Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + Download Section PDF Listen ++ For further information, see CMDT Part 16-05: Acute Liver Failure + Key Features Download Section PDF Listen +++ +++ 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 + Clinical Findings Download Section PDF Listen +++ +++ 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 + Diagnosis Download Section PDF Listen +++ +++ 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) ++Table Graphic Jump LocationTable 16–3.Liver biochemical tests: normal values and changes in hepatocellular and obstructive jaundice.View Table||Download (.pdf) Table 16–3. Liver biochemical tests: normal values and changes in hepatocellular and obstructive jaundice. Tests Normal Values Hepatocellular Jaundice Obstructive Jaundice Bilirubin1 Direct Indirect 0.1–0.3 mg/dL (1.71–5.13 mcmol/L) 0.2–0.7 mg/dL (3.42–11.97 mcmol/L) Increased Increased Increased Increased Urine bilirubin None Increased Increased Serum albumin 3.5–5.5 g/dL (35–55 g/L) Decreased Generally unchanged Alkaline phosphatase 30–115 units/L (0.6–2.3 mkat/L) Mildly increased (+) Markedly increased (++++) Prothrombin time INR of 1.0–1.4. After vitamin K, 10% decrease in 24 hours Prolonged if damage is severe; does not respond to parenteral vitamin K Prolonged if obstruction is marked; generally responds to parenteral vitamin K ALT, AST ALT, ≤ 30 units/L (0.6 mkat/L) (men), ≤ 19 units/L (0.38 mkat/L) (women); AST, 5–40 units/L (0.1–0.8 mkat/L) Increased, as in viral hepatitis Minimally increased 1Measured by the van den Bergh reaction, which overestimates direct bilirubin in normal persons.ALT, alanine aminotransferase; AST, aspartate aminotransferase; INR, international normalized ratio. + Treatment Download Section PDF Listen +++ +++ 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 + Outcome Download Section PDF Listen +++ +++ 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 + References Download Section PDF Listen +++ + +Doulberis M et al. Acute liver failure: from textbook to emergency room and intensive care unit with concomitant established and modern novel therapies. J Clin Gastroenterol. 2019 Feb;53(2):89–101. [PubMed: 30575637] + +Flamm SL et al. American Gastroenterological Association Institute guidelines for the diagnosis and management of acute liver failure. Gastroenterology. 2017 Feb;152(3):644–7. [PubMed: 28056348] + +Ganger DR et al; Acute Liver Failure Study Group. Acute liver failure of indeterminate etiology: a comprehensive systematic approach by an expert committee to establish causality. Am J Gastroenterol. 2018 Sep;113(9):1319–28. [PubMed: 29946176] + +Khan R et al. Modern management of acute liver failure. Gastroenterol Clin North Am. 2018 Jun;47(2):313–26. [PubMed: 29735026] + +Koch DG et al. The natural history of severe acute liver injury. Am J Gastroenterol. 2017 Sep;112(9):1389–96. [PubMed: 28440304] + +Leventhal TM et al. Acetaminophen is undetectable in plasma from more than half of patients believed to have acute liver failure due to overdose. Clin Gastroenterol Hepatol. 2019 Sep;17(10):2110–6. [PubMed: 30731196] + +Pyrsopoulos NT (guest editor). Acute liver failure. Clin Liver Dis. 2018 May;22(2):229–427. [Full issue] + +Reynolds AS et al. Neurological monitoring in acute liver failure. Hepatology. 2019 Nov;70(5):1830–5. [PubMed: 31077591] + +Stravitz RT et al. Acute liver failure. Lancet. 2019 Sep 7;394(10201):869–81. [PubMed: 31498101] + +Stravitz RT et al. Bleeding complications in acute liver failure. Hepatology. 2018 May;67(5):1931–42. [PubMed: 29194678]