ACUTE LIVER FAILURE
Acute liver failure (ALF) is a rare and often heterogeneous presentation of severe liver dysfunction in a patient with otherwise no pre-existing liver disease. Though it has high morbidity and mortality, its overall survival has improved through intensive care management and emergency liver transplantation advancements.
ALF is defined as the development of severe acute liver injury with encephalopathy and impaired synthetic function (INR of 1.5 or higher) in a patient without cirrhosis or preexisting liver disease and with an illness of fewer than 26 weeks duration.
Acute liver failure may be fulminant or subfulminant. Fulminant hepatic failure is characterized by the development of hepatic encephalopathy within 8 weeks after the onset of acute liver injury. Coagulopathy (international normalized ratio [INR] 1.5 or higher) is invariably present.
Subfulminant hepatic failure occurs when these findings appear between 8 weeks and 6 months after the onset of acute liver injury and carries an equally poor prognosis. Acute-on-chronic liver failure refers to acute deterioration in liver function in a person with preexisting chronic liver disease.
Who is at risk for acute liver failure?
You are at risk for acute liver failure if you:
- Take too much acetaminophen
- Have certain diseases or infections, such as hepatitis, Wilson disease, and herpes simplex virus
- Drink a lot of alcohol
- Have poor blood flow to the liver
Signs and symptoms of acute liver failure may include:
- Yellowing of your skin and eyeballs (jaundice)
- Pain in your upper right abdomen
- Abdominal swelling (ascites)
- A general sense of feeling unwell (malaise)
- Disorientation or confusion
- Breath may have a musty or sweet odor
- Acetaminophen toxicity is the most common cause, accounting for at least 45% of cases. Suicide attempts account for 44% of cases of acetaminophen-induced hepatic failure, and unintentional overdoses (“therapeutic misadventures”), which are often a result of a decrease in the threshold toxic dose because of chronic alcohol use or fasting and have been reported after weight loss surgery, account for at least 48%. Other causes include
- Idiosyncratic drug reactions (the second most common cause, with antituberculosis drugs, antiepileptics, and antibiotics implicated most commonly), viral hepatitis, poisonous mushrooms (Amanita phalloides), shock, hyperthermia, Budd-Chiari syndrome, malignancy (most commonly lymphomas), Wilson disease, Reye syndrome, fatty liver of pregnancy and other disorders of fatty acid oxidation, autoimmune hepatitis, parvovirus B19 infection and, rarely, grand mal seizures.
- The risk of acute liver failure is increased in patients with diabetes mellitus, and outcome is worsened by obesity.
- Herbal and dietary supplements are thought to be contributory to acute liver failure in a substantial portion of cases, regardless of cause, and may be associated with lower rates of transplant-free survival.
- Acute-on-chronic liver failure is often precipitated by a bacterial infection or an alcohol binge and alcoholic hepatitis.
- Viral hepatitis now accounts for only 12% of all cases of acute liver failure. The decline of viral hepatitis as the principal cause of acute liver failure is due to universal vaccination of infants and children against hepatitis B and the availability of the hepatitis A vaccine. Acute liver failure may occur after reactivation of hepatitis B in carriers who receive immunosuppressive therapy.
Pathophysiology of Acute Liver Failure
In acute liver failure, multiple organ systems malfunction, often for unknown reasons and by unknown mechanisms. Affected systems include
Hepatic: Hyperbilirubinemia is almost always present at presentation. The degree of hyperbilirubinemia is one indicator of the severity of liver failure. Coagulopathy due to impaired hepatic synthesis of coagulation factors is common. Hepatocellular necrosis, indicated by increased aminotransferase levels, is present.
Cardiovascular: Peripheral vascular resistance and blood pressure decrease, causing hyperdynamic circulation with increased heart rate and cardiac output.
Cerebral: Portosystemic encephalopathy occurs, possibly secondary to increased ammonia production by nitrogenous substances in the gut. Cerebral edema is common among patients with severe encephalopathy secondary to acute liver failure; uncal herniation is possible and usually fatal.
Renal: For unknown reasons, acute kidney injury occurs in up to 50% of patients. Because blood urea nitrogen (BUN) level depends on hepatic synthetic function, the level may be misleadingly low; thus, the creatinine level better indicates kidney injury. As in hepatorenal syndrome, urine sodium and fractional sodium excretion decrease even when diuretics are not used and tubular injury is absent (as may occur when acetaminophen toxicity is the cause).
Immunologic: Immune system defects develop; they include defective opsonization, deficient complement, and dysfunctional white blood cells and killer cells. Bacterial translocation from the gastrointestinal tract increases. Respiratory and urinary tract infections and sepsis are common; pathogens can be bacterial, viral, or fungal.
Metabolic: Both metabolic and respiratory alkalosis may occur early. If shock develops, metabolic acidosis can supervene. Hypokalemia is common, in part because sympathetic tone is decreased and diuretics are used. Hypophosphatemia and hypomagnesemia can develop. Hypoglycemia may occur because hepatic glycogen is depleted and gluconeogenesis and insulin degradation are impaired.
Pulmonary: Noncardiogenic pulmonary edema may develop.
The treatment of acute liver failure 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.
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 ammonia level.
Prophylactic antibiotic therapy decreases the risk of infection, observed in up to 90%, but has no effect on survival and is not routinely recommended.
Microbiological screening cultures should be obtained for patients admitted to hospital. For suspected sepsis, broad coverage is indicated.
Despite a high rate of adrenal insufficiency, corticosteroids do not reduce mortality and may lower overall survival in patients with a high MELD score, though they may reduce vasopressor requirements.
Stress gastropathy prophylaxis with an H2-receptor blocker or proton pump inhibitor is recommended. Administration of acetylcysteine (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 over 4 hours and then 100 mg/kg over 16 hours) is indicated for acetaminophen toxicity up to 72 hours after ingestion.
For massive acetaminophen overdoses, treatment with intravenous acetylcysteine may need to be extended in duration until the serum aminotransferase levels are declining and serum acetaminophen levels are undetectable. Treatment with acetylcysteine improves cerebral blood flow and oxygenation as well as transplant-free survival in patients with stage 1 or 2 encephalopathy due to fulminant hepatic failure of any cause. (Acetylcysteine treatment can prolong the prothrombin time, leading to the erroneous assumption that liver failure is worsening; it can also cause nausea, vomiting, and an anaphylactoid reaction [especially in persons with a history of asthma].)
Penicillin G (300,000 to 1 million units/kg/ day) or silibinin (silymarin or milk thistle), which is not licensed in the United States, is administered to patients with mushroom poisoning.
Nucleoside analogs are recommended for patients with fulminant hepatitis B, and intravenous acyclovir has shown benefit in those with herpes simplex virus hepatitis.
Plasmapheresis combined with D-penicillamine has been used in fulminant Wilson disease.
Subclinical seizure activity is common in patients with acute liver failure, but the value of prophylactic phenytoin is uncertain.
Early transfer to a liver transplantation center is essential.