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Cholestasis caused by drugs is an important liver disease in patients with a biochemical cholestatic pattern and normal hepatobiliary imaging.
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Cholestatic drug-induced liver injury (DILI) is more common than hepatocellular DILI among the elderly.
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Most cases of cholestatic DILI are mild but in rare cases, ductopenia and cholestatic cirrhosis can develop.
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Approximately 10% of patients with cholestatic jaundice caused by drugs develop liver failure.
Drug-Induced Cholestasis
Section snippets
Key points
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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