Acute hepatic failure

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  • Hyperacute liver failure: encephalopathy occurs within 7 days of the onset of jaundice; this subset is likely to survive with medical management despite the high incidence of cerebral edema
  • Acute liver failure: interval of 8-28 days from jaundice to encephalopathy; this subset has a high incidence of cerebral edema and a poorer prognosis without liver transplant
  • Subacute liver failure: interval of 5-12 weeks from the onset of jaundice to the onset of encephalopathy; this subset has a lower incidence of cerebral edema, but a poor prognosis


Acetaminophen Toxicity

  • Now the most common cause of acute liver failure in the US[2]
  • Small amount of Acetaminophen is metabolized by Cytochrome P450 into NAPQI, which is a toxic metabolite
  • In therapeutic doses, NAPQI combines rapidly with glutathione to form nontoxic metabolites that are excreted in the urine
  • In overdose, glutathione stores are used up and NAPQI binds to cell proteins in the liver which leads to cell death
  • See Acetaminophen toxicity

Viral Hepatitis

  • Hepatocellular pattern of injury, where AST and ALT are higher than Tbili and Alk Phos; likely to have significantly elevated ALT and AST (20x normal or higher)
  • Of note, transmission of Hepatitis B and Hepatitis C through donated blood, blood products, and organs is rare in the US since blood screening became available in 1992
  • Hepatitis A
    • Fecal-oral transmission
    • Associated with epidemics linked to a common source (water)
    • Most common risk factor is travel outside of the US [3]
    • Not associated with chronic carrier state; incubation period is approximately 30 days, and infectivity usually resolved prior to symptom onset
  • Hepatitis B
    • Transmitted parenterally, blood contact, and unprotected sex
    • 90% of exposed infants progress to chronic hepatitis; 10% of exposed adults progress to chronic hepatitis
    • Serology[4]
Clinical Scenario HBsAg anti-HBc anti-HBs
Susceptible to infection negative negative negative
Immune due to natural infection negative positive positive
Immune due to Hep B infection negative negative positive
Acutely infected positive anti-HBc- positive; IgM anti-HBc- positive negative
Chronically infected positive anti-HBc- positive; IgM anti-HBc- negative negative
  • Hepatitis C
    • Transmitted through IV drug use (most common) and infrequently through sexual contact
    • 90% of HCV infections progress to chronic hepatitis[5]
  • Hepatitis D
    • Transmission similar to Hepatitis B
    • Can only co-infect patients with Hepatitis B (actively producing HBsAg)
    • Presentation can range from acute self-limited disease to fulminant hepatitis or chronic infection
  • Hepatitis E
    • Fecal-oral transmission
    • Usually results in mild illness, but can cause fulminant hepatitis in pregnant women[6]

Alcohol-related Liver Disease

  • Presentation can range from mild abdominal pain, nausea and vomiting to acute liver failure
  • May have large palpable liver from fatty infiltration, or may have small nonpalpable liver secondary to cirrhosis from chronic disease
  • Will have moderate elevations in AST and ALT (levels >10x normal are unusual)
    • AST:ALT ration >2 is typical
  • May also have electrolyte abnormalities from malnutrition or alcoholic/starvation ketoacidosis

Drug or Toxin Related Liver Disease

  • Liver damage from drugs or toxins may be cytotoxic from the primary drug or its metabolites, or may be caused by veno-occlusive disease or hypersensitivity disease[7]
  • Common Drugs and Toxins
    • Acetaminophen
    • Amiodarone
    • Amphotericin
    • Anabolic steroids
    • Azathioprine
    • Carbamazepine
    • Chlorpromazine
    • Cisplatin
    • Contraceptives
    • Cyclophosphamide
    • Erythromycin
    • Gold salts
    • Haloperidol
    • Isoniazid
    • Ketoconazole
    • Lovastatin
    • Methotrexate
    • Methoxyflurane
    • Methyldopa
    • Phenobarbital
    • Phenytoin
    • Quinidine
    • Salicylates
    • Tetracycline
    • Valproic acid
    • Verapamil

Other Rare Causes of Acute Liver Failure

  • Wilson’s disease: unexplained elevations in LFTs, neuro-psychiatric symptoms, Kayser-Fleischer rings on eye exam
  • Auto-immune hepatitis: more common in women, liver disease without explanation, may have family history of other autoimmune disorders
  • Hemochromatosis: family history of liver disease and cardiac disease
  • Budd-Chiari: history of hypercoagulable disorder, abdominal pain, and ascites
  • Viral infections: HSV, Epstein-Barr, varicella-zoster, toxoplasmosis

Clinical Features

  • Common findings in acute liver failure
    • Tender hepatomegaly
    • Jaundice
    • Encephalopathy
    • Asterixis
  • Common findings in chronic liver failure
    • Ascites
    • Caput medusae
    • Palmar erythema
    • Spider angiomata
    • Gynecomastia
    • Testicular atrophy
    • Parotid gland enlargement
    • Muscular atrophy
    • May also have jaundice, encephalopathy, and asterixis as in acute liver failure

Differential Diagnosis

  • Encephalopathy (altered mental status)
    • Hypoglycemia
    • Hypoxia
    • Intracerebral hemorrhage or mass
    • Meningitis/encephalitis
    • CVA
    • Intoxication
    • Myxedema coma
    • Wernicke encephalopathy
    • Sepsis
    • Seizure/post-ictal state
    • Uremia
    • Electrolyte abnormality
  • Jaundice
    • Hepatitis
    • Hemolysis
    • Biliary pathology (CBD obstruction)
    • Pregnancy
    • Congenital diseases (more likely to present in early childhood)
  • Ascites
    • Hepatitis or cirrhosis
    • Heart failure or constrictive pericarditis
    • Malignancy (primary or metastatic peritoneal carcinoma)
    • Pancreatitis
    • Vasculitis
    • Connective tissue disorders
    • Chylous ascites



  • AST and ALT
    • Enzymes found mainly in hepatic cells, though ALT is more specific to the liver than AST
    • Extreme elevation in AST (>3000U/L, or >40x upper limit of normal) is consistent with acetaminophen toxicity or ischemic injury
    • Moderate elevations (10-40x upper limit of normal) is consistent with viral hepatitis
    • Mild elevations (<10x upper limit of normal) is consistent with alcoholic hepatitis
  • Alkaline Phosphatase
    • Found in bile canaliculi (but also in placenta, ileal mucosa, bone, and kidney)
    • Elevated in diseases of cholestasis
    • Rare for levels to be >3x normal limit in acute liver failure
  • Bilirubin
    • Elevated in diseases of cholestasis
    • In obstructive diseases, the direct bilirubin will usually be about 50% of the total bilirubin; if indirect bilirubin is higher, more suggestive of hemolysis or problem with conjugation
  • Coagulation Studies
    • Reflects the liver’s ability to synthesize clotting factors
    • INR >6.5 or PT >20 seconds indicates patients at high risk for death
  • Albumin
    • Reflects synthetic function of the liver
    • Has a long half-life (20 days) and may not be decreased early in disease
  • Ammonia
    • Elevated as a result of impaired clearance
    • Poor correlation between degree of elevation and severity of encephalopathy symptoms
  • Chemistry Panel
    • Electrolyte abnormalities may indicate malnutrition or dehydration
    • Creatinine is used as a prognostic indicator
    • Need to check a glucose because patients with liver failure are prone to hypoglycemia
  • CBC
    • Not useful in diagnosing the cause of liver failure, but helpful in determining coexisting infection, anemia, thrombocytopenia
  • Hepatic Viral Serologies
    • Consider for all patients with undifferentiated liver failure
    • IgM anti-HBc may be the only positive marker in acute Hepatitis B infection
    • Anti-HCV and HCV RNA are present in both chronic and acute Hepatitis C infections, so it is difficult to differentiate based on serologies, but presence of HCV RNA in the absence of anti-HCV is more suggestive of acute infection[8]
    • Only need to test for IgM anti-HEV in patients who are symptomatic and have just travelled from areas where Hepatitis E is endemic


  • Consider US or CT in patients with jaundice to evaluate for a mechanical obstruction
  • Otherwise, tailor imaging towards specific complaints


  • Treatment is mostly supportive and tailored towards the specific etiology
  • Early consideration regarding transporting patient to a transplant center given potential for rapid deterioration
  • Symptom specific supportive treatment options
    • Encephalopathy: consider lactulose of neomycin
    • Seizures: consider phenytoin over benzodiazepines (prevent benzodiazepine oversedation secondary to decreased hepatic clearance)
    • Intracranial Hypertension: elevated head of bed, mannitol, short-term hyperventilation; hypothermia may be a bridge to transplant; no benefit from steroids
    • Coagulopathy
      • Prophylactic normalization of the INR is not necessary unless procedure (such as paracentesis) is planned; then can give Vitamin K
      • Recommend platelet transfusion to 10K for asymptomatic patients, and to 50-70K for patients undergoing invasive procedures
    • See Acetaminophen (Tylenol) toxicity for specifics regarding treatment of acetaminophen toxicity
    • See Spontaneous Bacterial Peritonitis for specifics regarding diagnosis and treatment of SBP


  • Admission to ICU with early consideration for transportation to transplant center

See Also


  1. O’Grady, JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet. July 1993, Volume 342, Issue 8866, Page 273-275
  2. Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med. 2002 Dec 17; 137(12): 947-54.
  3. Oyama, LC: Disorders of the Liver and Biliary Tractin Marx JA, Hockberger RS, Walls RM, et al (eds): Rosen’s Emergency Medicine: Concepts and Clinical Practice, ed 8. St. Louis, Mosby, Inc., 2014, (Ch) 107: p 1186-1204.
  5. Oyama, LC: Disorders of the Liver and Biliary Tractin Marx JA, Hockberger RS, Walls RM, et al (eds): Rosen’s Emergency Medicine: Concepts and Clinical Practice, ed 8. St. Louis, Mosby, Inc., 2014, (Ch) 107: p 1186-1204
  6. Rein DB, Stevens GA, Theaker J, Wittenborn JS, Wiersma ST. The Global Burden of Hepatitis E Virus Genotypes 1 and 2 in 2005. Hepatology, Vol. 55, No. 4, 2012: 988-997
  7. Oyama, LC: Disorders of the Liver and Biliary Tractin Marx JA, Hockberger RS, Walls RM, et al (eds): Rosen’s Emergency Medicine: Concepts and Clinical Practice, ed 8. St. Louis, Mosby, Inc., 2014, (Ch) 107: p 1186-1204
  8. Bailey, C, Hern HG. Hepatic Failure: An Evidence-Based Approach In The Emergency Department. Emergency Medicine Practice. Vol. 12, No. 4, 2014.