Many medications (eg, statins) commonly cause asymptomatic elevation of hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase). However, clinically significant liver injury (eg, with jaundice, abdominal pain, or pruritus) or impaired liver function—ie, resulting in deficient protein synthesis (eg, with prolonged prothrombin time [PT] or with hypoalbuminemia)—is rare.
Withholding statin therapy in patients with chronic liver disease is not recommended. Statin use in patients with chronic liver disease is not different from its use in patients without baseline liver disease. In contrast, statins may have antifibrotic properties and can benefit patients with nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD), (1, 2). The guidelines (American Association for the Study of Liver Disease [AASLD]) state that patients with NAFLD are at high risk for cardiovascular morbidity and mortality and that patients with NAFLD or NASH are not at higher risk for serious liver injury from statins. These guidelines confirm that statins can be used to treat dyslipidemia in patients with NAFLD, NASH, and NASH cirrhosis. Statins can be used with caution at low doses in patients with decompensated cirrhosis after overall risk:benefit analysis (3).
The term drug-induced liver injury (DILI) may be used to mean clinically significant liver injury or all (including asymptomatic) liver injury. DILI includes injury caused by medicinal herbs, plants, and nutritional supplements as well as medications (3, 4, 5).
General references
1. Athyros VG, Tziomalos K, Gossios TD, et alLancet 376(9756):1916-1922, 2010. doi: 10.1016/S0140-6736(10)61272-X
2. Tikkanen MJ, Fayyad R, Faergeman O, et alInt J Cardiol 168(4):3846-3852, 2013. doi: 10.1016/j.ijcard.2013.06.024
3. Fontana RJ, Liou I, Reuben A, et al: AASLD practice guidance on drug, herbal, and dietary supplement–induced liver injury. Hepatology 00:1-29, 2022. doi: 10.1002/hep.32689
4. Chalasani N, Bonkovsky HL, Fontana R, et al: Features and outcomes of 899 patients with drug-induced liver injury: The DILIN prospective study. Gastroenterology 148(7):1340-1352, 2015. doi: 10.1053/j.gastro.2015.03.006
5. Navarro VJ, Barnhart H, Bonkovsky HL, et al: Liver injury from herbals and dietary supplements in the U.S. Drug-Induced Liver Injury Network. Hepatology 60(4):1399-1408, 2014. doi: 10.1002/hep.27317
Pathophysiology of Drug-Related Liver Injury
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:
Age ≥ 18 years
Obesity
Pregnancy
Concomitant alcohol consumption
Genetic polymorphisms (increasingly recognized)
Patterns of liver injury
DILI can be predictable (when injury usually occurs shortly after exposure and is dose-related) or unpredictable (when injury develops after a period of latency and has no relation to dose). Predictable DILI (commonly, ) is a common cause of acute jaundice and acute liver failure in the United States. Unpredictable DILI is a rare cause of severe liver disease. Subclinical DILI may be underreported.
Potentially Hepatotoxic Drugs
Finding | Drug |
|---|---|
Hepatocellular: Elevated ALT | ART drugs Germander Kava NSAIDs PD-1/PD-L1 inhibitors Statins Tetracyclines Trovafloxacin Valproate |
Cholestatic: Elevated alkaline phosphatase and total bilirubin | Anabolic steroids Oral contraceptives Erythromycins Estrogens Phenothiazines Tricyclic antidepressants |
Mixed: Elevated alkaline phosphatase and ALT | Sulfonamides |
ALT = alanine aminotransferase; ART = antiretroviral therapy; AST= aspartate aminotransferase; NSAID = nonsteroidal anti-inflammatory drug. | |
Biochemically, 3 types of liver injury are generally noted (see table Potentially Hepatotoxic Drugs):
Hepatocellular: Hepatocellular hepatotoxicity generally manifests as malaise and right upper quadrant abdominal pain, associated with marked elevation in aminotransferase levels (alanine aminotransferase [ALT], aspartate aminotransferase [AST], or both), which may be followed by hyperbilirubinemia in severe cases. Hyperbilirubinemia in this setting is known as hepatocellular jaundice and, according to Hy’s law, is associated with mortality rates as high as 50%. If hepatocellular liver injury is accompanied by jaundice, impaired hepatic synthesis, and encephalopathy, chance of spontaneous recovery is low, and liver transplantation
Cholestatic:
Mixed:
Diagnosis of Drug-Related Liver Injury
Identification of characteristic patterns of laboratory abnormalities
Exclusion of other causes
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 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). 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/).
Pearls & Pitfalls
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Diagnosis reference
1. European Association for the Study of the Liver: EASL clinical practice guidelines: Drug-induced liver injury. J Hepatol 70(6):1222-1261, 2019. doi: 10.1016/j.jhep.2019.02.014
Treatment of Drug-Related Liver Injury
Early drug withdrawal
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 may be required. Antidotes for drug-induced liver injury (DILI) are available for only a few hepatotoxins; such antidotes include NAmanita phalloides
Prevention of Drug-Related Liver Injury
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. TheLiverTox 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.
Key Points
Drugs are much more likely to cause an asymptomatic abnormality in liver function than clinically evident liver damage or dysfunction.
Risk factors for drug-induced liver injury (DILI) include age ≥ 18 years, obesity, pregnancy, concomitant alcohol consumption, and certain genetic polymorphisms.
DILI can be predictable and dose-related or unpredictable and unrelated to dose.
DILI can be hepatocellular, cholestatic (usually less serious than hepatocellular), or mixed.
To confirm the diagnosis, exclude other causes of liver disease, especially viral, biliary, alcoholic, autoimmune, and metabolic disorders.
Do not rechallenge patients with drugs suspected of causing DILI.
