Drug-Induced Cholestasis

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Key points

  • Cholestasis caused by drugs is an important liver disease in patients with a biochemical cholestatic pattern and normal hepatobiliary imaging.

  • Cholestatic drug-induced liver injury (DILI) is more common than hepatocellular DILI among the elderly.

  • Most cases of cholestatic DILI are mild but in rare cases, ductopenia and cholestatic cirrhosis can develop.

  • Approximately 10% of patients with cholestatic jaundice caused by drugs develop liver failure.

Approach to the patient with suspected drug-induced cholestatic liver injury

The clinical presentation of cholestatic liver disease is variable. Asymptomatic increase in liver enzymes can be observed, particularly increased ALP, but jaundice with or without pruritus is a common presentation. Some patients present with fever and abdominal pain that can simulate gallstone disease. Because some patients can have stones in the gallbladder, this can lead to unnecessary cholecystectomies. Unfortunately, there is no marker of hepatotoxicity that is completely reliable and

Incidence of cholestatic liver injury caused by drugs

Limited data exist on the incidence of DILI with cholestatic reactions included in the general population. A landmark population-based study on the incidence of DILI in society was undertaken in France in a defined population and revealed an incidence of 13.9 cases per 100,000 per year.14 Thirty-three percent of cases had a cholestatic or mixed pattern.14 In the largest series, cholestatic pattern was present in 20% to 40%, mixed pattern in 12% to 20% and hepatocellular pattern in 48% to 58% (

Chemical Properties of Drugs

For most drugs, little is known about the risk of DILI for the individual patient. The chemical properties of some drugs have indicated that some have hepatotoxic potential. Temafloxacin and trovafloxacin have a unique difluorinated side chain that does not occur in other quinolones. This makes these drugs extra lipophilic and they are associated with cholestatic liver disease.15 Drugs given orally in a daily dose of more than 50 mg are much more likely to lead to DILI than those with a lower

Vanishing bile duct syndrome

Chronic intrahepatic cholestatic patterns are rarely associated with DILI. The liver histology can mimic that of primary biliary cirrhosis with granulomatous duct injury.31 Vanishing bile duct syndrome is a rare syndrome and has been considered to occur in only 0.5% of cases of small duct biliary disease.32 In a minority of patients, progressive ductopenia occurs, which can lead to near complete absence of ducts with variable amount of inflammation.33 This is diagnosed mainly in patients with

The pathology of drug-induced cholestasis

For almost 2 centuries, pathologists have recognized morphologic changes in the liver in jaundiced patients,46, 47 although the molecular basis for cholestasis has only been revealed in the last 2 to 3 decades.48 There is a long tradition in pathology to use the term cholestasis in pathology reports on liver tissue. This morphologic cholestasis refers to the deposition of bile in hepatocytes and/or the biliary passages of the liver tissue, which can be detected under the microscope.49 The

The pathophysiology of drug-induced cholestasis

Hepatic detoxification of xenobiotics involves either phase I reactions followed by phase II reactions or phase I alone or rarely only phase II.55 Phase II reactions result in anionic conjugates with sulfate, glucuronate, or glutathione. These drug metabolites are transported across hepatocyte membranes by transporters (uptake or efflux transporters) on the apical or the canalicular membranes.56 This hepatic drug transport has been shown to be involved in the pathophysiology of cholestatic

Most important drugs leading to cholestatic liver injury

The list of drugs associated with cholestatic injury is long. A comprehensive list of drugs reported to have induced hepatotoxicity has been published.67 This article focuses on the most common types of drugs and new observations in this context.

The prognosis of patients with cholestasis caused by drugs

Drug-induced jaundice has been associated with a poor prognosis4 and a severe drug reaction on the liver was found by Hy Zimmerman to lead to at least 10% mortality.4 This has been named Hy’s law and was later validated in a large series of patients with DILI; the mortality/liver transplantation rate was 9% to 12%.5, 20, 68 Originally, this association was believed to be true only for hepatocellular jaundice, and the prognosis of those with cholestatic injury was mainly related to comorbidities

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References (119)

  • M.H. Davies et al.

    Antibiotic-associated acute vanishing bile duct syndrome: a pattern associated with severe, prolonged, intrahepatic cholestasis

    J Hepatol

    (1994)
  • G.M. Forbes et al.

    Carbamazepine hepatotoxicity: another cause of the vanishing bile duct syndrome

    Gastroenterology

    (1992)
  • C. Pauli-Magnus et al.

    Enterohepatic transport of bile salts and genetics of cholestasis

    J Hepatol

    (2005)
  • S.R. Vavricka et al.

    Interactions of rifamycin SV and rifampicin with organic anion uptake systems of human liver

    Hepatology

    (2002)
  • U. Bolder et al.

    Sulindac is excreted into bile by a canalicular bile salt pump and undergoes a cholehepatic circulation in rats

    Gastroenterology

    (1999)
  • M. Biour et al.

    Drug-induced liver injury; fourteenth updated edition of the bibliographic database of liver injuries and related drugs

    Gastroenterol Clin Biol

    (2004)
  • J.E. Polson

    Hepatotoxicity due to antibiotics

    Clin Liver Dis

    (2007)
  • A.J. Zapata Garrido et al.

    Terbinafine hepatotoxicity. A case report and review of literature

    Ann Hepatol

    (2003)
  • M.L. Hautekeete et al.

    Cholestatic hepatitis related to quinolones: a report of two cases

    J Hepatol

    (1995)
  • L. Bataille et al.

    Delayed and prolonged cholestatic hepatitis with ductopenia after long-term ciprofloxacin therapy for Crohn's disease

    J Hepatol

    (2002)
  • G. Roda et al.

    Severe cholestatic acute hepatitis following azathioprine therapy in a patient with ulcerative pancolitis

    Dig Liver Dis

    (2009)
  • D.E. Kleiner

    The pathology of drug-induced liver injury

    Semin Liver Dis

    (2009)
  • H. Zimmerman

    Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver

    (1999)
  • E. Bjornsson et al.

    Outcome and prognostic markers in severe drug-induced liver disease

    Hepatology

    (2005)
  • D. Moradpour et al.

    Chlorpromazine-induced vanishing bile duct syndrome leading to biliary cirrhosis

    Hepatology

    (1994)
  • J. Rochon et al.

    Reliability of the Roussel Uclaf Causality Assessment Method for assessing causality in drug-induced liver injury

    Hepatology

    (2008)
  • D.C. Rockey et al.

    Causality assessment in drug-induced liver injury using a structured expert opinion process: comparison to the Roussel-Uclaf causality assessment method

    Hepatology

    (2010)
  • P.H. Hayashi

    Causality assessment in drug-induced liver injury

    Semin Liver Dis

    (2009)
  • M.C. Maggio et al.

    Stevens-Johnson syndrome and cholestatic hepatitis induced by acute Epstein-Barr virus infection

    Eur J Gastroenterol Hepatol

    (2011)
  • E.C. Ratnayake et al.

    Cholestatic hepatitis in a patient with typhoid fever - a case report

    Ann Clin Microbiol Antimicrob

    (2011)
  • H.C. Choi et al.

    A case of acute q Fever with severe acute cholestatic hepatitis

    Gut Liver

    (2009)
  • M. Breidert et al.

    Weight loss and severe jaundice in a patient with hyperthyroidism

    Z Gastroenterol

    (2011)
  • M.I. Lucena et al.

    Trovafloxacin-induced acute hepatitis

    Clin Infect Dis

    (2000)
  • C. Lammert et al.

    Relationship between daily dose of oral medications and idiosyncratic drug-induced liver injury (DILI). Search for signals

    Hepatology

    (2008)
  • M.I. Lucena et al.

    Phenotypic characterization of idiosyncratic drug-induced liver injury: the influence of age and gender

    Hepatology

    (2009)
  • C. Lammert et al.

    Oral medications with significant hepatic metabolism at higher risk for hepatic adverse events

    Hepatology

    (2010)
  • Y. Meier et al.

    Interindividual variability of canalicular ATP-binding-cassette (ABC)-transporter expression in human liver

    Hepatology

    (2006)
  • M.C. Lindberg

    Hepatobiliary complications of oral contraceptives

    J Gen Intern Med

    (1992)
  • M.I. Prince et al.

    Hepatitis and liver dysfunction with rifampicin therapy for pruritus in primary biliary cirrhosis

    Gut

    (2002)
  • J. O’Donohue et al.

    Co-amoxiclav jaundice: clinical and histological features and HLA class II association

    Gut

    (2000)
  • R.J. Andrade et al.

    HLA class II genotype influences the type of liver injury in drug-induced idiosyncratic liver disease

    Hepatology

    (2004)
  • A.K. Daly et al.

    HLA-B*5701 genotype is a major determinant of drug-induced liver injury due to flucloxacillin

    Nat Genet

    (2009)
  • Y. Meier et al.

    Increased susceptibility for intrahepatic cholestasis of pregnancy and contraceptive-induced cholestasis in carriers of the 1331T>C polymorphism in the bile salt export pump

    World J Gastroenterol

    (2008)
  • P.J. Brown et al.

    Primary biliary cirrhosis after long-term practolol administration

    Br Med J

    (1978)
  • J. Ludwig

    Idiopathic adulthood ductopenia: an update

    Mayo Clin Proc

    (1998)
  • C. Degott et al.

    Drug-induced prolonged cholestasis in adults: a histological semiquantitative study demonstrating progressive ductopenia

    Hepatology

    (1992)
  • A.M. Ramos et al.

    Reversible vanishing bile duct syndrome induced by carbamazepine

    Eur J Gastroenterol Hepatol

    (2002)
  • M.S. Padda et al.

    Drug-induced cholestasis

    Hepatology

    (2011)
  • D.H. Gregory et al.

    Chronic cholestasis following prolonged tolbutamide administration

    Arch Pathol

    (1967)
  • G.A. Glober et al.

    Biliary cirrhosis following administration of methyltestosterone

    JAMA

    (1968)
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