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•  Acute hepatic disease + coagulopathy + encephalopathy; w/o known pre-existing liver dis.

•  Fulminant = develops w/in 8 wk; subfulminant = develops between 8 wk and 6 mo

Etiology (Lancet 2010;376:190)

•  Viral (12% of cases)

HAV, HBV, HCV (rare), HDV + HBV, HEV (esp. if pregnant)

HSV (immunosupp Pt), EBV, CMV, adenovirus, paramyxovirus, parvovirus B19

•  Drugs/toxins (nearly 80% of cases; Hep 2010;52:2065)

Drugs: acetaminophen (most common cause; >40% of all cases), phenytoin, INH, rifampin, sulfonamides, tetracycline, telithromycin, amiodarone, PTU, valproate

Toxins: fluorinated hydrocarbons, CCl4Amanita phalloides

•  Vascular: ischemic hepatitis, Budd-Chiari syndrome, hepatic SOS, malignant infiltration

•  Autoimmune hepatitis (initial presentation)

•  Misc.: Wilson’s, acute fatty liver of pregnancy (HELLP, Reye’s), idiopathic (up to 20%)

Clinical manifestations

•  Initial presentation usually nonspecific, w/ nausea, vomiting, malaise, followed by jaundice

•  Neurologic

encephalopathy: stage I = DMS; stage II = lethargy, confusion; stage III = stupor; stage IV = coma

asterixis in stage I/II/III encephalopathy; hyperreflexia, clonus, rigidity in stage III/IV

cerebral edema → ↑ ICP, ↓ CPP → cerebral hypoxia, uncal herniation, Cushing’s reflex (hypertension + bradycardia), pupillary dilatation, decerebrate posturing, apnea

•  Cardiovascular: hypotension with low SVR

•  Pulmonary: respiratory alkalosis, impaired peripheral O2 uptake, pulm edema, ARDS

•  Gastrointestinal: GIB (↓ clotting factors, ↓ plt, DIC), pancreatitis (? due to ischemia)

•  Renal: ATN, hepatorenal syndrome, hyponatremia, hypokalemia, hypophosphatemia

•  Hematology: coagulopathy (due to ↓ synthesis of clotting factors ± DIC)

•  Infection (~90% of Pts): esp. with StaphStrep, GNRs and fungi (↓ immune fxn, invasive procedures); SBP in 32% of Pts; fever and ↑ WBC may be absent

•  Endocrine: hypoglycemia (↓ glc synthesis), metabolic acidosis (↑ lactate), adrenal insuf.

Workup (Hep 2012;55:965)

•  Viral serologies (see “Acute Hepatitis Workup”)

•  AIH serologies, ceruloplasmin & serum/urine copper, pregnancy test, arterial NH3

•  Toxicology screen (acetaminophen levels q1–2h until peak determined)

•  Imaging studies (RUQ U/S or abd CT, Doppler studies of portal and hepatic veins)

•  Liver biopsy (unless precluded by coagulopathy → in which case consider transjugular)

Treatment (Hep 2012;55:965)

•  ICU care at liver transplant ctr for hemodynamic & ventilatory support; CVVH for ARF

•  IV N-acetylcysteine (same dose as for acetaminophen): all Pts w/ hepatic failure and grade 1–2 enceph: ↑ cerebral blood flow and ↑ transplant-free survival (Gastro 2009;137:856)

•  Cerebral edema: rare w/ NH3 <75 mM/L, invariable if >200 mM/L; consider ICP monitoring if stage III/IV enceph; if ↑ ICP → mannitol 0.5–1.0 mg/kg; prophylactic 3% saline for goal Na 145–155 mEq/L if NH3 >150 mM/L, grade 3/4 enceph, ARF or on vasopressors; barbiturates & hypothermia if ↑ ICP refractory to osmotic agents

•  Encephalopathy: intubate for grade III or IV; lactulose (avoid diarrhea & overdistension)

•  Coagulopathy: vit K; FFP/plts/cryo if active bleeding; ? recomb. factor VIIa; PPI prophylaxis

•  Infection: low threshold for abx (broad spectrum, eg, vancomycin & 3rd-gen ceph.), albeit no proven mortality benefit to empiric abx

•  Treatment of specific causes: nucleo(s/t)ides for HBV; steroids for AIH; consider plasma exchange for Wilson’s; IV acyclovir for HSV; gastric lavage & PCN-G for Amanita phalloides; delivery of child for pregnancy related; TIPS and anticoag for Budd-Chiari

•  Liver transplantation if poor prognosis w/ grade II or III encephalopathy (see below)


•  Non-acetaminophen ALF mortality ~80%, acetaminophen-induced ALF mortality ~30%

•  Predictors of poor outcome

Acetaminophen-induced: pH <7.3 after fluids or INR >6.5, Cr >3.4, or grade III/IV enceph.

Non-acetamin.-induced: INR >6.5 or 3 of the following: non-A/B viral hep; other drug toxicity; time from jaundice to enceph. >7 d; age <10 or >40 y; INR >3.5; Tbili >17.4

•  ALFED model: NH3, Tbili, INR, & ≥2 enceph (Gut 2012;61:1068) & ALFSG index: coma grade, INR, Tbili, PO4, & serum CK18 (Gastro 2012;143:1237) are new indices for predicting need for liver Tx and mortality

•  ~25–30% of Pts w/ ALF undergo liver transplantation w/ 5-y survival rate of 70%