Drug Induced Liver Injury
Drug-induced liver injury is the most common cause of acute liver failure in the United States. Diagnosis of drug-induced liver injury is particularly challenging, since there are no specific biomarkers and it is based largely on exclusion of other causes of liver injury.
LiverTox, the NIH sponsored website pertaining to hepatotoxicity, lists more than 1200 agents including prescription and over counter medications, herbal products, nutritional supplements, metals and toxins. The most commonly implicated agents are all antimicrobial agents; amoxicillin–clavulanate, isoniazid, nitrofurantoin, trimethoprim–sulfamethoxazole, minocycline, cefazolin, azithromycin, ciprofloxacin, and levofloxacin. Other commonly implicated drugs include diclofenac, phenytoin, methyldopa, and azathioprine. Herbal and dietary supplements are increasingly recognized as the cause of acute liver injury In the United States, the proportion of cases of liver injury caused by herbal or dietary supplements increased from 7 to 9% in 2004–2007 to 19 to 20% in 2010–2014. This increase is largely due to the increasing use of herbal and dietary supplements and the lack of regulatory oversight. Most of the implicated products include 5 to 20 ingredients in a proprietary blend.
Drug-induced liver injury is classified as either direct or idiosyncratic. Direct hepatotoxicity is caused by agents that are intrinsically toxic to the liver. Direct injury is common, predictable, dose-dependent, and reproducible in animal models. Direct liver injury can be caused by high doses of acetaminophen, aspirin, niacin, amiodarone and many antineoplastic medications. Amanita phalloides mushrooms and environmental toxins can cause acute hepatic necrosis.
Direct injury occurs abruptly, within 1 to 5 days after a high dose of a medication has been started. This is the pattern often associated with intentional or accidental drug overdose. Initially, alanine aminotransferase (ALT) and alkaline phosphatase are elevated in the absence of hyperbilirubinemia. Serum alanine aminotransferase levels rise to high values, whereas alkaline phosphatase levels are minimally elevated. Coagulopathy and hyperammonemia occur within days in severe cases of hepatic failure. Acute hepatic necrosis is the most common form of clinically apparent direct hepatotoxicity and can be fatal.The elevation of liver enzymes resolves almost as quickly as they rose when the drug is stopped, or the dose is lowered.
Idiosyncratic hepatotoxicity is caused by agents that have little or no intrinsic toxicity and that cause liver injury only in rare cases. Liver injury is unpredictable, not dose-dependent, and not reproducible in animal models. Common causes of drug induced idiosyncratic acute liver injury are isoniazid, nitrofurantoin and diclofenac. The latency period generally ranges from 5 to 90 days. Symptoms resemble those of acute viral hepatitis, with a 5 to 50-fold elevation in ALT and modest increase in alkaline phosphatase. Liver histologic studies show changes suggestive of acute viral hepatitis, but eosinophils may be prominently increased. Idiosyncratic liver injury is responsible for 11 to 15% of cases of acute liver failure
References
Hoofnagle JH and Bjornsson ES. Drug Induced Liver Injury – Types and Phenotypes, N Engl J Med 2019,381:264-73
LiverTox: clinical and research information on drug-induced liver injury. Bethesda, MD: National Institutes of Health (https://www.LiverTox.nih.gov).
