Acute Liver Failure & Drug-Induced Liver Injury

Definition and causes

Definition. Acute liver failure (ALF) is severe acute liver injury with coagulopathy (INR ≥1.5) and hepatic encephalopathy of any grade, developing within 26 weeks of illness onset in a patient without pre-existing cirrhosis. Wilson disease, vertically acquired hepatitis B and autoimmune hepatitis can qualify even when cirrhosis is present, if recognized within 26 weeks. Coagulopathy without encephalopathy is severe acute liver injury, which needs close watching because encephalopathy can follow quickly.

Tempo. The jaundice-to-encephalopathy interval defines hyperacute (<1 week), acute (1–4 weeks) and subacute (>4 weeks) ALF. Hyperacute cases—acetaminophen, hepatitis A, ischemia—carry the most cerebral edema yet the best spontaneous survival; subacute cases—idiosyncratic DILI, indeterminate ALF—have less edema but poor survival without transplant.

Acetaminophen. In overdose, conjugation saturates, CYP2E1 produces more of the toxic metabolite NAPQI, glutathione is depleted, and centrilobular (zone 3) necrosis follows, with aminotransferases that can exceed 10,000 U/L. Chronic alcohol use and fasting lower the toxic threshold. After a single acute ingestion, a level drawn 4–24 hours later is plotted on the Rumack-Matthew nomogram (treatment line 150 μg/mL at 4 hours); staggered or chronic ingestions are treated if the level is detectable or AST is raised. N-acetylcysteine (NAC), a glutathione precursor, works best within 8 hours but helps at any stage.

Evaluation and ICU care

N-acetylcysteine. Give IV NAC for acetaminophen ALF regardless of timing or drug level. In adults with non-acetaminophen ALF and early (grade I–II) encephalopathy, NAC also improves transplant-free survival.

Metabolic care. Failed gluconeogenesis and depleted glycogen cause profound hypoglycemia that mimics or deepens encephalopathy: check glucose every 1–2 hours and infuse dextrose. Replace phosphate, potassium and magnesium, and watch for lactic acidosis.

Cerebral edema. Intracranial hypertension is a leading cause of death; risk rises with hyperacute ALF, grade III–IV encephalopathy and arterial ammonia above 150–200 μmol/L. Raise the head of the bed to 30°, intubate for grade III–IV encephalopathy, keep sodium at 145–155 mEq/L with hypertonic saline, give mannitol for ICP surges, and reserve brief hyperventilation for impending herniation. Avoid fever, hypotension and stimulation; lactulose has no proven benefit in ALF.

Coagulopathy. Give plasma or factors only for active bleeding or before invasive procedures. The INR is a key prognostic marker, plasma adds volume, and hemostasis is rebalanced—protein C, protein S and antithrombin fall along with procoagulant factors—so spontaneous bleeding is uncommon. One dose of IV vitamin K excludes deficiency; a PPI or H2 blocker prevents stress ulcers.

Infection, sedation and kidneys. Bacterial and fungal infections are frequent and often afebrile: obtain surveillance cultures and start broad-spectrum antimicrobials at the first sign of deterioration. Avoid benzodiazepines and other sedatives that cloud the neurologic exam. Treat acute kidney injury with continuous renal replacement therapy rather than intermittent hemodialysis, and support blood pressure with norepinephrine.

Falling aminotransferases with a rising INR and bilirubin signal massive necrosis, not recovery.

Transplant referral

Refer early. Contact a transplant center at the first sign of encephalopathy or a rising INR rather than waiting for criteria. King's College criteria identify patients unlikely to survive without transplant:

Spontaneous survival is best with acetaminophen, hepatitis A, ischemia and pregnancy-related ALF, and worst with idiosyncratic DILI, hepatitis B, Wilson disease and indeterminate cases.

Drug-induced liver injury

Types and diagnosis. Intrinsic hepatotoxins such as acetaminophen cause predictable, dose-related injury; idiosyncratic DILI is unpredictable, largely dose-independent, and follows a latency of days to about 6 months. DILI is a diagnosis of exclusion: establish the timeline, document improvement after stopping the agent (dechallenge), and exclude viral hepatitis (including HEV), autoimmune hepatitis, biliary obstruction and ischemia. Rechallenge is avoided. The R ratio—(ALT ÷ ULN) ÷ (ALP ÷ ULN)—classifies injury as hepatocellular (≥5), cholestatic (≤2) or mixed (2–5).

Key culprits. Amoxicillin-clavulanate is the most common cause of idiosyncratic DILI in the US and Europe, typically cholestatic or mixed injury in older men that may begin days to several weeks after the course ends—so ask about antibiotics from the previous 2 months—and usually resolves over weeks to months. Valproate hepatotoxicity is most dangerous in young children on several antiepileptics and in those with POLG mitochondrial mutations. Herbal and dietary supplements—green tea extract, bodybuilding products laced with anabolic steroids, multi-ingredient weight-loss products—are a growing share of DILI.

Monitoring and stopping rules

Hy's law. Hepatocellular injury (ALT >3× ULN) with jaundice (total bilirubin >2× ULN), without an initial cholestatic ALP rise or another explanation, carries roughly a 10% risk of death or transplant. Stop the drug immediately and follow the INR and mental status. Named for Hyman Zimmerman, it is used by regulators to flag hepatotoxic drugs.

Isoniazid. Asymptomatic aminotransferase rises occur in 10–20% of patients and often settle despite continued therapy. Hepatitis is more likely with older age, alcohol use, pregnancy or the postpartum period, HIV and chronic liver disease; these patients get baseline and monthly liver tests, and all patients are told to stop and report symptoms. Stop isoniazid if ALT exceeds 3× ULN with symptoms (nausea, abdominal pain, jaundice) or 5× ULN without symptoms. Pyridoxine prevents neuropathy but does not protect the liver.

Statins. Asymptomatic ALT elevation below 3× ULN is common, often transient and not a reason to stop. Routine monitoring after the baseline test is unnecessary, serious statin hepatotoxicity is rare, and statins are safe in MASLD and compensated chronic liver disease—stopping them trades a tiny hepatic risk for a real cardiovascular one.