcerative colitis (UC). Thus, the ‘‘typical" an initial dose of 0.5 mg/kg/d and should be progres- PSC patient is a young to middle-aged man with IBD sively tapered once ALT levels show a response .
who presents with biochemical and/or clinical signs of Budesonide is a promising treatment option for patients a cholestatic liver disease.
with AIH and has also been used with success in somepatients with PBC–AIH overlap syndrome The role 5.1. Diagnosis of PSC of other immunosuppressants, e.g., azathioprine, in thelong-term management of these patients is unclear, but A diagnosis of PSC is made in patients with elevated its successful use in AIH makes azathioprine an attrac- serum markers of cholestasis (AP, cGT) not otherwise European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 explained, when magnetic resonance cholangiopancrea- cific. A routine autoantibody screening is not required to tography (MRCP) or endoscopic cholangiopancreatog- establish a diagnosis of PSC. Analysis of ANA and raphy (ERCP) show characteristic bile duct changes SMA may be relevant in a subgroup of patients to sup- with multifocal strictures and segmental dilatations, port a suspicion of ‘‘autoimmune" features that may and causes of secondary sclerosing cholangitis and have therapeutic implications (see ‘‘PSC–AIH overlap other cholestatic disorders are excluded. Patients who present with clinical, biochemical and histological fea-tures compatible with PSC, but have a normal cholangi- 5.1.4. Liver biopsy ogram, are classified as small duct PSC.
Liver histological findings may support a diagnosis of PSC, but they are non-specific and may show consider- 5.1.1. Signs and symptoms able variation. PSC has been described to progress About 50% of PSC patients are symptomatic at first through four stages. The initial changes (stage 1, portal presentation. Typical symptoms include pruritus, pain stage) are limited to the portal tracts with features in the right upper abdominal quadrant, fatigue, weight including portal oedema, mild portal hepatitis, a non- loss, and episodes of fever and chills, which are reported destructive cholangitis with infiltration of lymphocytes in a variable number of patients Symptoms of liver in the bile ducts, and ductular proliferation. Periductal cirrhosis and portal hypertension with ascites and vari- fibrosis and fibrous-obliterative cholangitis may be pres- ceal hemorrhage are more rarely reported at diagnosis ent. In stage 2 (periportal stage), the lesion extends to in PSC. Hepatomegaly and splenomegaly are the most involve periportal fibrosis, sometimes with interphase frequent findings at clinical examination at the time of hepatitis. Portal tracts are often enlarged. In stage 3 diagnosis in PSC. Osteopenic bone disease is a complica- (septal stage) there is development of bridging fibrous tion of advanced PSC, although less frequent than that septa, while bile ducts degenerate and disappear. Stage reported in PBC. Fat malabsorption with steatorrhea 4 is characterized by cirrhosis . Periductal concentric and malabsorption of fat-soluble vitamins occur only fibrosis is considered highly suggestive of PSC, but this with prolonged cholestasis.
finding is relatively infrequent in needle biopsies inPSC and may also be associated with other conditions.
5.1.2. Biochemical tests Histological changes can be very subtle, and a liver Elevation of serum AP is the most common biochem- biopsy may even appear normal because of sampling ical abnormality in PSC However, a normal AP variability and since the liver is not uniformely involved.
activity should not preclude further steps to diagnose In PSC patients with relatively high serum aminotrans- PSC if suspected on clinical basis. Serum aminotransfer- ferase levels, particularly in combination with positive ase levels are elevated at diagnosis in the majority of ANA and/or SMA titres and markedly elevated IgG lev- patients, typically to levels 2–3 times upper limits of nor- els, a liver biopsy may be indicated to disclose features mal, but normal levels are also observed. Serum biliru- of a PSC–AIH overlap syndrome.
bin levels are normal at diagnosis in up to 70% ofpatients. Elevated levels of IgG have been noted in 61% of patients, most often to a level up to 1.5 times Ultrasonography (US): In PSC, US is not diagnostic upper limit of normal In one retrospectively studied and often normal, but bile duct wall thickening and/or cohort, 9% of PSC patients were reported with slightly focal bile duct dilatations may be observed by experts.
elevated IgG4 levels, but total IgG was not reported in One or more gallbladder abnormalities, including wall these patients. It remains unclear whether some of these thickening, gallbladder enlargement , gallstones, patients suffered from cholecystitis, and mass lesions, have been reported on (IAC) rather than PSC . Increased IgM levels have the basis of US or cholangiography in up to 41% of been reported in up to 45% of PSC cases PSC patients .
Cholangiography: A detailed cholangiographic assess- 5.1.3. Autoantibodies ment of the biliary tree is essential in making a diagnosis A variety of autoantibodies have been detected in of PSC . Efforts should be made to adequately visu- PSC The autoantibodies most frequently reported alize also the intrahepatic ducts to avoid false-negative are perinuclear antineutrophil cytoplasmic antibodies results by overlooking subtle changes. The characteristic (pANCA) (26–94%), antinuclear antibodies (ANA) (8– cholangiographic findings of PSC include mural irregu- 77%), and smooth muscle antibodies (SMA) (0–83%) larities and diffusely distributed multifocal, short, annu- . The pANCA pattern in PSC is ‘‘atypical", as the lar strictures alternating with normal or slightly dilated putative antigen is located in the nucleus rather than segments producing a ‘‘beaded" pattern Sometimes in the cytoplasm. Atypical pANCA is frequently present outpouchings have a diverticular appearance . With in UC and AIH, and specificity in the diagnosis of PSC more advanced disease, long, confluent strictures may be is low. Positive titres of ANA and SMA also are unspe- seen . In the majority of cases, both the intra- and European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 extrahepatic bile ducts are involved. A variable propor- a negative mutation analysis of ABCB4 in patients with- tion of patients (<25%) is described to have isolated out IBD. Diagnostic criteria in small duct PSC are how- intrahepatic disease, whereas lesions confined to the ever still being discussed.
extrahepatic ducts are rarely observed (usually <5%)and should only be diagnosed in the presence of ade- 5.1.7. PSC in children quate filling of the intrahepatic ducts. Since intrahepatic Criteria for diagnosis of PSC in adults also apply to bile duct abnormalities can also be seen in other chronic children. Of note, levels of serum AP activity were liver diseases, one must be cautious when diagnosing observed within the normal range for the age group in PSC in the presence of intrahepatic changes only. The up to 47% of cases . Patients with normal AP gallbladder and cystic duct are involved in some cases, usually had elevated cGT activity . Presentation and abnormalities of the pancreatic duct resembling of PSC in children is frequently reported with features those of chronic pancreatitis have been noted in a vari- similar to those of autoimmune hepatitis, including able number of PSC patients .
high IgG concentrations, positive ANA and/or SMA titers and interphase hepatitis in the liver biopsy (ERCP) has been the gold standard in diagnosing PSC but ERCP is associated with complications suchas pancreatitis and sepsis Clinicians may be reluc-tant to proceed with an ERCP in the assessment of cho- 5.1.8. Differential diagnosis of PSC versus secondary lestasis, and therefore, PSC most likely has been an forms of sclerosing cholangitis underdiagnosed condition. Magnetic resonance cholan- Before the diagnosis of PSC can be settled, causes of giopancreatography (MRCP) is a non-invasive method secondary sclerosing cholangitis such as previous bili- that in experienced centres is now generally accepted ary surgery, cholangiolithiasis and disorders mimicking as a primary diagnostic modality in cases of suspected PSC such as carcinoma of the bile ducts have to be PSC. Studies comparing ERCP and MRCP have shown excluded although cholangiolithiasis and cholangiocar- similar diagnostic accuracy, although the depiction of cinoma may also be the consequence of PSC Clin- bile ducts may be poorer with MRCP than with ERCP ical and cholangiographic findings resembling those of Sensitivity and specificity of MRCP has been PSC have most commonly been described in relation to P80% and P87%, respectively, for the diagnosis of intraductal stone disease, surgical trauma from chole- PSC MRCP is superior in visualizing bile ducts cystectomy, abdominal injury, intra-arterial chemother- proximal to duct obstructions. The method can also apy, and recurrent pancreatitis . A variety of other reveal changes within the bile duct walls and pathologies conditions have also been associated with features in the liver parenchyma as well as in other organs. How- imitating those of PSC, including IgG4-associated ever, cases with mild PSC changes without bile duct dila- cholangitis/autoimmune pancreatitis (see below), hepa- tation may be missed by MRCP and one should tic inflammatory pseudotumor, eosinophilic cholangi- therefore be cautious to exclude early PSC on the basis tis, mast cell cholangiopathy, portal hypertensive of a normal MRCP. Thus, diagnostic ERCP still has a biliopathy, AIDS cholangiopathy, recurrent pyogenic role in equivocal cases. The main role of ERCP, how- cholangitis, ischemic cholangitis, as well as others ever, lies in therapeutic procedures and in diagnostic . Differentiating between primary and secondary purposes like cytology sampling in PSC.
sclerosing cholangitis may be particularly difficult sincePSC patients themselves may have undergone bile duct 5.1.6. Small duct PSC surgery or have concomitant intraductal stone disease The term small duct PSC refers to a disease entity or even cholangiocarcinoma (CCA). Factors like clini- which is characterized by clinical, biochemical, and his- cal history, the distribution of the cholangiographic tological features compatible with PSC, but having a abnormalities, as well as the presence of concomitant normal cholangiogram . One report has restricted IBD, have to be taken into account when determining the diagnosis of small duct PSC to patients with con- whether a pathological cholangiogram is due to PSC or comitant IBD , whereas IBD has only been present secondary to a benign or malignant bile duct stricture in a proportion (50–88%) of cases in other studies without PSC .
These studies carry the risk to include patientswith other cholangiopathies such as ABCB4 deficiency which cause histological features compatible with smallduct PSC . A high-quality cholangiogram is manda- 1. A diagnosis of PSC is made in patients with biochem- tory in order to exclude PSC with isolated intrahepatic ical markers of cholestasis not otherwise explained, distribution. One future approach for the diagnosis of when MRCP shows typical findings and causes of sec- small duct PSC is to accept a negative MRC in patients ondary sclerosing cholangitis are excluded (II-2/B1).
with concomitant IBD, but require a normal ERCP and A liver biopsy is not essential for the diagnosis of European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 PSC in these patients, but allows activity and staging incidence of 10–15% whereas gallbladder carci- of the disease to be assessed.
noma and HCC are observed in up to 2% of 2. A liver biopsy should be performed to diagnose small PSC patients, each. Up to 50% of CCA are diagnosed duct PSC if high-quality MRCP is normal, (III/C2).
within the first year of diagnosis of PSC. After the first A liver biopsy may also be helpful in the presence year, the yearly incidence rate is 0.5–1.5% .
of disproportionally elevated serum transaminases Although factors like older age, alcohol consumption and/or serum IgG levels to identify additional or and smoking, long duration of IBD before diagnosis alternative processes (III/C1).
of PSC, and a history of colorectal malignancy, have 3. ERCP can be considered been associated with an increased risk of CCA in PSC, If high-quality MRCP is uncertain (III/C2): the no clinically useful prognostic variables have been iden- diagnosis of PSC is made in the case of typical tified so far. Possible genetic markers should be further ERCP findings.
explored . The symptoms of CCA complicating PSC In patients with IBD with normal high-quality may be very difficult to differentiate from those of PSC MRCP but high suspicion for PSC (III/C2).
without concomitant malignancy, but awareness ofCCA must in particular be raised in cases of rapid clin-ical deterioration.
5.2. Follow-up of PSC Median levels of the serum tumour marker carbohy- drate antigen 19-9 (CA 19-9) are significantly higher in 5.2.1. Inflammatory bowel disease and risk of colon PSC patients with CCA than in those without , but in the individual case CA 19-9 cannot be relied upon in PSC is strongly associated with IBD, with a preva- the differential diagnosis between PSC with and without lence of IBD in Western countries commonly in the CCA Distinguishing benign from malignant range of 60–80% whereas in a recent report on changes in PSC by imaging modalities like US, CT, 391 Japanese patients only 125 had a history of concom- MRCP/MRI as well as ERCP, is equally difficult itant IBD . UC accounts for the majority (80%) of Serum CA 19-9 combined with cross-sectional IBD cases in PSC, while around 10% have Crohn‘s dis- liver imaging may be useful as a screening strategy , ease and another 10% are classified as indeterminate but further validation is needed. Whether dynamic (18F)- colitis IBD can be diagnosed at any time during fluoro-deoxy-D-glucose positron emission tomography the course of PSC, but in a majority of cases IBD pre- (FDG-PET) is more effective when combined with cedes PSC. Since the colitis in PSC characteristically is CT or MRI, needs to be shown. Brush cytology sampling, mild and sometimes even asymptomatic, colonoscopy and biopsy when feasible, during ERCP adds to the diag- with biopsies is recommended as part of the routine nostic accuracy of CCA in PSC but meth- work-up in a patient diagnosed with PSC. A diagnosis odological refinement including validation of digital of IBD has implications for follow-up and dysplasia/ image analysis (DIA) and fluorescence in situ hybridiza- cancer surveillance as patients with UC and PSC have tion (FISH) of cell samples is needed.
a higher risk of dysplasia and colon cancer than patients Gallbladder mass lesions in PSC frequently (>50%) with UC only Compared to UC patients with- represent adenocarcinomas independently of their size out PSC, the colitis in PSC more frequently is a panco- Cholecystectomy is recommended in PSC patients litis (87% vs. 54%), with backwash ileitis (51% vs. 7%), with a gallbladder mass even <1 cm in diameter .
and rectal sparing (52% vs. 6%) . Patients with The risk for pancreatic carcinoma was 14-fold increased PSC and Crohn‘s disease characteristically only have in a Swedish cohort of PSC patients in comparison to a colonic involvement. We recommend that PSC patients matched-control population , but its incidence in with colitis are enrolled in a surveillance program with PSC is markedly lower than that of hepatobiliary malig- annual colonoscopy with biopsies from the time of diag- nancies, and regular screening strategies are, therefore, not recommended at present.
5.2.2. Hepatobiliary malignancies in PSC PSC is associated with an increased risk of hepatob- iliary malignancies, in particular cholangiocarcinoma 1. Total colonoscopy with biopsies should be performed (CCA). In a large cohort of 604 Swedish PSC patients in patients in whom the diagnosis of PSC has been followed for (median) 5.7 years, hepatobiliary malignan- established without known IBD (III/C1) and should cies (CCA, hepatocellular carcinoma (HCC), and gall- be repeated annually (or every 1–2 years in individu- alized patients) in PSC patients with colitis from the corresponding to a risk 161 times that of the general time of diagnosis of PSC (III/C1).
population CCA is by far the most common hepa- 2. Annual abdominal ultrasonography should be con- tobiliary malignancy in PSC, with a cumulative life-time sidered for gallbladder abnormalities (III/C2).
European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 3. There is at present no biochemical marker or imaging aborted because of an enhanced risk in the UDCA treat- modality which can be recommended for early detec- ment group to reach primary endpoints such as liver tion of cholangiocarcinoma. ERCP with brush cytol- transplantation or development of varices in more ogy (and/or biopsy) sampling should be carried out advanced disease while biochemical features improved when clinically indicated (III/C2).
in the whole UDCA group . Thus, the role forUDCA in slowing the progression of PSC-related liver 5.3. Treatment of PSC disease is as yet unclear and high dose UDCA may beharmful in late-stage disease.
5.3.1. Ursodeoxycholic acid (UDCA) UDCA and chemoprevention: Recent work has sug- UDCA and disease progression: UDCA is an effective gested that UDCA may have a role in the prevention treatment of primary biliary cirrhosis (PBC) as outlined of colonic neoplasia in patients with PSC associated above (2.2.1). UDCA has, therefore, also been investi- with underlying IBD. Experimental studies in vitro gated as a potential candidate for the treatment of and in vivo had suggested that UDCA might prevent PSC. Small pilot trials of UDCA in the early 1990's development of colon carcinoma. A cross-sectional demonstrated biochemical and in some cases histologi- study of 59 PSC patients with ulcerative colitis (UC) cal improvement in PSC patients using doses of 10– undergoing colonoscopic surveillance found a signifi- 15 mg/kg/day A more substantial trial was cantly reduced risk of colonic dysplasia in patients tak- published by Lindor in 1997 recruiting 105 ing UDCA although in comparison to an exceptionally patients in a double-blind placebo-controlled trial of high rate of dysplasia in the control group A his- 13–15 mg/kg of UDCA for 2 years. The results indicated torical cohort study compared 28 PSC patients under improvement in serum liver tests but not in symptoms UDCA treatment with UC to 92 PSC patients with and, most importantly, no improvement in liver histol- UC not treated with UDCA and found a trend ogy as evaluated by disease stage Higher doses towards a lower risk of colonic dysplasia and neoplasia of UDCA were then studied on the grounds that larger under UDCA treatment (adjusted relative risk 0.59, doses might be necessary to provide sufficient enrich- 95% CI 0.26–1.36, p = 0.17) and a lower mortality ment of the bile acid pool in the context of cholestasis, and that these doses might also enhance the potential p = 0.02) A third study followed 52 patients with immunomodulatory effect of the drug. Studies using PSC and UC for 355 patient-years who participated in 20–25 mg/kg/day demonstrated significant improve- a randomized, placebo-controlled UDCA trial showing ments in the histological grade of liver fibrosis and the a significant reduction to 0.26 (95% CI 0.06–0.92, cholangiographic appearances of PSC, as well as the p = 003) in UDCA-treated patients in the relative expected biochemical improvement A shorter, risk of developing colorectal dysplasia or carcinoma open-label trial using 25–30 mg/kg/day showed a signif- icant improvement in projected survival using the Mayo Limited evidence for a beneficial effect of UDCA on risk score, but no direct measurement of the progression the risk to develop CCA comes from observational stud- of the disease, such as liver biopsy or cholangiography ies. The Scandinavian and American randomized, pla- was undertaken. Confirmatory results were obtained in cebo-controlled UDCA trials with 219 and 150 PSC a 2-year dose ranging pilot study of 30 patients in which patients, respectively, did not observe a difference the low dose (10 mg/kg/d) and the standard dose between UDCA- and placebo-treated patients regarding (20 mg/kg/d) tended to improve and the high dose CCA development . A German cohort study (30 mg/kg/d) significantly improved projected survival including 150 patients followed for a median of 6.4 years under UDCA treatment found CCA in 5 patients The Scandinavian UDCA trial deserves major credit (3.3%), which represents about half the expected inci- for recruiting the largest group of PSC patients dence of CCA in PSC A Scandinavian study of (n = 219) for the longest treatment period (5 years) ever 255 PSC patients listed for liver transplantation over a studied using a dose of 17–23 mg/kg/day. It demon- period of 11 years revealed lack of ursodeoxycholic acid strated a trend towards increased survival in the treatment as an independent risk factor for the develop- UDCA-treated group when compared with placebo ment of hepatobiliary malignancy . But despite the relatively large number of patientsrecruited, it was still insufficiently powered to produce a 5.3.2. Immunosuppressive and other agents statistically significant result. In comparison to other Corticosteroids and other immunosuppressants have studies, the biochemical response was unexpectedly poor not demonstrated improvement in disease activity or out- in this trial which prompted questions about adequate come of PSC. Small randomized, placebo-controlled or compliance in a part of the study population. Recently, pilot trials have investigated the role of agents with a multicentre study using high doses of 28–30 mg/kg/d of UDCA in 150 PSC patients over 5 years has been budesonide, azathioprine, cyclosporine, methotrexate, European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 mycophenolate, and tacrolimus, agents with TNFa regard to cholangitis and stent occlusion rates .
antagonizing effects like pentoxifyllin, etanercept and The strategy of short-term stenting for 2–3 weeks is fol- anti-TNF monocolonal antibodies and anti-fibrotic lowed by some experienced centers. Other studies have agents like colchicine, penicillamine, or pirfenidone.
compared the role of stenting with balloon dilatation, There is no evidence that these drugs are effective and, with similar efficacy and lower rates of complications therefore, none can be recommended for classic PSC.
such as cholangitis (18% vs. 50%) associated with bal- These drugs may well have a role in the context of a loon dilatation alone . Multiple dilatations are PSC–AIH overlap syndrome (see below) since pediatric usually required over months or years in order to main- patients and those with evidence of a PSC–AIH overlap tain patency once dominant strictures are identified and syndrome are more likely to respond to immunosuppres- treated, and not all strictures are amenable to endo- sive treatment . A retrospective study in adults scopic intervention. In these patients, careful consider- also suggested a beneficial role of steroids in a subgroup ation should be made regarding a conservative, with AIH overlap features radiological or surgical (including liver transplantation)approach to treatment.
5.3.3. ERCP and endoscopic therapy Diagnostic ERCP has been the procedure of choice 5.3.4. Liver transplantation for suspected PSC in the past, but is associated with sig- Liver transplantation is the only therapy of late-stage nificant risks including pancreatitis and cholangitis PSC that can cure advanced disease. One and ten-year Whilst a low complication rate was found in survival after liver transplantation has lately been above patients undergoing ‘diagnostic' ERCP, the complica- 90% and 80%, respectively, in experienced centers.
tion rate increased up to 14% when interventions such Resection of the extrahepatic biliary tree and Roux-en as balloon dilatation, endoscopic sphincterotomy and Y choledochojejunostomy are widely regarded as the stenting were performed method of choice for biliary reconstruction after liver Dominant bile duct strictures have been defined as transplantation in PSC Recurrence of PSC after stenoses <1.5 mm in diameter in the common bile duct liver transplantation has been reported at various rates and <1 mm in the right and left hepatic duct The up to a third of patients transplanted, but is difficult prevalence of dominant bile duct strictures in large duct to define due to similarities in bile duct damage with PSC is variously reported as being 10–50%. Studies in ischemic type biliary lesions, infections, medication- animals and humans have suggested that decompres- induced injury, preservation injury, or chronic rejection sion of biliary obstruction may prevent further damage . In different cohorts, PSC recurrence was associ- and can reverse fibrotic liver disease Endoscopic ated with steroid-resistant rejection, OKT3 use, preser- treatment of biliary strictures often improves liver vation injury, ABO incompatibility, cytomegalovirus biochemistry and pruritus and may reduce the risk of infection, male sex, or donor-recipient gender mismatch recurrent cholangitis. Therefore, repeated endoscopic . Colectomy prior to liver transplantation for dilatation of dominant biliary strictures has been car- advanced colitis or colon dysplasia protected against ried out in symptomatic patients . Non-ran- PSC recurrence as did the absence of ulcerative colitis transplantation and actuarial survival rates with esti-mates from prognostic models have suggested a trend towards a benefit of endoscopic intervention for domi-nant biliary strictures although patients also received 1. The available data base shows that UDCA (15– UDCA In contrast, a Swedish study which 20 mg/d) improves serum liver tests and surrogate compared liver biochemistry in those with and without markers of prognosis (I/B1), but does not reveal a dominant strictures suggested that variations in chole- proven benefit on survival (III/C2). The limited data stasis and jaundice are a feature of PSC liver disease base does not yet allow a specific recommendation and not related to dilatation of dominant strictures for the general use of UDCA in PSC.
The optimum method and frequency of dilatation 2. Currently there is suggestive but limited evidence for of dominant strictures is unclear. The most widely used the use of UDCA for chemoprevention of colorectal technique to facilitate biliary drainage has been plastic cancer in PSC (II-2/C2). UDCA may be particularly stent insertion with or without prior dilatation. The considered in high-risk groups such as those with a problem with this approach is that further ERCP's strong family history of colorectal cancer, previous are required to remove or replace the stent and there colorectal neoplasia or longstanding extensive colitis is a high rate of stent occlusion and/or cholangitis within 3 months of insertion. One study assessed the 3. Corticosteroids and other immunosuppressants are effectiveness and safety of short-term stenting (mean 9 not indicated for treatment of PSC in adults unless days) resulting in improved outcome, particularly with there is evidence of an overlap syndrome (III/C2).
European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 4. Dominant bile duct strictures with significant chole- stasis should be treated with biliary dilatation (II-2/B1). Biliary stent insertion should be reserved for UDCA is widely used in the treatment of PSC although cases where stricture dilatation and biliary drainage long-term efficacy remains unproven so far are unsatisfactory (III/C2). Prophylactic antibiotic UDCA has been used in combination with immunosup- coverage is recommended in this setting (III/C1).
pressive regimens in PSC–AIH overlap syndrome 5. Liver transplantation is recommended in patients A response to immunosuppressive therapy has with late-stage PSC (II-2/A1) and may be considered been documented in children . UDCA in combination in patients with evidence of cholangiocyte dysplasia with an immunosuppressive regimen might, therefore, be or severe recurrent bacterial cholangitis (III/C2).
an adequate medical treatment for most patients withPSC–AIH overlap syndrome although no data of 6. PSC–AIH overlap syndrome controlled trials exist. Prognosis of PSC–AIH overlapsyndrome was reported to be better than that of PSC but worse than that of AIH . Liver transplan-tation is indicated in end-stage disease.
immune-mediated disorder which is predominantly found in children, adolescents and young adults. Its characteristics include clinical, biochem- ical, and histologic features of AIH as summarized in the immune-mediated disorder characterized by histolog- modified AIH score defined by an international group of ical features of AIH and cholangiographic findings experts for study purposes and cholangiographic fea- typical of PSC (III/C2).
tures typical of PSC Retrospective diagnosis of an 2. Medical treatment of AIH–PSC overlap syndrome overlap syndrome by use of the modified AIH score was with UDCA and immunosuppressive therapy is established in 8% of 113 PSC patients from The Nether- recommended, but is not evidence-based due to lack lands and in 1.4% of 211 PSC patients from the of adequate studies (III/C2). Liver transplantation U.S. (with somewhat incomplete data available for retro- is the treatment of choice for end-stage disease (III/ spective analysis) Prospective analysis of 41 consec- utive PSC patients from Italy for the presence of: (i) arevised AIH score >15; (ii) ANA or ASMA antibodiespresent in a titre of at least 1:40; and (iii) liver histology 7. Immunoglobulin G4-associated cholangitis with piecemeal necrosis, lymphocyte rosetting, and mod-erate or severe periportal or periseptal inflammation revealed a PSC–AIH overlap syndrome as defined bythese criteria in 17% These patients were treated Immunoglobulin G4-associated cholangitis (IAC) is a with UDCA (15–20 mg/kg daily), prednisolone (0.5 mg/ recently described biliary disease of unknown etiology kg daily, tapered to 10–15 mg/d) and 50–75 mg azathio- that presents with biochemical and cholangiographic prine with good biochemical response.
features indistinguishable from PSC, frequently involves The largest case series reported so far consisted of 27 the extrahepatic bile ducts, responds to anti-inflamma- children with PSC–AIH overlap syndromes from Eng- tory therapy, is often associated with autoimmune land out of 55 children with clinical, biochemical, pancreatitis and other fibrosing conditions, and is char- and histological signs of AIH, followed prospectively acterized by elevated serum IgG4 and infiltration of for 16 years. Children and adolescents with PSC–AIH IgG4-positive plasma cells in bile ducts and liver tissue overlap syndrome more commonly suffered from IBD In contrast to PSC, IAC is not associated and more often were positive for atypical pANCA in with IBD. Preliminary data suggest that immunopatho- serum than those with AIH only. Otherwise, they pre- genesis of IAC strikingly differs from other immune- sented with similar signs and symptoms. Serum trans- mediated cholestatic liver diseases like PSC and PBC aminases tend to be higher in AIH, but serum AP in that T helper 2 (Th2) and T regulatory (Treg) cyto- although mostly elevated in PSC, may be normal both kines were markedly overexpressed in IAC patients in PSC–AIH overlap syndrome and AIH. Increasing In the largest cohorts of 53 and 17 IAC patients, awareness for the PSC–AIH overlap syndrome has led respectively median age at diagnosis of the to the observation that AIH and PSC may be sequential mostly male patients (7/8) was around 60 years.
in their occurrence, and this has been described in chil- The diagnosis of IAC was recently proposed to be dren and adults . Thus, in patients with AIH definitive if a patient with biliary stricture(s) in the intra- who become cholestatic and/or resistant to immunosup- hepatic, proximal extrahepatic and/or intrapancreatic pression, PSC should be ruled out.
European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 (i) has recently undergone pancreatic/biliary surgery IgG4; or (iii) two diagnostic biochemical, histological or core biopsy of the pancreas showing diagnostic and imaging criteria and an adequate response to a 4- features of autoimmune pancreatitis (AIP)/IAC; or week course of corticosteroid treatment to allow bili- (ii) shows classical imaging findings of AIP and ele- ary stent removal without relapse of obstructive cho- lestasis, and to reach serum liver tests <2 ULN (III/ (iii) fulfils two of the following criteria (elevated serum IgG4; suggestive pancreatic imaging findings; 3. Long-term treatment of IAC with corticosteroids other organ manifestations including sclerosing and/or azathioprine may be needed after relapse or sialadenitis, retroperitoneal fibrosis, or gastroin- for inadequate response (III/C2).
testinal involvement and abdominal lymphade-nopathy with infiltration of IgG4-positive plasma 8. Genetic cholestatic liver diseases cells; >10 IgG4-pos. plasma cells per high powerfield in bile duct biopsies) and shows an adequate 8.1. Cystic fibrosis-associated liver disease response to a 4-week course of corticosteroid treat-ment to allow stent removal without relapse of Cystic fibrosis-associated liver disease (CFALD) was obstructive cholestasis, to reach serum liver tests observed in up to 27% of patients with CF during long- <2 ULN, and to present decreasing IgG4 and term follow-up as defined by hepatomegaly, persistent elevation of at least two serum liver tests and abnormalfindings on ultrasound and may manifest as neona- Although not yet cross-validated in an independent tal cholestasis, hepatic steatosis, focal or multilobular cohort of IAC patients, this diagnostic recommendation cirrhosis. Complications of CFALD represent today may temporarily serve as a guideline for diagnosis of IAC.
the second most frequent cause of disease-related deathin patients with CF.
Immunosuppressive treatment has been shown to Diagnostic criteria for CFALD are not well defined.
exert a marked effect on inflammatory activity of IAC, CF-related hepatomegaly is found in a third of CF and complete long-term remission after three months patients and may be caused by CFALD or as a conse- of treatment has been reported. However, the extent of quence of cor pulmonale with liver congestion. Serum disease may affect the long-term response, and a retro- liver tests (AP, ALT, AST, bilirubin) are recommended spective analysis showed that patients with alterations at yearly intervals in CF patients Elevation above of proximal extrahepatic and intrahepatic bile ducts 1.5 ULN of serum liver tests should induce control are prone to a higher risk of relapse after stop of treat- after 3–6 months and when persisting should prompt ment than patients with distal bile duct strictures only further investigations to more closely evaluate liver Thus, corticosteroids are regarded as the initial damage (prothrombin time, albumin) and exclude other treatment of choice in this disease, and azathioprine at causes of liver disease (e.g., drugs, toxins, infections, bil- doses up to 2 mg/kg/d should be considered in those iary atresia, gallstones, antitrypsine deficiency, autoim- with proximal and intrahepatic stenoses and those after mune hepatitis, PSC or other causes of bile duct relapse during/after corticosteroid therapy. Treatment obstruction). Ultrasound may reveal signs of CFALD duration of 3 months may be sufficient for some such as hepatomegaly or bile duct alterations .
patients, but long-term maintenance therapy at low Liver biopsy is controversially discussed due to the focal doses may be required when disease activity has not nature of fibrosis/cirrhosis in many cases.
completely come to a standstill or has relapsed.
No therapy of proven benefit for the long-term prog- nosis of CFALD exists. Optimization of nutritional state 1. IAC is a corticosteroid-responsive (II-2/C2) scleros- in cholestatic patients to avoid vitamin deficiency and ing cholangitis of unknown immunopathogenesis malnutrition is recommended, but not of proven efficacy.
which, unlike PSC, affects mostly older patients and UDCA at doses of 20–30 mg/kg/d has been shown to has a good long-term prognosis after adequate consistently improve serum liver tests , to stim- response to immunosuppressive treatment (II-2/C2).
ulate impaired biliary secretion, to improve histological 2. The diagnosis of IAC is proposed to be made in appearance (over 2 years) and nutritional status.
patients with cholangiographic findings typical of The optimal dose of UDCA and its impact on survival sclerosing cholangitis on the basis of (i) histological in CF remain to be established.
features of autoimmune pancreatitis (AIP)/IAC or Treatment of complications of cirrhosis is not (ii) classical imaging findings of AIP and elevated different from other liver diseases. Medical treatment of European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 portal hypertension with beta blockers and/or endo- PFIC type 3 typically presents in the first years of scopic treatment of varices has not been adequately eval- childhood with progressive cholestasis although uated in CFALD whereas elective shunt surgery in portal disease manifestation and cirrhosis in adulthood has hypertensive patients has allowed long-term survival in a also been described most recently In contrast to case series . Outcome of liver transplantation is PFIC1 and PFIC2, cGT is usually markedly elevated comparable to that for other end-stage liver diseases.
in PFIC3 and histology reveals, in addition to portalinflammation and fibrosis/cirrhosis, massive bile duct proliferation. PFIC3 may be associated with intrahe-patic gallstone disease. PFIC3 is caused by mutations 1. CFALD affects a third of patients with CF during in the ABCB4 gene which encodes the canalicular long-term follow-up, but is not well defined. It may phospholipid transporter, ABCB4/MDR3 .
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).
No medical therapy of proven benefit for the long- 2. UDCA (20–30 mg/kg/d) improves serum liver tests term prognosis of PFIC exists. Supplementation with medium chain triglycerides and fat-soluble vitamins is CFALD. No medical therapy of proven long-term generally recommended in children. UDCA has been benefit exists in CFALD (III/C2). Liver transplanta- reported to improve biochemical tests in almost 50% tion is the treatment of choice in end-stage CFALD of patients with PFIC3 , but generally does not affect PFIC1 and PFIC2. Rifampicin may alleviate pru-ritus. Partial biliary diversion and ileal exclusion have 8.2. Progressive familial intrahepatic cholestasis been reported in case series to improve signs and symp-toms of particularly PFIC1 and also PFIC2 8.2.1. Classification Liver transplantation is the recommended treatment of Progressive familial intrahepatic cholestasis (PFIC) end-stage disease in PFIC.
summarizes a group of three inherited cholestatic dis-eases which may start early after birth or at young age and may rapidly progress to end-stage disease .
Mutations in canalicular transporter genes of the 1. PFIC type 1, 2 and 3 are rare chronic progressive ATP-binding cassette (ABC) transporters are responsi- cholestatic disorders of early childhood and adoles- ble for these rare disorders.
cence. PFIC type 1 and 2 are characterized by low PFIC type 1 (formerly ‘‘Byler disease") typically pre- and various extrahepatic sents in the neonatal period with signs and symptoms (pruritus!) of liver disease. Elevation of serum transam- 2. No medical therapy of proven benefit for the long- inases, bilirubin and bile acids is contrasted by low levels term prognosis of PFIC exists (III/C2). UDCA of cGT (in contrast to biliary atresia and Alagille syn- improves serum liver tests in a part of PFIC3 patients drome). Liver histology reveals fibrosis, but no bile duct (III/C2). Rifampicin may alleviate pruritus (III/C2).
proliferation. Most patients develop end-stage liver dis- Partial biliary diversion has shown beneficial clinical ease before the end of the first decade of life. Diarrhea, and biochemical effects in PFIC1 and PFIC2 (III/ pancreatitis, failure to thrive, and hearing deficits are C2). Liver transplantation is recommended for end- extrahepatic manifestations of this genetic defect caused stage disease (III/B1).
by mutations in the ATP8B1 gene which encodes aphospholipid 8.3. Benign recurrent intrahepatic cholestasis PFIC type 2 (formerly ‘‘Byler syndrome") presents like PFIC type 1 in early childhood with clinical and Benign recurrent intrahepatic cholestasis (BRIC) biochemical signs and symptoms of progressive liver dis- type 1 and 2 are acute cholestatic disorders of adoles- ease, but low levels of cGT. Histology reveals portal cence and adulthood and represent the benign forms inflammation and giant cell hepatitis. Electron micro- of PFIC1 and PFIC2 mainly caused by missense muta- scopic studies show coarse granular bile in PFIC1 and tions in the ATP8B1 and ABCB11 genes amorphous bile in PFIC2. PFIC2 is caused by muta- BRIC is characterized by acute episodes of cholestasis, tions in the ABCB11 gene which encodes the canalicular jaundice and severe pruritus caused by unknown factors bile salt export pump, ABCB11/BSEP The course which after weeks or months completely resolve to start of PFIC2 is complicated by development of hepatocellu- again after an asymptomatic period of months to years.
lar carcinoma at considerable rates making liver BRIC1 like PFIC1 may be accompanied by pancreatitis, transplantation an attractive treatment option.
whereas BRIC2 may be accompanied by gallstone dis- European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 ease . Liver fibrosis has been described in cases of elevated above ULN) >5, whereas mixed type injury BRIC indicating a continuum between BRIC and PFIC is defined by an ALT/AP ratio of 2–5. Drug-induced cholestatic injury has a better prognosis than hepato- No effective medical therapy of BRIC exists. UDCA cellular injury Several hundred drugs, herbal and rifampicin have been anecdotally reported to affect remedies, and illegal compounds have been reported the course of BRIC as has nasobiliary drainage to trigger drug-induced cholestatic injury. Adverse liverreactions are predictable and dose dependent only in a very few cases, whereas the vast majority is caused byunpredictable idiosyncratic or hypersensitive mecha- 1. BRIC is characterized by acute episodes of cholesta- nisms. For many drugs, the reported prevalence of sis, jaundice and severe pruritus which after weeks DILI is between 1 in 10,000 and 1 in 100,000 patients, to months completely resolve (III/C1).
and about 30% of cases with DILI are cholestatic.
2. No evidence-based treatment of BRIC is known.
However, these estimates are weakened by considerable Treatment attempts with UDCA, rifampicin or underreporting of DILI. Both environmental and nasobiliary drainage are still experimental (III/C2).
genetic factors may determine susceptibility .
Genetically determined variations of hepatobiliarytransporter and biotransformation enzyme expression 8.4. Alagille syndrome and function may be important risk factors for an indi-vidual's susceptibility to cholestasis under conditions of Alagille syndrome is an autosomal dominant multior- xenobiotic stress by drugs.
gan disease of children and adolescents which is charac-terized ductopenia without relevant inflammatory changes inliver histology The extrahepatic signs and symp- Because there are no specific diagnostic tests, diag- toms with involvement of nearly every organ system nosis requires clinical suspicion, a careful drug history, including heart, kidney, skeleton, central nervous system consideration of the temporal relationship between and a typical facies with hypertelorism, deep-set eyes drug intake and liver disease and exclusion of other and a flat nasal bridge may lead to the diagnosis of Ala- disorders. Rechallenge could confirm the diagnosis, gille syndrome in young cholestatic patients suffering but is potentially harmful, unethical and not indicated from often severe itch. The disease is caused by muta- in clinical practice; inadvertent re-challenge neverthe- tions in the JAG1 gene in 70% of patients. No effective less may sometimes lead to diagnosis. When drug- medical treatment exists. Anecdotally, partial biliary induced cholestatic injury is assumed, liver biopsy is diversion has been reported to cause relief from severe usually not required, and the natural course after stop- ping of drug administration is carefully followed untilnormalization of serum liver tests within 3 months in most cases. A severe, progressive or prolonged coursemay require liver biopsy to get additional information 1. Alagille syndrome is characterized by cholestasis with on the type of liver injury and to exclude other causes pruritus and ductopenia at early age in combination of liver cholestasis. Abdominal ultrasound is indicated with various extrahepatic stigmata and symptoms to exclude other liver diseases (see Introduction 1).
indicating multiorgan involvement as a consequenceof JAG1 mutations (III/C2).
9.2. Pathogenetic mechanisms and most frequent drugs 2. No effective medical treatment is known (III/C2).
Drug-induced cholestasis may be based on two major mechanisms and sites of action, inhibition of hepato- 9. Drug-induced cholestatic liver disease cellular transporter expression and/or function withalteration of bile secretion at the hepatocellular level Acute drug-induced cholestatic injury represents one and induction of an idiosyncratic inflamma- of three major forms of drug-induced liver injury tory or hypersensitive reaction at the bile ductular/cho- (DILI) and has been defined by an international con- langiocellular level with ductular/ductal cholestasis, sensus panel by an isolated elevation of serum alkaline which can also interfere with hepatocyte bile secretion phosphatase (AP) >2 ULN or an alanine aminotrans- ). Rarely, drugs induce a vanishing bile duct ferase (ALT)/AP ratio (both elevated above ULN) <2 syndrome (VBDS) that can progress to biliary cirrhosis comparison, drug-induced Various factors such as age, gender, dose, or injury as the predominant form of DILI is defined by co-administered medications may affect the risk to isolated ALT >2 ULN or an ALT/AP ratio (both develop drug-induced hepatic injury European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 mended (III/C2). Therapeutic attempts with UDCA Most frequent drugs causing hepatocellular or ductular/ductal cholestasis.
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 preg- nancy (starting in the second or third trimester of preg- nancy in most patients), (ii) elevated serum ALT activities and fasting serum bile acid levels, and (iii) NSAIDS, nimesulide spontaneous relief of signs and symptoms after delivery(within 4–6 weeks) In Europe, about 0.4–2.0% of pregnancies are affected The clinicalimportance of ICP lies in the potential fetal risks events during delivery, intrauterine death), albeit peri- There is no effective treatment for drug-induced cho- natal mortality rates from recent studies (9/1000) are lestasis except for withdrawal of the drug . Preven- comparable to whole population figures, most likely tion and early detection of abnormal serum liver tests, due to improvements in obstetric and neonatal care together with prompt withdrawal of the suspected drug Pruritus (typically worse at night) impairs the are crucial to avoid serious liver injury. In some cases, mother's quality of life. Only infrequently, ICP is asso- hepatotoxicity is severe, disabling or life-threatening ciated with steatorrhea and postpartum haemorrhage and liver transplantation may be required. Some studies due to vitamin K deficiency.
have reported that ursodeoxycholic acid (UDCA) may The pathogenesis of ICP is multifactorial, with beneficially affect cholestasis in two-thirds of cases genetic, hormonal and environmental factors playing . A potential benefit of corticosteroid therapy in important roles. During ICP, there is an increased flux cases of drug-induced cholestasis has been reported of bile acids from the mother to the fetus, as indicated occasionally and may be particularly expected in hyper- by elevated bile acid levels in amniotic fluid, cord sensitivity-induced cholestasis, but no relevant con- blood and meconium . The central role of hor- trolled trials are available on this subject The monal factors is supported by the higher ICP inci- outcome of drug-induced cholestatic injury, after with- dence in twin pregnancies and the observation that drawal of the drug, is generally good Occasionally high-dose oral contraceptives and progesterone can it is followed by prolonged cholestasis. The prototype trigger ICP . An increased ICP incidence in fam- drug causing cholestasis longer than 6 months is chlor- ily members and ethnic differences point to genetic promazine; it can cause the ‘‘vanishing bile duct syn- factors. Recent genetic studies have identified gene drome in drug-induced liver disease", leading to permanent liver damage A minority of the (ATP-binding cassette [ABC] transporter B4 = phos- patients who had a drug-related liver injury shows, dur- phatidylcholine floppase, ABC transporter B11 = bile ing follow-up, abnormal liver test and persistent liver salt export pump, ABC transporter C2 = conjugated damage at histology .
organic anion transporter, ATP8B1 = FIC1) and theirregulators (e.g., the bile acid sensor farnesoid X recep- tor, FXR) in some ICP patients . Mild malfunc-tion of these hepatocanalicular transporters could 1. Diagnosis of drug-induced cholestatic liver disease trigger cholestasis when their transport capacity for (AP >2 ULN or ALT (ULN)/AP (ULN) ratio hormones or other substrates is exceeded during preg- <2) is mainly supported by a temporal relationship nancy. Currently, genetic tests are performed in between drug intake and onset of clinical picture research laboratories only and are not applicable for and exclusion of other causes (III/C1). A liver biopsy diagnosis or risk stratification. However, mutation is not mandatory (III/C2).
analysis of ABCB4 might be considered in the future 2. Acute withdrawal of the suspected drug and careful if cholestasis (with increased cGT levels) persists after clinical and biochemical monitoring are recom- European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 10.1.1. Diagnosis The skin should be inspected to differentiate scratching Ursodeoxycholic acid (UDCA, 10–20 mg/kg per day) lesions from other skin disorders such as eczema and pru- is regarded as the first-line treatment for ICP based on ritic eruption of pregnancy. Although pruritus can pre- evidence obtained from randomized clinical trials cede any abnormalities in liver function, serum liver . UDCA may improve pruritus and tests (ALT, bilirubin, cGT, bile acids, prothrombin time) serum liver tests in 67–80% of ICP patients, but reduc- are to be performed in every pregnant woman who expe- tion of fetal complication rates is uncertain as fetal com- riences itching and to be repeated if normal in case of per- plication rates were low in recent trials both in UDCA sistent pruritus. The diagnosis of cholestasis of pregnancy and placebo-treated patients.
is based on otherwise unexplained pruritus and elevated Dexamethasone (12 mg/day for 7 days) promotes serum bile acid concentrations (P11 lmol/L) Iso- fetal lung maturity, but is ineffective in reducing pruritus lated elevation of bile acids may occur but this is and ALT levels in patients with ICP Thus, this uncommon; in the majority of patients, ALT activities drug is not an adequate treatment of ICP .
are elevated as well. Bile acids are the most sensitive S-Adenosyl-L-methionine is less effective than UDCA indicator for cholestasis of pregnancy and may precede , but may have an additive effect . If pruritus the abnormalities of other serum liver tests. Bile acid does not adequately respond to UDCA standard therapy levels >40 lmol/L any time during pregnancy and early for several days, the dose may be increased up to 25 mg/ onset of ICP (<33 weeks of gestation) might be associ- kg/day , or alternatively, treatment with S-adenosyl- ated with significantly increased fetal complication methione (combined with UDCA) or rifampicin might be rates . ICP patients with ABCB4 variants considered on an individual basis (see Section ). Topi- tend to display elevated c GT levels, which are other- cal emollients are safe but their efficacy is unknown.
wise normal in ICP. Mild jaundice with serum levels Active obstetric management (including amnioscopy of conjugated bilirubin only moderately elevated occurs and generous induction of labour) has been reported in 10–15% of cases. Liver biopsy is generally not to reduce perinatal mortality but increases intervention and complication rates . The practice of Pre-eclampsia and acute fatty liver of pregnancy are considering delivery at (36 to) 38 weeks of gestation pregnancy specific causes of abnormal serum liver tests appears to prevent stillbirth beyond that gestation, but that may form part of the differential diagnosis in atyp- is not evidence-based .
ical or early ICP cases Persistent abnormalities after delivery should prompt 10.2. Diagnosis and treatment of obstructive cholestasis reconsideration of other chronic liver diseases like PBC, PSC, ABCB4 deficiency or chronic hepatitis C, whichmay be associated with development of pruritus during Although up to 10% of patients develop stones or late pregnancy.
sludge over the course of one pregnancy, symptomatic Table 6Characteristics of ICP, HELLP Syndrome and acute fatty liver of pregnancy .
Presence of preeclampsia Typical clinical features Liver failure with mild jaundice, Elevated serum ALT/ Elevated serum liver tests AST fasting bile acids hypoglycemia, DIC (often <50,000/lL) ALT (above normal) Mild to 10–20-fold Mild to 10–20-fold 5–15-fold, variable <5 mg/dL (<85 lmol/l) Mostly <5 mg/dL (<85 lmol/l) Often <5 mg/dL (<85 lmol/l) Hepatic infarcts, hematomas, Fatty infiltration Maternal mortality (%) Fetal/perinatal mortality (%) Recurrence in subsequent 20–70 (carriers of LCHAD mutations)Rare (others) LCHAD: a-subunit, long-chain 3-hydroxyacyl-CoA dehydrogenase.
European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 gallstones occur in only 1.2% of these pregnancies .
The diagnosis is based on clinical symptoms, elevated Medical treatment options in cholestatic disorders during pregnancy serum liver tests (ALT, bilirubin, cGT, AP) and abdom-inal (or endoscopic) ultrasound. Obstructive cholestasis due to an impacted common bile duct stone or worsen-ing gallstone pancreatitis are indications to proceed to Low risk: increased sphincterotomy and stone extraction under antibiotic risk of cleft palate coverage. Several series have demonstrated the safety adrenal insufficiency of ERCP in pregnancy An experienced physi- cian should perform the intervention. Ultrasound-guid- Bacterial cholangitis ance might be helpful to minimize ionising radiation of the fetus (uterus dose 24 mSv/min). For deep sedation, Sedation and analgesia consultation of an anesthesiologist and obstetrician is recommended. Meperidine, propofol, fentanyl and midazolam may be used at low doses Ampicillin is the preferred antibiotic and is compatible with breast- Avoid in first(and second) trimester Fetal risk categories (FDA): A – no risk; B – risk in animal studies, butnot in humans; C – human risk cannot be excluded; D – risk; X – 10.3. Drugs for cholestatic conditions during pregnancy Women with cholestatic liver diseases may be of childbearing age, and an uncomplicated pregnancywith no disease flare is expected in those with mild or inactive disease. The course of autoimmune hepatitisor overlap syndrome in pregnancy is highly variable, 1. Diagnosis of ICP is based on (i) pruritus in preg- and a flare of activity may occur during pregnancy nancy, (ii) elevated serum ALT activities and fasting or, more likely, in the post partum period. bile acid levels, and (iii) exclusion of other causes of summarizes the safety of drugs for cholestatic liver dis- liver dysfunction or itching (II-2/C2). ICP is con- firmed when serum liver tests completely normalize UDCA. Although UDCA is not approved, but likely after delivery.
to be compatible, for use during early pregnancy, 2. Women with ICP should be advised that the incidence UDCA can be administered in cholestatic liver disease, of premature birth is increased, both spontaneous when the pregnant woman is symptomatic during the and iatrogenic (II-2/B1). No specific fetal monitoring second or third trimesters . No adverse effects in can be recommended (III/C2). UDCA ameliorates mothers or newborns have been observed including pruritus and improves serum liver tests (I/B1), but recent RCT, using UDCA for up to 8 weeks there are insufficient data concerning protection . UDCA is not approved during breastfeeding, but against fetal complications (II-1/C2). Vitamin K likely to be safe for the baby, since significant amounts should be supplemented when prothrombin time is of UDCA cannot be found in milk during lactation.
prolonged (III/C2). Timing of delivery should be dis- Corticosteroids. The use of prednisolone is considered cussed on an individual basis (II-2/C2).
safe during pregnancy and lactation, but is associated 3. UDCA can be administered to pregnant women with with an increased risk of cleft palate in children to cholestatic liver diseases during the second or third women using the drug in the first trimester An trimesters, when the patients are symptomatic (I/ increased risk of premature rupture of membranes and B1). Prednisolone ± azathioprine for treatment of adrenal insufficiency was reported in the transplant set- autoimmune hepatitis should be continued during pregnancy to prevent disease flares, which might be Azathioprine. Azathioprine appears to be a safe drug more deleterious to pregnancy outcome than any during pregnancy, although it is teratogenic in animals.
potential risk of the medication (III/C2).
Steadily increasing experience is being reported in 4. Symptomatic bile duct stones in pregnancy are treated women with autoimmune hepatitis, rheumatoid arthri- by endoscopic sphincterotomy and stone extraction tis, inflammatory bowel diseases, and after organ trans- (II-3/B1). X-ray is not absolutely contraindicated even plantation . The benefits and risks of therapy in the first trimester (III/C2). Patients with simulta- should be discussed in detail with the patient. Although neous gallbladder and bile duct stones who are asymp- very little azathioprine is excreted in breast milk, breast- tomatic after clearance of the bile duct should undergo feeding should be discussed on an individual basis.
cholecystectomy post partum (III/C2).
European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 11. Management of extrahepatic manifestations gabapentin and cimetidine in cases of resistance pruri-tus. The use of antihistamines, ondansetron and pheno- barbitone is not recommended for reasons of lack ofefficacy, limited efficacy and excessive side-effect profile, Pruritus can be a feature of any cholestatic disease and can be of sufficient severity, in some instances, also There is case report evidence to advocate the use of disabling. The precise mechanism of cholestatic pruri- invasive physical approaches in resistant pruritus cases.
tus remains unclear Fluctuation is characteristic (both within the day and over longer periods of time), dialysis , plasmapheresis and bile duct and pruritus can lessen as end-stage liver disease devel- drainage . The invasive nature of these ops. In the absence of obstructive bile duct lesions ame- approaches makes them only suitable in patients who nable to endoscopic, radiological or surgical correction are resistant to medical therapies. Transplantation is treatment ) focuses entirely on systemic medica- effective for the control of cholestatic itch but raises tion (no topical agents have demonstrated efficacy).
issues of organ allocation priority and patient risk in There is no evidence to suggest that UDCA lessens patients who would not otherwise require transplanta- cholestatic itch (indeed paradoxical worsening of itch tion . Itch quantification using a visual analogue has been reported anecdotally following introduction scale can help in the assessment of response to inter- of this agent) except in the context of intrahepatic cho- ventions. Objectification of itch through physical mea- lestasis of pregnancy. Cholestyramine is widely used as surement of scratching activity has been advocated as a first-line treatment although the evidence basis to sup- more accurate measure. It is, in practice, limited to use port this is limited, largely because the agent entered as a research tool. Treatment of pruritus in cholestatic widespread use before the era of evidence-based medi- liver disease has been subjected to systematic review cine . Poor tolerance due to the taste of this agent can be a problem (which can sometimes be addressedby flavoring with fruit juice). When both agents are Recommendations ( used UDCA and cholestyramine should be spaced aminimum of four hours apart to prevent binding and 1. Cholestyramine 4 g up to four times daily or other loss of efficacy resins are regarded as first-line treatment of pruritus The pregnane X receptor (PXR) agonist, rifampicin, (II-2/B1). Resins should be spaced away from UDCA is widely used as second-line treatment and has a strong and other drugs by at least 4 hours (II-3/B1).
evidence base Ongoing efficacy is reported 2. Rifampicin is regarded as second-line treatment intro- over up to 2 years of treatment (mirroring clinical expe- duced at 150 mg with monitoring of serum liver tests rience) Urine, tears and other body secretions are which may be increased to a maximum of 600 mg discoloured during treatment and, in case series, drug- daily (I/A1).
induced hepatitis and significant liver dysfunction after 3. Naltrexone, an oral opiate antagonist, at a dose of two to three months have been reported in up to 12% 50 mg daily should be considered as third-line treat- of cholestatic patients In light of this, low dose ini- ment starting at a low dose of 25 mg (I/B1). It should tiation with monitoring before dose escalation is only be considered following proven lack of efficacy, intolerance or side-effects with cholestyramine or Oral opiate antagonists can be used as third-line other resins and rifampicin (III/C1).
agents However problems have been reported with 4. Sertraline may be considered for patients resistant to an opiate withdrawal-like reaction on initiation (which above mentioned treatments as fourth-line treatment can be ameliorated, to some extent by use of an i.v. nal- oxone induction phase in which the dose is rapidly esca- 5. Patients resistant to the above agents can be treated lated to a level at which conversion to the lowest dose with drugs with anecdotal support, or referred to spe- oral opiate antagonist preparation can be instituted cialized centers, where more invasive approaches and ongoing problems resulting from pain should be considered (III/C2).
and confusion.
6. Liver transplantation is effective, but should only be There is evidence to support the use of sertraline, considered when all available interventions above although the mechanism of its action remains unclear have proven ineffective (III/C1).
Clinical experience of both opiate-antagonistsand sertraline used for pruritus treatment has been dis-appointing for many clinicians and the importance of fully exploring the use of cholestyramine and rifampicintherapy before resorting to these agents is emphasized.
PBC can be characterized by fatigue, the degree of There are anecdotal observations to support the use of which is unrelated to the severity of the underlying European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 Pruritus
Cholestasis present?
Investigate other causes
Specific management
Bile duct obstruction?
Specific management
(up to 4g qds)
Monitor fat sol. vitamins
150 mg daily
Monitor serum liver tests
Increase stepwise to BENEFIT
max 600mg daily
(every other week)
(up to 50mg daily)
(up to 100mg daily)
Consider experimental BENEFIT
Consider transplant
Fig. 2. Management of pruritus in cholestasis. Abbreviations: US, ultrasound; MRCP, magnetic resonance cholangiopancreatography; ERCP,endoscopic retrograde cholangiopancreatography.
liver disease. The issue of the extent to which other therapy. Fatigue in PBC shows only a limited associa- cholestatic liver diseases can be associated with fatigue tion with depression but stronger associations is poorly studied. Before ascribing fatigue to PBC it is with autonomic dysfunction (in particular orthostatic essential to exclude other associated or non-associated hypotension ) and sleep disturbance (in particular causes of fatigue which may be amenable to specific excessive daytime somnolence ) and which may intervention. This includes the presence of AIH-like themselves be amenable to specific intervention (there features which may be amenable to immunosuppressive is, in particular, case series evidence to support the European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 use of modafinil in patients with fatigue associated with low-up assessment at between 1 and 5 years depending prominent daytime somnolence There are on outcome and general osteoporosis risk no specific interventions able to reverse fatigue inPBC, although supportive and understanding clinical care will improve patients' capacity to cope Fati-gue may not improve significantly following liver trans- 1. The risk for osteoporosis should be clinically assessed plantation which is therefore not appropriate in for all cholestatic patients with emphasis on reversible patients lacking other indications.
risk factors and lifestyle advice (III/C2).
2. Bone mineral density should be assessed by DEXA in chronic cholestatic liver disease at presentation (III/C2). Rescreening should be performed up to annually 1. Associated disease (e.g., hypothyroidism, anemia, depending on degree of cholestasis or other individual diabetes, depression etc.) or medication use character- risk factors (III/C2).
ized by fatigue should be actively excluded (III/C2).
3. Supplementation with calcium (1000–1200 mg/day) 2. Supportive measures including minimization of fac- and vitamin D (400–800 IU/day) in all patients with tors likely to exacerbate autonomic dysfunction cholestatic liver disease should be considered but is (e.g., excessive anti-hypertensive medication) and not evidence-based (III/C2).
sleep disturbance (e.g., caffeine in the evenings) 4. Alendronate or other bisphosphonates are indicated should be considered (III/C2). Psychological support at a T score < 2,5 (DEXA) or following pathological should be considered to assist with development of fracture (I/B1) and may be appropriate at a T score coping strategies (II-2 & II-3/C2).
< 1,5 (III/C2).
3. Liver transplantation is not appropriate for treatment of fatigue in the absence of other indications (III/C1).
11.4. Fat-soluble vitamin substitution 11.3. Osteoporosis Fat malabsorption can complicate highly cholestatic The degree to which patients with cholestatic liver disease variants, although the risk is lower in less disease are at increased risk of osteoporosis is unclear, cholestatic patients than has previously been consid- with contradictory reports in the literature. This largely ered to be the case (with the exception of children reflects the case mix in different centres (with significant where degrees of fat malabsorption are typically age, disease severity and degree of cholestasis differ- higher). Parenteral vitamin K supplementation should ences). A consensus view would be that patients with be given prophylactically in overt cholestasis prior to end-stage liver disease and/or a high degree of cholesta- any invasive procedure and in the context of bleeding sis are at increased risk of developing osteoporosis, with Assessment of blood levels of fat-soluble vitamins has a significantly smaller risk in other groups. In these lat- been advocated to guide the need for supplementation ter groups established population risk factors for osteo- but this approach is not widely used and is not porosis (smoking, inactivity, family history, low body weight, age and female gender) outweigh any cholesta-sis-related risk. Compared to healthy controls, male patients with cholestatic liver disease have a higher dis-ease-related osteoporosis risk increase (although lower 1. Calcium and vitamin D enteral supplementation absolute risk) than female patients. The use of calcium should be considered in all cholestatic patients as part and vitamin D supplements is supported by epidemio- of the osteoporosis prevention protocol (III/C2).
logical data (reduction or reversal of the natural rate 2. Vitamin A, E and K should be supplemented enterally of bone loss) but there are no trial data to support or in adults in the context of overt cholestasis, where the refute this treatment approach Hormone replace- clinical features of steatorrhea are present or where ment therapy is effective in post-menopausal female fat-soluble vitamin levels are proven to be low (III/C2).
patients . Testosterone therapy should be 3. Parenteral vitamin K should be given prophylacti- avoided in male patients because of risk of hepatocellu- cally prior to invasive procedures in overt cholestasis lar carcinoma. There are trial data to support the use of and in the context of bleeding (II-2/C1).
bisphosphonates (particularly alendronate) where osteo-porosis is present There are limited data to 11.5. Varices and hepatocellular carcinoma support the use of raloxifene and sodium fluorideBone mineral density assessment (DEXA) is Varices and hepatocellular carcinoma (HCC) devel- a useful guide to treatment and should be undertaken opment occur in advanced cholestatic liver disease as where possible in all patients at presentation, with fol- in other forms of chronic liver disease and are associated European Association for the Study of the Liver / Journal of Hepatology 51 (2009) 237–267 with impaired prognosis Screening, prophy- [3] Heathcote EJ. Diagnosis and management of cholestatic liver laxis and treatment approaches should be adopted as disease. Clin Gastroenterol Hepatol 2007;5:776–782.
[4] Freeman ML, Nelson DB, Sherman S, Haber GB, Herman ME, in other chronic liver disease settings . How- Dorsher PJ, et al. Complications of endoscopic biliary sphinc- ever, a platelet count of <200,000/mm3, serum albumin terotomy. N Engl J Med 1996;335:909–918.
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[8] Invernizzi P, Lleo A, Podda M. Interpreting serological tests in Conflicts of interest disclosure – Ulrich Beuers has received lecture fees from the Falk [9] Vergani D, Alvarez F, Bianchi FB, Cancado EL, Mackay IR, Manns MP, et al. Liver autoimmune serology: a consensus Foundation, Gilead, Roche, Schering-Plough and statement from the committee for autoimmune serology of the – Kirsten M. Boberg has received research funding from Meda A/S.
[10] Ludwig J, Dickson ER, McDonald GS. Staging of chronic – Roger W. Chapman has received research support nonsuppurative destructive cholangitis (syndrome of primarybiliary cirrhosis). Virchows Arch A Pathol Anat Histol and lecture fees from the Falk Foundation.
– Olivier Chazouille res has nothing to disclose.
[11] Scheuer PJ. Primary biliary cirrhosis: diagnosis, pathology and – Pietro Invernizzi has acted as an advisor and lecturer pathogenesis. Postgrad Med J 1983;59:106–115.
for Instrumentation Laboratory, Inova Diagnostics, [12] Beuers U. Drug insight: mechanisms and sites of action of Menarini Diagnostics and Euroimmun.
ursodeoxycholic acid in cholestasis. Nat Clin Pract GastroenterolHepatol 2006;3:318–328.
– David E.J. Jones has nothing to disclose.
[13] Poupon RE, Balkau B, Eschwege E, Poupon R. A multicenter, – Frank Lammert has nothing to disclose.
controlled trial of ursodiol for the treatment of primary biliary – Albert Pare s has received research support from Gambro Dialysatoren GmbH, Hechingen, Germany.
– Michael Trauner has received research support and [14] Heathcote EJ, Cauch-Dudek K, Walker V, Bailey RJ, Blendis LM, Ghent CN, et al. The Canadian Multicenter Double-blind lecture fees from the Falk Foundation.
Randomized Controlled Trial of ursodeoxycholic acid in primary – Antonio Benedetti has nothing to disclose.
biliary cirrhosis. Hepatology 1994;19:1149–1156.
– Peter L.M. Jansen is acting as an advisor to Biolex [15] Lindor KD, Dickson ER, Baldus WP, Jorgensen RA, Ludwig J, and Debiopharm and has received funds from Special Murtaugh PA, et al. Ursodeoxycholic acid in the treatment of primary biliary cirrhosis. Gastroenterology 1994;106:1284–1290.
[16] Combes B, Carithers Jr RL, Maddrey WC, Lin D, McDonald – Hanns-Ulrich Marschall has received research sup- MF, Wheeler DE, et al. A randomized, double-blind, placebo- port from the Falk Foundation and MEDA AB.
controlled trial of ursodeoxycholic acid in primary biliary – James Neuberger has received speaker support from cirrhosis. Hepatology 1995;22:759–766.
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Plaza A, et al. Long-term effects of ursodeoxycholic acid inprimary biliary cirrhosis: results of a double-blind controlled – Gustav Paumgartner has received speaker support multicentric trial. UDCA-Cooperative Group from the Spanish from the Falk Foundation.
– Raoul Poupon has received lecture fees from the Falk Foundation, Sanofi-Aventis, Schering-Plough, Roche [18] Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R.
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