Liver Injury Caused by Drugs

The pathophysiology of drug-induced liver injury (DILI) varies depending on the drug (or other hepatotoxin) and, in many cases, is not entirely understood. Drug-induced injury mechanisms include covalent binding of the drug to cellular proteins resulting in immune injury, inhibition of cell metabolic pathways, blockage of cellular transport pumps, induction of apoptosis, and interference with mitochondrial function.

In general, the following are thought to increase risk of DILI:

Presentation varies widely, ranging from absent or nonspecific symptoms (eg, malaise, nausea, anorexia) to jaundice, impaired hepatic synthesis, and encephalopathy. Early recognition of drug-induced liver injury (DILI) improves prognosis.

Key to the diagnosis of DILI are identification of a potential hepatotoxin, a pattern of liver test Laboratory Tests of the Liver and Gallbladder Laboratory tests are generally effective for the following: Detecting hepatic dysfunction Assessing the severity of liver injury Monitoring the course of liver diseases and the response to treatment... read more abnormalities that is characteristic of the substance (its signature), and injury onset that is temporally consistent with the offending hepatotoxin's typical profile. Possible causative agents can be evaluated using the LiverTox database. This easily accessible internet database is funded by the National Institutes of Health. It includes information on the likelihood that a substance causes DILI, the pattern of injury, the time course to injury, and the suspected recovery period. It also includes links to case reports on potential causative agents. (The database can be accessed at the following link: LiverTox: Clinical and Research Information on Drug-Induced Liver Injury.)

Because there is no confirmatory diagnostic test, other causes of liver disease, especially viral, biliary, alcoholic, autoimmune, and metabolic causes, need to be excluded (1 Diagnosis reference Many medications (eg, statins) commonly cause asymptomatic elevation of hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase). However, clinically... read more ). Drug rechallenge should be avoided. Suspected cases of DILI should be reported to the Food and Drug Administration’s (FDA’s) adverse drug reaction monitoring program (MedWatch) , as well as to the DILIN (Drug-Induced Liver Injury Network), a research organization sponsored by the National Institutes of Health (NIH) to improve the understanding of causes and outcomes of DILI in the United States. Information on study eligibility can be found at DILIN's web site (https://dilin.org/for-practitioners/) .

Management emphasizes drug withdrawal, which, if done early, usually results in recovery. In severe cases, consultation with a specialist is indicated, especially if patients have hepatocellular jaundice and impaired liver function, because liver transplantation Liver Transplantation Liver transplantation is the 2nd most common type of solid organ transplantation. (See also Overview of Transplantation.) Indications for liver transplantation include Cirrhosis (70% of transplantations... read more may be required. Antidotes for drug-induced liver injury (DILI) are available for only a few hepatotoxins; such antidotes include N-acetylcysteine for acetaminophen toxicity and silymarin or penicillin for Amanita phalloides toxicity. Occasionally, corticosteroids can help in DILI with DRESS syndrome (drug reaction with eosinophilia and systemic symptoms) or in autoimmune-like injury, as with minocycline or PD-1/PD-L1 checkpoint inhibitor toxicity.

Efforts to avoid drug-induced liver injury (DILI) begin during the drug-development process, although apparent safety in small preclinical trials does not ensure eventual safety of the drug after it is in widespread use. Postmarketing surveillance, now increasingly mandated by the Food and Drug Administration (FDA), can call attention to potentially hepatotoxic drugs. The LiverTox database can be very useful.

Routine monitoring of liver enzymes has not been shown to decrease the incidence of hepatotoxicity. Use of pharmacogenomics may allow tailoring of drug use and avoidance of potential toxicities in susceptible patients.