Lipid lowering medication and hepatotoxicity

Drug-induced liver injuries represent an important challenge for physicians, the pharmaceutical industry and health authorities. Practically the whole spectrum of acute and chronic hepatobiliary disease can be reproduced by toxicity attributed to drugs. Drugs are a leading cause of fulminant hepatitis in Western countries and may also cause chronic liver disease with development of liver cirrhosis. Hepatotoxicity is the principal cause for withdrawal of drugs in clinical trials and after marketing for safety reasons [1]. One recent example illustrating the seriousness of this problem is the recent withdrawal of troglitazone because of hepatotoxicity. Drug induced hepatotoxicity may mimic almost any type of hepatobiliary disease. Most drug toxicity to the liver are acute, presenting as cytotoxic hepatocellular hepatitis, cholestatic disease or mixed pictures. Less common reactions include chronic hepatitis, chronic cholestasis, granulomatous hepatitis, steatosis, steatohepatitis, veno-occlusive disease, neoplasia, ®brosis and cirrhosis [2]. Life threatening liver failure may develop not only in acute fulminant hepatitis, but also in drug reactions with an insidious course leading to cirrhosis. Liver cirrhosis is the late stage of a longstanding process in which ®brosis accumulates in an attempt to encapsulate injury. Once cirrhosis occurs, patients may develop the end-stage complications of liver disease; portal hypertension, haemorrhage, hepatic insuf®ciency and primary liver cancer. An important step in the understanding of liver ®brosis has been the identi®cation of hepatic stellate cells (HSC) as the main ®brogenic cell type in the liver [3]. HSC are normally located in the perisinusoidal space of Disse as quiescent cells rich in vitamin A. Following liver injury, HSC undergo a process known as `activation', characterized by a phenotypic conversion from quiescent vitamin A-rich cells into highly proliferative myo®broblast-like cells producing connective tissue components generating ®brosis (Fig. 1). HSC activation is initiated by mediators released from injured hepatocytes and neighbouring endothelial and Kupffer cells (resident macrophages in the liver). Amongst numerous mediators involved in HSC activation, transforming growth factor-b has been identi®ed as the principal ®brogenic mediator, whilst platelet-derived growth factor-BB is the most potent mitogenic factor. Hepatocytes are also a potent source of lipid peroxides, which may be important in many forms of liver ®brosis. The toxic effects of drugs on the liver are most probably underestimated. For most drugs the prevalence of liver toxicity is relatively low, which explains why toxicity often is not detected during clinical development of the drug. Instead, the evaluation of adverse liver reactions relies to a large extent on spontaneous reporting of individual cases to drug safety authorities after marketing authorization has been obtained. Moreover, the diagnosis of drug hepatotoxicity is admitted to be dif®cult and requires a high level of suspicion and may therefore easily be overlooked in clinical practice. Once suspicion of drug induced liver disease has been evoked in a case, the major challenge will be the attribution of causality. Except for those cases in which a positive rechallenge (unacceptably dangerous in most cases but sometimes accidental) con®rms the hepatotoxic role of a certain drug, the diagnosis of drug induced liver disease is subjective and based on circumstantial evidence. The development of clinical scales for causality assessment, which generate a numerical score intended to identify the probability of causality, has helped to standardize and to improve the level of reliability and objectivity of the evaluation of drug hepatotoxicity. The system most widely used was developed by an international consensus group in 1990 [4]. The principles of this system relies on the attribution of Journal of Internal Medicine 2001; 250: 183±185