Drug-Induced Liver Injury

Abstract

Drug hepatoxicity can be nonidiosyncratic (predictable), as in the case of acetaminophen, or idiosyncratic (unpredictable). This review article focuses primarily on idiosyncratic drug-induced liver injury (DILI). New epidemiologic data suggest that approximately 20 new cases of DILI per 100,000 persons occur each year. Idiosyncratic DILI accounts for 11% of the cases of acute liver failure in the United States. Risk factors for DILI include medication dose, drug lipophilicity, and extent of hepatic metabolism. There is mixed evidence to support the role of host factors such as age, sex, and chronic liver disease in the development of DILI. For specific drugs, a genetic predisposition appears to be a risk factor for DILI. Suspected cases of idiosyncratic DILI should be categorized as hepatitic, cholestatic, or mixed on the basis of the degree/ratio of abnormalities in the alanine aminotransferase and alkaline phosphatase. A careful evaluation for other causes of liver disease should be performed, though a liver biopsy is rarely needed. There is evidence that some patients with DILI may actually have hepatitis E and this diagnosis should be considered. Amoxicillin/clavulanate isoniazid, and nonsteroidal anti-inflammatory drugs are among the most common causes of DILI. Drug discontinuation or dechallenge should lead to an improvement in liver biochemistries in most patients, though a bilirubin value of more than 3 g/dL is associated with mortality of at least 10%. New biomarkers for DILI using proteomics and micro RNA appear promising but require further study. New studies on drugs with potential for causing DILI are reviewed herein, including tumor necrosis factor-alpha antagonists, fluoroquinolones, tyrosine kinase inhibitors, statins, and supplements. PubMed was used with search terms of drug induced liver injury OR DILI with filter settings of "English language" and "humans" and custom date range of "January 1, 2000." The authors also manually searched bibliographies from key references and included seminal references before the year 2000.

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…2013a; Leise et al. 2014). This variety of liver lesions actually reflects the occurrence of different mechanisms of toxicity and the potential involvement of several types of hepatic cells such as hepatocytes, cholangiocytes, stellate cells, activated lymphocytes, and Kupffer cells (Stirnimann et al.…”

Noninvasive Preclinical and Clinical Imaging of Liver Transporter Function Relevant to Drug-Induced Liver Injury

“…Imaging probes and technologies that evaluate other processes relevant to DILI would be complementary. Processes meriting particular attention include oxidative stress and inflammation, in view of their known role in DILI pathogenesis [1,9].…”

“…Many hundreds of different drugs cause liver injury in humans which occurs only infrequently and in certain susceptible individuals, and cannot be anticipated from nonclinical safety studies undertaken in vivo in experimental animals [1,2]. Hence their ability to cause human drug-induced liver injury (DILI) only starts to be appreciated in Phase 2 or Phase 3 clinical trials, or even postlicensing [2,3].…”

“…Hence their ability to cause human drug-induced liver injury (DILI) only starts to be appreciated in Phase 2 or Phase 3 clinical trials, or even postlicensing [2,3]. The consequences in affected patients may be marked symptomatic liver damage, or even acute liver failure, and currently it is not possible to predict and identify "at risk" patients prior to their exposure to the relevant drugs [1,2]. Because of this, unexpected "idiosyncratic" human DILI continues to be a leading cause of failed development of new drugs, of withdrawal from use of previously licensed drugs and of cautionary labeling that restricts prescribing [1][2][3][4][5].…”

“…The mechanisms by which drugs cause human idiosyncratic DILI are complex, and involve both drug-related adverse biochemical processes and susceptibility factors specific to susceptible patients [1,2]. Important drug-related adverse processes which can initiate idiosyncratic DILI include formation of chemically reactive metabolites, injury to mitochondria, and inhibition of the activity of the bile salt export pump (BSEP), which mediates efflux of toxic bile salts from hepatocytes into bile [6][7][8].…”