Drug-induced liver injury cholestasis

The best clinical evidence that BSEP is involved in hepatotoxicity is provided by human genetic studies which found four highly conserved non-synonymous mutations in two hepatobiliary transporters (BSEP and MDR3) that were specific for drug-induced liver injury [118]. Recently, a consortium of investigators identified a remarkable 82 different ABCBll mutations in 109 families that caused severe BSEP deficiency [119]. It is therefore expected that at least some of these genetic mutations and polymorphisms will put patients at an increased risk of drug-induced cholestasis. Does this justify the implementation of a simple BSEP inhibition screen for all new chemical entities The answer is not quite that simple. 

Weden [27] described a protracted cholestasis which was thought to be induced by the use of a COC. The patient s liver biopsy revealed changes including eosinophilia and sinusoidal dilatation, which could be linked to a drug-induced liver injury. The cholestasis gradually disappeared, but an elevated serum alkaline phosphatase level continued for up to ten years after discontinuation of the COC [27]. Another paper has discussed oestrogen-induced cholestasis and highlights the link between the use of COCs and intrahepatic cholestasis... 

Measurement of serum y-GT activity has clinical significance. The enzyme is present in all tissues, but the highest level is in the kidney however, the serum enzyme originates primarily from the hepatobiliary system. Elevated levels of serum y-GT are found in the following disorders intra- and posthepatic biliary obstruction (elevated serum y-GT indicates cholestasis, as do leucine aminopeptidase, 5 -nucleotidase, and alkaline phosphatase) primary or disseminated neoplasms some pancreatic cancers, especially when associated with hepatobiliary obstruction alcohol-induced liver disease (serum y-GT may be exquisitely sensitive to alcohol-induced liver injury) and some prostatic carcinomas (serum from normal males has 50% higher activity than that of females). Increased activity is also found in patients receiving phenobarbital or phenytoin, possibly due to induction of y-GT in liver cells by these drugs. 

In vivo, measuring bile acids in plasma and urine should be revived as potential biomarkers in the modern metabolomic era. Then the first-order scientific question will become whether early and time-controlled fasting-level measurement of bile acid concentration in plasma and urine can become a sensitive and specific biomarker for drug-induced cholestasis and ultimately liver injury at later time-points [117] Clinical trials should be conducted to evaluate whether such bile acid measurements can be used as part of a predictive panel to identify patients who are at increased risk of drug-induced cholestasis. 

Critical Review Is There a Link between BSEP Inhibition, Drug-Induced Cholestasis and Idiosyncratic Liver Injury ... 

Fatal cholestatic hver failure occurred in a 45-year-old woman with metastatic breast cancer who was given gemcitabine and carboplatin and pre-existing liver damage. After four courses of gemcitabine -I- carboplatin she developed severe decompensated cholestatic hepatitis (9). Liver biopsy showed marked cholestasis and hepatocellular injury consistent with drug-induced hepatotoxicity. 

G4000SW+G3000SW. Sample serum of normal female (a), patients with liver cirrhosis (b), acute hepatitis (c), primary biliary cirrhosis (d), intrahepatic cholestasis (e) and drug induced injury (f). Elution positions and other HPLC conditions as in Fig. 14. 

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