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 metabolic dysfunction–associated steatohepatitis (MASH) and metabolic dysfunction–associated steatotic liver disease (MASLD) (1, 2). American Association for the Study of Liver Disease practice guidelines (3) state that patients with MASLD are at high risk for cardiovascular morbidity and mortality and that patients with MASLD or MASH 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 MASLD, MASH, and MASH-related cirrhosis. Statins can be used with caution at low doses in patients with decompensated cirrhosis after overall risk:benefit analysis (4).
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 (5–7).
References
1. Athyros VG, Tziomalos K, Gossios TD, et al. Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: A post-hoc analysis. Lancet. 376(9756):1916-1922, 2010. doi: 10.1016/S0140-6736(10)61272-X
2. Tikkanen MJ, Fayyad R, Faergeman O, et al. Effect of intensive lipid lowering with atorvastatin on cardiovascular outcomes in coronary heart disease patients with mild-to-moderate baseline elevations in alanine aminotransferase levels. Int J Cardiol. 168(4):3846-3852, 2013. doi: 10.1016/j.ijcard.2013.06.024
3. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice guideline by the American Gastroenterological Association, American Association for the Study of Liver Diseases, and American College of Gastroenterology [published correction appears in Gastroenterology. 2012 Aug;143(2):503]. Gastroenterology. 2012;142(7):1592-1609. doi:10.1053/j.gastro.2012.04.001)
4. Fontana RJ, Liou I, Reuben A, et al. AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury. Hepatology. 2023;77(3):1036-1065. doi:10.1002/hep.32689
5. 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
6. 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
7. European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; Clinical Practice Guideline Panel: Chair:; Panel members; EASL Governing Board representative:. EASL Clinical Practice Guidelines: Drug-induced liver injury. J Hepatol. 2019;70(6):1222-1261. doi:10.1016/j.jhep.2019.02.014
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.
Risk factors for DILI are poorly understood, and different risk factors seem to be associated with increased risk for certain drugs but not necessarily all drugs (1). Examples include:
Age ≥ 18 years: Can cause increased risk with amoxicillin-clavulanate, isoniazid
Obesity and diabetes: Can cause increased severity and incidence of DILI with some drugs
Preexisting liver disease: Can cause increased risk of DILI in those on methotrexate or anti-tuberculosis therapy
Concomitant alcohol consumption, tobacco use: Risk of DILI not clearly understood
Genetic polymorphisms (increasingly recognized): PTPN22 gene, a common polymorphism associated with DILI with many drugs
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, acetaminophen poisoning) 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 | Acarbose Acetaminophen Allopurinol Amiodarone Antiretroviral therapy drugs Bupropion Fluoxetine Germander Green tea extract Baclofen Isoniazid Kava Ketoconazole Lisinopril Losartan Methotrexate NSAIDs Omeprazole PD-1/PD-L1 inhibitors Paroxetine Pyrazinamide Rifampin Risperidone Sertraline Statins Tetracyclines Trazodone Trovafloxacin Valproate |
Cholestatic: Elevated alkaline phosphatase and total bilirubin | Amoxicillin/clavulanate Anabolic steroids Chlorpromazine Clopidogrel Oral contraceptives Erythromycins Estrogens Irbesartan Mirtazapine Phenothiazines Terbinafine Tricyclic antidepressants |
Mixed: Elevated alkaline phosphatase and ALT | Amitriptyline Azathioprine Captopril Carbamazepine Clindamycin Cyproheptadine Enalapril Nitrofurantoin Phenobarbital Phenytoin Sulfonamides Trazodone Trimethoprim/sulfamethoxazole Verapamil |
ALT = alanine aminotransferase; 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, together with increased ALT and AST levels, according to Hy’s law, is associated with high mortality rates (2). If hepatocellular liver injury is accompanied by jaundice, impaired hepatic synthesis, and encephalopathy, chance of spontaneous recovery is low, and liver transplantation should be considered. This type of injury can result from drugs such as acetaminophen and isoniazid.
Cholestatic: Cholestatic hepatotoxicity is characterized by development of pruritus and jaundice accompanied by marked elevation of serum alkaline phosphatase levels. Usually, this type of injury is less serious than severe hepatocellular syndromes, but recovery may be protracted. Substances known to lead to this type of injury include amoxicillin/clavulanate and chlorpromazine. Rarely, cholestatic hepatotoxicity leads to chronic liver disease and vanishing bile duct syndrome (progressive destruction of intrahepatic bile ducts).
Mixed: In these clinical syndromes, neither aminotransferase nor alkaline phosphatase elevations are clearly predominant. Symptoms may also be mixed. Drugs such as phenytoin can cause this type of injury.
Pathophysiology references
1. 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
2. Robles-Diaz M, Lucena MI, Kaplowitz N, et al. Use of Hy's law and a new composite algorithm to predict acute liver failure in patients with drug-induced liver injury. Gastroenterology. 2014;147(1):109-118.e5. doi:10.1053/j.gastro.2014.03.050
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. Improvement in liver tests after stopping the offending agent is an additional key diagnostic feature. Possible causative agents can be evaluated using the LiverTox database. In the United States, 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.
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). Clinically significant DILI is commonly defined as at least 1 of the following (2):
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 5 × upper limit of normal (ULN) or alkaline phosphatase > 2 × ULN on 2 occasions at least 24 hours apart
Total bilirubin > 2.5 mg/dL with elevated transaminase or alkaline phosphatase
International normalized ratio (INR) > 1.5 with elevated transaminase or alkaline phosphatase
Drug rechallenge for any reason should be avoided. In the United States, 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) dedicated to improving understanding of the causes and outcomes of DILI. Information on study eligibility can be found at the DILIN's website.
Pearls & Pitfalls
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Diagnosis references
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
2. Fontana RJ, Liou I, Reuben A, et al. AASLD practice guidance on drug, herbal, and dietary supplement-induced liver injury. Hepatology. 2023;77(3):1036-1065. doi:10.1002/hep.32689
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 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.
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 U.S. 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.
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) may include age ≥ 18 years, obesity, 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.
