Drug- & Toxin-Induced Liver Injury

How drugs injure the liver

Intrinsic versus idiosyncratic. Intrinsic hepatotoxins injure anyone given a large enough dose, predictably and within hours to days; acetaminophen, Amanita amatoxin, and carbon tetrachloride are the classic examples. Idiosyncratic injury is rare, not clearly dose-related, appears after days to months, and depends on host immune or metabolic susceptibility; isoniazid, halothane, valproate, ketoconazole, and amoxicillin-clavulanate belong here.

Patterns. Drugs can mimic almost any liver disease: hepatocellular necrosis, cholestasis, steatosis, granulomas, fibrosis, or vascular injury. Enzymes sort the first two: the R ratio, (ALT/ULN) ÷ (ALP/ULN), is above 5 in hepatocellular, below 2 in cholestatic, and 2 to 5 in mixed injury. Hy's law warns that drug-induced hepatocellular injury (ALT >3× ULN) with jaundice (bilirubin >2× ULN) carries roughly 10% or greater mortality, so the drug must be stopped.

Acetaminophen

Metabolism. About 90% of a therapeutic dose is glucuronidated or sulfated, and about 5% is oxidized by CYP2E1 to the reactive metabolite NAPQI, which glutathione neutralizes. After an overdose the conjugation pathways saturate, more drug flows to CYP2E1, glutathione is exhausted, and NAPQI binds cellular proteins, causing mitochondrial and oxidative injury. Necrosis concentrates in zone 3, the CYP2E1-rich centrilobular region. Acetaminophen is the leading cause of acute liver failure in the US.

Susceptibility. Chronic alcohol use induces CYP2E1 and depletes glutathione; fasting or malnutrition shrinks glutathione stores; and CYP inducers such as isoniazid, rifampin, phenytoin, and carbamazepine increase NAPQI formation. Each lowers the toxic threshold, sometimes to labeled doses. Acute alcohol, by contrast, competes for CYP2E1 and may transiently protect.

Treatment. After a single acute ingestion, a serum level drawn 4 hours or later is plotted on the Rumack-Matthew nomogram; levels above the treatment line (150 μg/mL at 4 hours) call for N-acetylcysteine. NAC supplies cysteine to rebuild glutathione and helps detoxify NAPQI (fomepizole, by contrast, blocks alcohol dehydrogenase in methanol and ethylene glycol poisoning). It is nearly fully protective when started within 8 hours but still benefits patients who present later, even with established liver failure. Activated charcoal helps only within a few hours of ingestion, and transplant is reserved for fulminant failure.

Hepatocellular injury: idiosyncratic drugs and amatoxin

Isoniazid. About 10–20% of users develop asymptomatic ALT elevations, and a small minority develop clinical hepatitis; risk climbs with age, alcohol use, and rifampin co-therapy.

Halothane. Its CYP2E1-derived metabolite forms trifluoroacetylated liver proteins that act as neoantigens. Typically after a repeat exposure, patients develop fever, eosinophilia, and massive centrilobular necrosis. Modern fluorinated anesthetics form far fewer adducts.

Valproate and ketoconazole. Valproate hepatotoxicity, often with microvesicular steatosis and hyperammonemia, is most dangerous in children under 2 years taking multiple anticonvulsants or with mitochondrial (POLG) disease; L-carnitine is given for toxicity. Ketoconazole's boxed warning for hepatotoxicity has largely retired its oral use; it also inhibits steroid synthesis and CYP3A4.

Amanita phalloides. The death cap's α-amanitin is heat-stable, so cooking does not help. It inhibits RNA polymerase II, halting mRNA synthesis and killing hepatocytes and renal tubular cells. Profuse watery diarrhea starts 6 to 24 hours after the meal, a deceptive lull follows, and acute liver failure arrives by days 2 to 4. Care is supportive, with silibinin and, when needed, transplant.

Cholestatic injury

Bland cholestasis. Estrogens (including oral contraceptives) and 17α-alkylated anabolic steroids such as methyltestosterone, stanozolol, and danazol impair canalicular bile secretion. Biopsy shows bile plugs with little inflammation; patients have pruritus, jaundice, a high ALP, and a near-normal ALT. Women with prior intrahepatic cholestasis of pregnancy are especially susceptible to the estrogen form.

Cholestatic hepatitis. Cholestasis with portal inflammation, often with hypersensitivity features, follows amoxicillin-clavulanate, the most commonly implicated drug in idiosyncratic liver injury, whose onset can lag weeks after the course ends. Chlorpromazine and erythromycin estolate are classic causes; the latter can bring fever, eosinophilia, and right-upper-quadrant pain that mimics cholecystitis.

Steatosis, granulomas, fibrosis, and vascular injury

Steatosis. Microvesicular fat signals mitochondrial failure: valproate impairs β-oxidation, and NRTIs inhibit mitochondrial DNA polymerase γ, which also causes lactic acidosis. Amiodarone steatohepatitis can mimic alcoholic hepatitis under the microscope in a patient who does not drink.

Fibrosis. Long-term methotrexate causes steatosis progressing to fibrosis and cirrhosis, with risk rising with cumulative dose, alcohol, obesity, and diabetes, often despite only modest enzyme changes. Excess vitamin A overloads the stellate (Ito) cells that normally store it, activating them to lay down perisinusoidal collagen.

Sinusoidal obstruction syndrome (veno-occlusive disease) classically appears within about 3 weeks of stem-cell transplant conditioning. The large hepatic veins remain patent on Doppler, which separates it from Budd-Chiari syndrome; hepatic graft-versus-host disease and CMV hepatitis are the other post-transplant considerations. Defibrotide treats severe cases.

Drug-related liver tumors are a separate topic: oral contraceptives and anabolic steroids cause hepatic adenomas, and vinyl chloride, arsenic, and Thorotrast cause angiosarcoma.