Drug-induced liver injury

Abstract

Drug-induced liver injury (DILI) remains the most common cause of acute liver failure (ALF) in the western world. Excluding paracetamol overdose, nearly all DILI encountered in the clinical setting is idiosyncratic in nature because affected individuals represent only a small proportion of those treated with such drugs. In many cases, the mechanism for idiosyncrasy is immune-mediation and is often identifi ed by genetic risk determined by human leukocyte antigen variants. In the absence of diagnostic tests and/or biomarkers, the diagnosis of DILI requires a high index of suspicion after diligently excluding other causes of abnormal liver tests. Antibiotics are the class of drugs most frequently associated with idiosyncratic DILI, although recent studies indicate that herbal and dietary supplements are an increasingly recognised cause. It is imperative that upon development of DILI the culprit drug be discontinued, especially in the presence of elevated transaminases (aspartate aminotransferase/alanine aminotransferase ratio ≥5 times the upper limit of normal) and/or jaundice. Risk factors for the development ALF include hepatocellular DILI and female gender, the treatment being supportive with some benefi t of N-acetylcysteine in the early stages. In view of the poor transplant-free survival in idiosyncratic DILI, early consideration for liver transplant is mandatory. KEYWORDS : Autoimmune hepatitis , cholestasis , drug-induced acute liver failure , herbal and dietary supplements , hepatocellular DILI , hepatotoxicity IntroductionAt a regulatory level, drug-induced liver injury (DILI) is the commonest reason for withdrawing drugs from the market and/or issuing warnings and modification of use.1 DILI is classified as either predictable or unpredictable (idiosyncratic). 2The former tends to be dose-related, has a short latency (days), is due to direct toxicity of the drug or its metabolite, and is ABSTRACT Drug-induced liver injuryreproducible in animal models (eg paracetamol overdose). 3The vast majority of DILI, however, is idiosyncratic or unpredictable -it is unexpected based on the pharmacological actions of the drug and in most cases routine animal toxicology fails to identify the risk of subsequent clinical toxicity. 4 This review shall largely focus on idiosyncratic DILI .

A three‐dimensional microfluidized liver system to assess hepatic drug metabolism and hepatotoxicity

“…Drug‐induced liver injury is a primary cause of drug attrition in preclinical and clinical testing (Katarey & Verma, ) playing the liver a key role in xenobiotic and drug metabolism. During the development of a new drug the candidate molecule is fully characterized for its absorption, distribution, metabolism, excretion, and toxicity (ADME/Tox) properties (Li, ).…”

Carvedilol-Induced Liver Injury, a Rare Cause of Mixed Hepatitis: A Clinical Case

“…In most cases, the incidence of DILI is extremely low, varying between 1/10,000 and 1/100,000 [8]. They are usually idiosyncratic reactions that occur in susceptible patients, without a clear dose-response relation, being associated with certain HLA alleles [3,4]. Clinical and laboratory manifestations are varied in latency, presentation, and course.…”

“…DILI is the most frequent adverse drug effect, ranging from discrete and asymptomatic enzymatic changes to acute hepatic failure [3,4]. More than 900 drugs, herbs, and toxins have documented this possibility, being the most frequent cause of acute hepatic failure in developed countries and the biggest responsible factor for drug withdrawal from the market [5][6][7].…”

Assessment of Hepatotoxic Effects of Quetiapıne at Repeated Doses in Rats

“…For this reason, it is difficult to detect liver injury in the early stages [24][25][26]. Clinically, liver damage is detected by biomarkers that indicate the changes of normal liver function, such as plasma bilirubin levels, and biomarkers that indicate the changes of tissue and cell integrations, such as plasma ALT and AST.…”