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Liver Injury Caused by Drugs

By

Danielle Tholey

, MD, Sidney Kimmel Medical College at Thomas Jefferson University

Reviewed/Revised Mar 2023
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Topic Resources

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 Metabolic Dysfunction–Associated Liver Disease (MASLD) Steatotic liver disease is due to excessive accumulation of lipid in hepatocytes. Metabolic dysfunction–associated liver disease (MASLD) includes simple fatty infiltration (a benign condition... read more (NAFLD), (1, 2 General references Many medications (eg, statins) commonly cause asymptomatic elevation of hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase). However, clinically... read more ). 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 General references Many medications (eg, statins) commonly cause asymptomatic elevation of hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase). However, clinically... read more ).

General 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. 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

Table

Biochemically, 3 types of liver injury are generally noted (see table ):

  • 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 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 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.

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 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/) .

Pearls & Pitfalls

  • Do not rechallenge with a drug suspected of causing liver injury.

Diagnosis reference

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 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.

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. 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) 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.

Drugs Mentioned In This Article

Drug Name Select Trade
Atorvaliq, Lipitor
7T Gummy ES, Acephen, Aceta, Actamin, Adult Pain Relief, Anacin Aspirin Free, Aphen, Apra, Children's Acetaminophen, Children's Pain & Fever , Children's Pain Relief, Comtrex Sore Throat Relief, ED-APAP, ElixSure Fever/Pain, Feverall, Genapap, Genebs, Goody's Back & Body Pain, Infantaire, Infants' Acetaminophen, LIQUID PAIN RELIEF, Little Fevers, Little Remedies Infant Fever + Pain Reliever, Mapap, Mapap Arthritis Pain, Mapap Infants, Mapap Junior, M-PAP, Nortemp, Ofirmev, Pain & Fever , Pain and Fever , PAIN RELIEF , PAIN RELIEF Extra Strength, Panadol, PediaCare Children's Fever Reducer/Pain Reliever, PediaCare Children's Smooth Metls Fever Reducer/Pain Reliever, PediaCare Infant's Fever Reducer/Pain Reliever, Pediaphen, PHARBETOL, Plus PHARMA, Q-Pap, Q-Pap Extra Strength, Silapap, Triaminic Fever Reducer and Pain Reliever, Triaminic Infant Fever Reducer and Pain Reliever, Tylenol, Tylenol 8 Hour, Tylenol 8 Hour Arthritis Pain, Tylenol 8 Hour Muscle Aches & Pain, Tylenol Arthritis Pain, Tylenol Children's, Tylenol Children's Pain+Fever, Tylenol CrushableTablet, Tylenol Extra Strength, Tylenol Infants', Tylenol Infants Pain + Fever, Tylenol Junior Strength, Tylenol Pain + Fever, Tylenol Regular Strength, Tylenol Sore Throat, XS No Aspirin, XS Pain Reliever
Nydrazid
Amoxil, Dispermox, Moxatag, Moxilin , Sumox, Trimox
Thorazine
Dilantin, Dilantin Infatabs, Dilantin-125, Phenytek
Acetadote, CETYLEV, Mucomyst, Mucosil Acetylcysteine
Amzeeq, Arestin, Dynacin, Minocin, minolira, Myrac, Solodyn, Ximino, Zilxi
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