EASL Clinical Practice Guidelines: Management of cholestatic liver diseases
Introduction
EASL Clinical Practice Guidelines (CPG) on the management of cholestatic liver diseases define the use of diagnostic, therapeutic and preventive modalities, including non-invasive and invasive procedures, in the management of patients with cholestatic liver diseases. They are intended to assist physicians and other healthcare providers as well as patients and interested individuals in the clinical decision-making process by describing a range of generally accepted approaches for the diagnosis, treatment and prevention of specific cholestatic liver diseases. The clinical care for patients with cholestatic liver diseases has advanced considerably during recent decades thanks to growing insight into pathophysiological mechanisms and remarkable methodological and technical developments in diagnostic procedures as well as therapeutic and preventive approaches. Still, various aspects in the care of patients with cholestatic disorders remain incompletely resolved. The EASL CPG on the management of cholestatic liver diseases aim to provide current recommendations on the following issues:
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Diagnostic approach to the cholestatic patient.
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Diagnosis and treatment of primary biliary cirrhosis (PBC).
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Diagnosis and treatment of PBC–autoimmune hepatitis (AIH) overlap syndrome.
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Diagnosis and treatment of primary sclerosing cholangitis (PSC).
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Diagnosis and treatment of PSC–AIH overlap syndrome.
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Diagnosis and treatment of immunoglobulin G4-associated cholangitis (IAC).
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Diagnosis and treatment of drug-induced cholestatic liver diseases.
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Diagnosis and treatment of genetic cholestatic liver diseases.
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Diagnosis and treatment of cholestatic liver diseases in pregnancy.
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Treatment of extrahepatic manifestations of cholestatic liver diseases.
A panel of experts selected by the EASL Governing Board in May 2008 wrote and discussed these guidelines between June and November 2008. These guidelines have been produced using evidence from PubMed and Cochrane database searches before 1 October, 2008. Where possible, the level of evidence and recommendation are cited (Table 1a, Table 1b). The evidence and recommendations in these guidelines have been graded according to the Grading of Recommendations Assessment Development and Evaluation (GRADE system) [1]. The strength of recommendations thus reflects the quality of underlying evidence which has been classified in one of three levels: high [A], moderate [B] or low-quality evidence [C]. The GRADE system offers two grades of recommendation: strong [1] or weak [2] (Table 1b). The CPG thus consider the quality of evidence: the higher, the more likely a strong recommendation is warranted; the greater the variability in values and preferences, or the greater the uncertainty, the more likely a weaker recommendation is warranted. Where no clear evidence exists, guidance is based on the consensus advice of expert opinion in the literature and the writing committee.
Section snippets
Diagnostic approach to cholestasis
Cholestasis is an impairment of bile formation and/or bile flow which may clinically present with fatigue, pruritus and, in its most overt form, jaundice. Early biochemical markers in often asymptomatic patients include increases in serum alkaline phosphatase (AP) and γ-glutamyltranspeptidase (γGT) followed by conjugated hyperbilirubinemia at more advanced stages. Cholestasis may be classified as intrahepatic or extrahepatic. Intrahepatic cholestasis may result from hepatocellular functional
Diagnosis of PBC
Patients with PBC may present with symptoms as fatigue, pruritus and/or jaundice, but the majority of them are asymptomatic at diagnosis. At first presentation, very few patients present in advanced stage of disease and with complications of portal hypertension (ascites, hepatic encephalopathy or esophageal variceal bleeding). Currently, a diagnosis of PBC is made with confidence on a combination of abnormal serum liver tests (elevation of AP of liver origin for at least 6 months) and presence
PBC–AIH overlap syndrome
Primary biliary cirrhosis (PBC) and autoimmune hepatitis (AIH) are classically viewed as distinct liver diseases. However, patients presenting with clinical, biochemical, serological, and/or histological features reminiscent of both diseases, either simultaneously or consecutively have been repeatedly recognized. The ill-defined term “overlap syndrome” is used to describe these settings [57], [58], [59], [60]. The pathogenesis of PBC–AIH overlap syndrome is debated and it remains unclear
Primary sclerosing cholangitis
Primary sclerosing cholangitis (PSC) is a chronic, cholestatic liver disease that is characterized by an inflammatory and fibrotic process affecting both intra- and extrahepatic bile ducts [74]. The disease leads to irregular bile duct obliteration, including formation of multifocal bile duct strictures. PSC is a progressive disorder that eventually develops into liver cirrhosis and liver failure. The etiology of PSC is unknown, but there is evidence that genetic susceptibility factors are
Diagnosis
PSC–AIH overlap syndrome is an ill-defined immune-mediated disorder which is predominantly found in children, adolescents and young adults [98], [140], [141], [142], [143], [144], [145], [146], [147], [148]. Its characteristics include clinical, biochemical, and histologic features of AIH as summarized in the modified AIH score defined by an international group of experts for study purposes [62] and cholangiographic features typical of PSC [60]. Retrospective diagnosis of an overlap syndrome by
Diagnosis
Immunoglobulin G4-associated cholangitis (IAC) is a recently described biliary disease of unknown etiology that presents with biochemical and cholangiographic features indistinguishable from PSC, frequently involves the extrahepatic bile ducts, responds to anti-inflammatory therapy, is often associated with autoimmune pancreatitis and other fibrosing conditions, and is characterized by elevated serum IgG4 and infiltration of IgG4-positive plasma cells in bile ducts and liver tissue [153], [154]
Cystic fibrosis-associated liver disease
Cystic fibrosis-associated liver disease (CFALD) was observed in up to 27% of patients with CF during long-term follow-up as defined by hepatomegaly, persistent elevation of at least two serum liver tests and abnormal findings on ultrasound [160] and may manifest as neonatal cholestasis, hepatic steatosis, focal or multilobular cirrhosis. Complications of CFALD represent today the second most frequent cause of disease-related death in patients with CF.
Drug-induced cholestatic liver disease
Acute drug-induced cholestatic injury represents one of three major forms of drug-induced liver injury (DILI) and has been defined by an international consensus panel by an isolated elevation of serum alkaline phosphatase (AP) >2× ULN or an alanine aminotransferase (ALT)/AP ratio (both elevated above ULN) <2 [178]. In comparison, drug-induced hepatocellular injury as the predominant form of DILI is defined by isolated ALT >2× ULN or an ALT/AP ratio (both elevated above ULN) >5, whereas mixed
Intrahepatic cholestasis of pregnancy (ICP)
Intrahepatic cholestasis of pregnancy (ICP, also known as obstetric cholestasis) is a reversible form of cholestasis characterized by (i) intense pruritus in pregnancy (starting in the second or third trimester of pregnancy in most patients), (ii) elevated serum ALT activities and fasting serum bile acid levels, and (iii) spontaneous relief of signs and symptoms after delivery (within 4–6 weeks) [188], [189]. In Europe, about 0.4–2.0% of pregnancies are affected [188], [190]. The clinical
Pruritus
Pruritus can be a feature of any cholestatic disease and can be of sufficient severity, in some instances, also disabling. The precise mechanism of cholestatic pruritus remains unclear [214]. Fluctuation is characteristic (both within the day and over longer periods of time), and pruritus can lessen as end-stage liver disease develops. In the absence of obstructive bile duct lesions amenable to endoscopic, radiological or surgical correction treatment (Fig. 2) focuses entirely on systemic
Conflicts of interest disclosure
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Ulrich Beuers has received lecture fees from the Falk Foundation, Gilead, Roche, Schering-Plough and Zambon.
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Kirsten M. Boberg has received research funding from Meda A/S.
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Roger W. Chapman has received research support and lecture fees from the Falk Foundation.
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Olivier Chazouillères has nothing to disclose.
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Pietro Invernizzi has acted as an advisor and lecturer for Instrumentation Laboratory, Inova Diagnostics, Menarini Diagnostics and Euroimmun.
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David E.J. Jones has nothing to disclose.
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Frank
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Contributors: Clinical Practice Guidelines Panel: Ulrich Beuers, Kirsten M. Boberg, Roger W. Chapman, Olivier Chazouillères, Pietro Invernizzi, David E.J. Jones, Frank Lammert, Albert Parès, Michael Trauner; Reviewers: Antonio Benedetti, Peter L.M. Jansen, Hanns-Ulrich Marschall, James Neuberger, Gustav Paumgartner, Raoul Poupon, Jesús Prieto.