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.

Identification of a potential hepatotoxin and 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) make the diagnosis likely.

Because there is no confirmatory diagnostic test, other causes of liver disease, especially viral, biliary, alcoholic, autoimmune, and metabolic causes, need to be excluded. Drug rechallenge, although it can strengthen evidence for the diagnosis, should be avoided. Suspected cases of DILI should be reported to MedWatch (the Food and Drug Administration's [FDA’s] adverse drug reaction monitoring program; 1 Treatment Many drugs (eg, statins) commonly cause asymptomatic elevation of hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase). However, clinically... read more ).

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. Occassionally, corticosteroids can help in DILI with DRESS syndrome 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 FDA, can call attention to potentially hepatotoxic drugs.

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) has established a database (LiverTox) to collect and analyze cases of severe liver injury caused by prescription drugs, over-the-counter (OTC) drugs, and alternative medicines such as herbal products and dietary supplements Overview of Dietary Supplements Dietary supplements are the most commonly used of all integrative, complementary, and alternative therapies, primarily because they are widely available, relatively inexpensive, and can be bought... read more . This is a searchable database that provides easily accessible and accurate information regarding known hepatotoxicity related to drugs and supplements.

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.