Liver Failure, Acute

Essentials of Diagnosis

• May be fulminant or subfulminant and both carry an equally poor prognosis

• Acetaminophen and idiosyncratic drug reactions are the most common causes

General Considerations

• Acute liver failure may occur after reactivation of hepatitis B in carriers who receive immunosuppressive therapy

• In fulminant liver failure, encephalopathy and coagulopathy develop within 8 weeks after the onset of acute liver injury

• Subfulminant liver failure occurs when encephalopathy and coagulopathy appear between 8 weeks and 6 months after the onset of acute liver injury

• Acute-on-chronic liver failure

  • Refers to acute deterioration in liver function in a person with preexisting chronic liver disease

  • Often precipitated by infection or an alcohol binge and alcoholic hepatitis

• Toxicity caused by acetaminophen accounts for 45% of cases; idiosyncratic drug reactions are the second most common

• Among cases caused by acetaminophen

  • 44% are due to suicide attempts

  • 48% are due to unintentional overdose (the threshold for liver failure is lowered by chronic alcohol use)

ETIOLOGY

• Acetaminophen toxicity

• Idiosyncratic drug reactions

• Mushroom poisoning (Amatoxins)

• Viruses (hepatitis A, B, C, D, E, CMV, EBV, HSV, parvovirus B19, influenza virus, yellow fever virus, Middle East respiratory syndrome virus, Ebola virus, SARS coronavirus)

• Shock

• Hyperthermia

• Budd-Chiari syndrome

• Malignancy (especially lymphomas)

• Wilson disease

• Reye syndrome

• Fatty liver of pregnancy and other disorders of fatty acid oxidation

• Autoimmune hepatitis

• Grand mal seizures (rarely)

• Cause is indeterminate in approximately 5.5% of cases

Demographics

• Most cases in the United States are caused by

  • Acetaminophen toxicity

  • Idiosyncratic drug reactions

  • Acute viral hepatitis, especially hepatitis B

  • Some cases are due to hepatitis A or unknown (non-ABCDE) viruses

• In endemic areas, hepatitis E is an important cause of acute liver failure particularly in pregnant women

• Hepatitis C is a rare cause of acute liver failure; acute hepatitis A or B superimposed on chronic hepatitis C has a high risk of acute liver failure

Symptoms and Signs

• Gastrointestinal symptoms (nausea, vomiting, anorexia)

• Jaundice may be absent or minimal early

• Systemic inflammatory response

• Acute kidney injury

• Clinically significant bleeding is uncommon and reflects severe systemic inflammation rather than coagulopathy

Laboratory Tests

• Severe hepatocellular damage (Table 16–3)

• Coagulopathy

• Elevated serum ammonia; correlates with development of encephalopathy and intracranial hypertension

• In acetaminophen toxicity, serum aminotransferase elevations are often towering (> 5000 units/L), and acetaminophen is undetectable in plasma in 50% of cases

• Acetaminophen-protein adducts in serum and other biomarkers for early detection are under study

• In acute liver failure due to microvesicular steatosis (eg, fatty liver disease of pregnancy), serum aminotransferase elevations may be modest (< 300 units/L)

Medications

• Prophylactic antibiotic therapy

  • Decreases the risk of infection in 90% of patients

  • However, no effect on survival so not routinely recommended

• For suspected sepsis, broad-spectrum antimicrobial therapy is indicated

• Acetylcysteine

  • Acetaminophen toxicity is an indication for its early administration

  • For massive acetaminophen overdoses, the duration of intravenous acetylcysteine therapy may need to be extended until the serum aminotransferase levels are declining and serum acetaminophen levels are undetectable

  • Improves cerebral blood flow and oxygenation in fulminant liver failure due to any cause

  • Dosage is either 140 mg/kg orally followed by 70 mg/kg orally every 4 hours for an additional 17 doses; or 150 mg/kg in 5% dextrose intravenously over 15 minutes followed by 50 mg/kg intravenously over 4 hours and then 100 mg/kg intravenously over 16 hours

  • Can prolong the prothrombin time leading to the erroneous perception that liver failure is worsening

  • Can cause nausea, vomiting, and anaphylactoid reaction, especially in persons with a history of asthma

  • May be detrimental in children with non-acetaminophen acute liver failure

• Penicillin G (300,000 to 1 million units/kg/day intravenously) or silibinin (not licensed in the United States; also called silymarin or milk thistle) is given for mushroom poisoning

• Nucleoside analogs are recommended for acute liver failure caused by HBV (see Hepatitis B, Chronic)

• Intravenous acyclovir has shown benefit in patients with herpes simplex virus hepatitis

• Plasmapheresis combined with D-penicillamine has been used in acute liver failure due to Wilson disease

• Lactulose is of uncertain value

• Mannitol, 0.5 g/kg or 100–200 mL of a 20% solution by intravenous infusion over 10 min, may decrease cerebral edema but should be used with caution in advanced chronic kidney disease

• Intravenous hypertonic saline may also reduce intracranial pressure

• If these measures fail, hypothermia to 33.1°C or short-acting barbiturates may reduce intracranial hypertension

• The value of hyperventilation and intravenous prostaglandin E₁ is uncertain

Surgery

• Early transfer to a liver transplantation center is essential

Therapeutic Procedures

• The head of the patient's bed should be elevated to 30 degrees

• Patients with stage 3 or 4 encephalopathy should be intubated

• Treatment is directed toward achieving metabolic and hemodynamic stability

  • Intravascular volume should be preserved, but large-volume infusions of hypotonic fluids should be avoided

  • Norepinephrine is the preferred vasopressor, and vasopressin may be added for persistent hypotension

  • Hypoglycemia should be prevented

  • Intermittent renal replacement therapy may be required

  • To preserve muscle mass and immune function, enteral administration of protein, 1–1.5 g/kg/day, is advised, with careful monitoring of the plasma ammonia level

• The Molecular Adsorbents Recirculating System (MARS); hepatic-assist devices using living hepatocytes; extracorporeal whole liver perfusion; hepatocyte transplantation; and liver xenografts have shown promise; one of these may serve as a patient's "bridge" to liver transplantation

Complications

• Adrenal insufficiency

• Subclinical myocardial injury manifesting as an elevated serum troponin I level

Follow-Up

• Extradural sensors are placed to monitor intracranial pressure for impending cerebral edema

• Monitor kidney function, acid-base status

Prognosis

• The mortality rate of acute liver failure with severe encephalopathy is as high as 80%

• The outlook is especially poor in patients younger than 10 and older than 40 years of age and in those with an idiosyncratic drug reaction

• Other adverse prognostic factors

  • Serum bilirubin level > 18 mg/dL (307.8 mcmol/L)

  • INR > 6.5

  • Onset of encephalopathy more than 7 days after the onset of jaundice

  • Low factor V level (< 20% of normal)

• Acetaminophen-induced acute liver failure

  • Transplant-free survival is 75%

  • No more than 8% of affected patients require transplantation

  • Survival rates are also favorable for hepatitis A, ischemic hepatitis, and pregnancy-related liver disease

  • Indicators of a poor outcome

    • Acidosis (pH < 7.3)

    • INR > 6.5

    • Azotemia (serum creatinine ≥ 3.4 mg/dL [283.22 mcmol/L])

    • Hyperphosphatemia (> 3.7 mg/dL [1.2 mmol/L])

    • Elevated blood ammonia level (> 211 mcg/dL [124 mcmol/L])

    • Elevated blood lactate level (> 3.5 mEq/L [3.5 mmol/L])

    • Thrombocytopenia is associated with the development of multiorgan system failure

  • A rising serum alpha-fetoprotein level predicts a favorable outcome

• For patients with acute liver failure not due to acetaminophen, the outlook is poor in patients

  • Younger than 10 and older than 40 years of age

  • With an idiosyncratic drug reaction

• Acute liver failure superimposed on chronic liver disease (acute-on-chronic liver failure) has a poor prognosis when associated with kidney dysfunction

• Emergency liver transplantation

  • Is considered for patients with stage 2 to stage 3 encephalopathy or a MELD score of 30.5 or higher

  • Is associated with an 70% survival rate at 1 year

• With earlier recognition of acute liver failure, the frequency of cerebral edema has declined, and the overall mortality rate has declined steadily and is as low as 25%

When to Admit

• All patients with acute liver failure should be hospitalized