acute liver failure

**Definition:** Acute liver failure = INR ≥1.5 + any degree of hepatic encephalopathy in a patient without preexisting cirrhosis, with illness duration <26 weeks. Older terms: fulminant hepatic failure (<8 weeks from jaundice to encephalopathy). Subclassified as hyperacute (<7 days), acute (7–21 days), subacute (>21 days to <26 weeks). Hyperacute has the best spontaneous survival (e.g., acetaminophen, HAV), despite the highest degree of cerebral edema risk; subacute has the worst prognosis without transplant.

**Etiologies (high-yield):** - Acetaminophen (APAP) overdose: most common cause in US/UK. Dose-dependent. Toxic metabolite NAPQI is normally detoxified by glutathione; depletion leads to centrilobular (zone 3) necrosis. Risk is increased with chronic alcohol use, fasting/malnutrition, and CYP2E1 induction. Labs: very high AST/ALT (often >3000-10,000) with a rapid rise and fall, and a relatively low bilirubin. Treatment: N-acetylcysteine (NAC), which replenishes glutathione. Use the Rumack-Matthew nomogram for acute single ingestion (4–24 h post-ingestion). - Idiosyncratic drug reactions: isoniazid, amoxicillin-clavulanate, phenytoin, valproate, halothane, propylthiouracil, and others. Also herbal and dietary supplements. - Viral: HAV, HBV (including reactivation with immunosuppression or chemotherapy), HEV (especially in pregnancy), HSV, VZV, CMV, EBV. - Toxins: Amanita phalloides mushroom (α-amanitin; treat with activated charcoal, silibinin, and NAC), carbon tetrachloride. - Vascular: Budd-Chiari syndrome, ischemic hepatitis (shock liver), and veno-occlusive disease. - Metabolic/autoimmune: Wilson disease (young patient, Coombs-negative hemolytic anemia, low alkaline phosphatase, with a ratio of ALP to total bilirubin <4, and AST:ALT >2.2), autoimmune hepatitis, acute fatty liver of pregnancy, HELLP syndrome, Reye syndrome (aspirin in children with viral illness; microvesicular steatosis), and galactosemia/hereditary fructose intolerance in infants. - Malignant infiltration and heat stroke are less common causes. - Indeterminate etiology: ~15%.

**Pathophysiology/Clinical features:** - Massive hepatocyte necrosis/apoptosis leads to loss of synthetic function (↓ clotting factors, except factor VIII, which is also made by endothelium; ↓ albumin later), impaired detoxification (ammonia accumulation), and impaired clearance. - Hepatic encephalopathy: ammonia is converted to glutamine in astrocytes, causing osmotic swelling, cerebral edema, and elevated ICP, which can lead to herniation. Cerebral edema is much more frequent in ALF than in chronic liver disease and is a leading cause of death (grade III–IV encephalopathy has the highest risk). - Coagulopathy: elevated PT/INR (an important prognostic marker). Despite the high INR, spontaneous bleeding is uncommon because pro- and anticoagulant factors are both reduced. Do not give FFP prophylactically, since it obscures INR monitoring as a prognostic tool. Give it only for active bleeding or before invasive procedures. - Other complications: hypoglycemia (impaired gluconeogenesis and glycogen stores), lactic acidosis, AKI/hepatorenal-like physiology, hypotension/vasodilation (SIRS-like), infection (bacterial and fungal; a leading cause of death), pancreatitis, adrenal insufficiency, hyponatremia, hypophosphatemia, and respiratory alkalosis then ARDS. - Presentation: malaise, nausea, jaundice, RUQ pain, then altered mental status (asterixis, confusion, coma). Liver may be small (shrinking from massive necrosis). Absence of stigmata of chronic liver disease (no spider angiomata, ascites, splenomegaly), which helps distinguish from decompensated cirrhosis.

**Workup:** AST/ALT, bilirubin, ALP, INR, glucose, ammonia (arterial), lactate, acetaminophen level, viral serologies (HAV IgM, HBsAg, anti-HBc IgM, HEV, HSV PCR), autoimmune markers (ANA, ASMA, IgG), ceruloplasmin, urine/serum toxicology, pregnancy test, and liver ultrasound with Doppler (Budd-Chiari). Transjugular biopsy if the cause is unclear.

**Management:** - Admit to ICU, preferably at a transplant center. Early transfer is key. - Treat the underlying cause: NAC for APAP (and now often for non-APAP ALF with early-stage encephalopathy), nucleos(t)ide analogs for HBV, acyclovir for HSV, delivery for acute fatty liver of pregnancy/HELLP, discontinuation of the offending drug, and silibinin/charcoal for Amanita. - Supportive: glucose monitoring/infusion, avoid sedatives, and treat cerebral edema (head elevation, hypertonic saline, mannitol, intubation with hyperventilation as a temporizing measure for herniation, and ICP monitoring in selected cases). Lactulose has no proven benefit in ALF. Treat or prophylax against infections, give stress ulcer prophylaxis, and provide renal support (CRRT preferred over intermittent dialysis in unstable patients). - Liver transplantation is definitive therapy for patients unlikely to recover spontaneously. Criteria: King's College Criteria (APAP: arterial pH <7.3 after resuscitation, OR INR >6.5 + creatinine >3.4 mg/dL + grade III–IV encephalopathy; non-APAP: INR >6.5, OR any 3 of: age <10 or >40, unfavorable etiology [non-A, non-B, halothane, idiosyncratic drug], jaundice-to-encephalopathy >7 days, INR >3.5, bilirubin >17.5 mg/dL). MELD is also used.

**Board pearls:** - ALF = coagulopathy + encephalopathy without preexisting liver disease. If cirrhosis is present, it is acute-on-chronic liver failure instead. - Acetaminophen: give NAC; time to treatment matters, and the earlier the better (but still beneficial late). - Wilson disease: Kayser-Fleischer rings (may be absent in ALF), hemolysis, low ALP, and low uric acid; treatment is transplant. - Acute fatty liver of pregnancy: third trimester, microvesicular fatty change, hypoglycemia, elevated ammonia, and DIC; treat with delivery. - Death usually from cerebral edema/herniation, sepsis, or multiorgan failure. - Hepatic encephalopathy in cirrhosis (as opposed to ALF) is treated with lactulose and rifaximin.