49 This variant BSEP is now considered a risk factor for drug-induced cholestasis because it is found more frequently in such patients,49 as well as in patients with intrahepatic cholestasis of pregnancy,77, 78 than in controls.[77] In the same Swiss study, full-length sequencing of BSEP and MDR3 also revealed learn more a heterozygous p.D676Y mutation in BSEP in a patient taking fluvastatin, and a heterozygous p.I764L mutation in MDR3 in a patient taking risperidone.49 Whether these mutations account for the

cholestatic event remains uncertain. A recent study of contraceptive-induced cholestasis revealed an association with BSEP 1331TC polymorphism as a susceptibility factor but not for MRP2.79 Other examples of genetically determined drug-induced cholestasis involve

susceptibility to diclofenac-induced toxicity. Allelic variants in the drug-metabolizing enzymes UGT2B7 and CYP2C8 and canalicular MRP2 presumably lead to an increase in the level of reactive metabolites and higher levels of protein–diclofenac adducts that then produce toxicity.80 Other studies have identified a PXR polymorphism as a risk factor for flucloxacillin-induced liver injury. Flucloxacillin is a PXR agonist. The variant PXR (rs3814055; C-25385T) was found to be more common in patients who developed flucloxacillin drug-induced cholestasis, and reporter gene Smoothened antagonist experiments demonstrated that the C allele had lower promoter activity than the T allele.81 These findings are a reminder that there is still much to be learned about the role of polymorphisms of nuclear receptors that regulate

drug metabolism and transport in patients with drug-induced cholestasis.76, 82 A detailed history is critical in the diagnosis of drug-induced cholestasis. The use of prescribed medications, over-the-counter medications, herbal drugs, and naturopathic substances as well as parenteral nutrition should always be explored.83,84 Temporal relationships between the initiation of the offending agent and development of the symptoms can provide the clue to the diagnosis. The period between drug ingestion and the onset of symptoms may provide a clue as to the offending agent. This latency period may be short (hours to days), intermediate or delayed (1-8 weeks), or long (1-12 months) depending on the agent. All drugs used by the patient within the last 3-6 months should be enumerated. This relationship click here may not be obvious in patients with chronic liver disease from other causes or when taking multiple medications that may lead to drug–drug interactions. Increase of serum AP activity (usually more than three times the upper limit of normal) is the most common laboratory finding in patients with drug-induced cholestasis. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels may be normal or minimally elevated.85 International criteria for liver toxicity were established by the Council of International Organizations of Medical Sciences (CIOMS) in 1990.