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Acute Liver Failure

(Fulminant Liver Failure)

By

Danielle Tholey

, MD, Sidney Kimmel Medical College at Thomas Jefferson University

Last full review/revision Jan 2021| Content last modified Jan 2021
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Topic Resources

Acute liver failure is caused most often by drugs and hepatitis viruses. Cardinal manifestations are jaundice, coagulopathy, and encephalopathy. Diagnosis is clinical. Treatment is mainly supportive, sometimes with liver transplantation and/or specific therapies (eg, N-acetylcysteine for acetaminophen toxicity).

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Etiology of Acute Liver Failure

Overall, the most common causes of acute liver failure are

  • Viruses, primarily hepatitis B

  • Drugs and toxins, most commonly acetaminophen

In developing countries, viral hepatitis is usually considered the most common cause; in developed countries, toxins are usually considered the most common cause.

Overall, the most common viral cause is hepatitis B Hepatitis B, Acute Hepatitis B is caused by a DNA virus that is often parenterally transmitted. It causes typical symptoms of viral hepatitis, including anorexia, malaise, and jaundice. Fulminant hepatitis and... read more , often with hepatitis D Hepatitis D Hepatitis D is caused by a defective RNA virus (delta agent) that can replicate only in the presence of hepatitis B virus. It occurs uncommonly as a coinfection with acute hepatitis B or as... read more coinfection; hepatitis C is not a common cause. Other possible viral causes include cytomegalovirus Cytomegalovirus (CMV) Infection Cytomegalovirus (CMV, human herpesvirus type 5) can cause infections that have a wide range of severity. A syndrome of infectious mononucleosis that lacks severe pharyngitis is common. Severe... read more , Epstein-Barr virus Infectious Mononucleosis Infectious mononucleosis is caused by Epstein-Barr virus (EBV, human herpesvirus type 4) and is characterized by fatigue, fever, pharyngitis, and lymphadenopathy. Fatigue may persist weeks or... read more Infectious Mononucleosis , herpes simplex virus Herpes Simplex Virus (HSV) Infections Herpes simplex viruses (human herpesviruses types 1 and 2) commonly cause recurrent infection affecting the skin, mouth, lips, eyes, and genitals. Common severe infections include encephalitis... read more Herpes Simplex Virus (HSV) Infections , human herpesvirus 6, parvovirus B19 Erythema Infectiosum Erythema infectiosum, acute infection with parvovirus B19, causes mild constitutional symptoms and a blotchy or maculopapular rash beginning on the cheeks and spreading primarily to exposed... read more Erythema Infectiosum , varicella-zoster virus Chickenpox Chickenpox is an acute, systemic, usually childhood infection caused by the varicella-zoster virus (human herpesvirus type 3). It usually begins with mild constitutional symptoms that are followed... read more Chickenpox , hepatitis A virus (rarely), hepatitis E virus (especially if contracted during pregnancy), and viruses that cause hemorrhagic fever (see Most viruses associated with... Arbovirus (arthropod-borne virus) applies to any virus that is transmitted to humans and/or other vertebrates by certain species of blood-feeding arthropods, chiefly insects (flies and mosquitoes)... read more ).

The most common toxin is acetaminophen Acetaminophen Poisoning Acetaminophen poisoning can cause gastroenteritis within hours and hepatotoxicity 1 to 3 days after ingestion. Severity of hepatotoxicity after a single acute overdose is predicted by serum... read more ; toxicity is dose-related. Predisposing factors for acetaminophen-induced liver failure include preexisting liver disease, chronic alcohol use, and use of drugs that induce the cytochrome P-450 enzyme system (eg, anticonvulsants). Other toxins include amoxicillin/clavulanate, halothane, iron compounds, isoniazid, nonsteroidal anti-inflammatory drugs (NSAIDs), some compounds in herbal products, and Amanita phalloides mushrooms (see Liver Injury Caused by Drugs Liver Injury Caused by Drugs Many drugs (eg, statins) commonly cause asymptomatic elevation of hepatic enzymes (alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase). However, clinically... read more ). Some drug reactions are idiosyncratic.

Less common causes include

  • Vascular disorders

  • Metabolic disorders

  • Autoimmune hepatitis

Vascular causes include hepatic vein thrombosis (Budd-Chiari syndrome Budd-Chiari Syndrome Budd-Chiari syndrome is obstruction of hepatic venous outflow that originates anywhere from the small hepatic veins inside the liver to the inferior vena cava and right atrium. Manifestations... read more ), ischemic hepatitis Ischemic Hepatitis Ischemic hepatitis is diffuse liver damage due to an inadequate blood or oxygen supply. (See also Overview of Vascular Disorders of the Liver.) Causes are most often systemic: Impaired hepatic... read more , portal vein thrombosis Portal Vein Thrombosis Portal vein thrombosis causes portal hypertension and consequent gastrointestinal bleeding from varices, usually in the lower esophagus or stomach. Diagnosis is based on ultrasonography. Treatment... read more , and hepatic sinusoidal obstruction syndrome (also called hepatic veno-occlusive disease Sinusoidal Obstruction Syndrome Hepatic sinusoidal obstruction syndrome is caused by endothelial injury, leading to nonthrombotic occlusion of the terminal hepatic venules and hepatic sinusoids, rather than of the hepatic... read more ), which is sometimes drug- or toxin-induced. Metabolic causes include acute fatty liver of pregnancy Fatty liver of pregnancy Hepatic disorders in pregnancy may be Unique to pregnancy Preexisting Coincident with pregnancy and possibly exacerbated by pregnancy Jaundice may result from nonobstetric or obstetric conditions. read more , HELLP syndrome (hemolysis, elevated values on liver tests, and low platelets), Reye syndrome Reye Syndrome Reye syndrome is a rare form of acute encephalopathy and fatty infiltration of the liver that tends to occur after some acute viral infections, particularly when salicylates are used. Diagnosis... read more , and Wilson disease Wilson Disease Wilson disease results in accumulation of copper in the liver and other organs. Hepatic or neurologic symptoms develop. Diagnosis is based on a low serum ceruloplasmin level, high urinary excretion... read more Wilson Disease . Other causes include autoimmune hepatitis Overview of Chronic Hepatitis Chronic hepatitis is hepatitis that lasts > 6 months. Common causes include hepatitis B and C viruses, nonalcoholic steatohepatitis (NASH), alcohol-related liver disease, and autoimmune liver... read more , metastatic liver infiltration, heatstroke, and sepsis. The cause cannot be determined in up to 20% of cases.

Pathophysiology of Acute Liver Failure

In acute liver failure, multiple organ systems malfunction, often for unknown reasons and by unknown mechanisms. Affected systems include

Symptoms and Signs of Acute Liver Failure

Characteristic manifestations are altered mental status (usually part of portosystemic encephalopathy Portosystemic Encephalopathy Portosystemic encephalopathy is a neuropsychiatric syndrome that can develop in patients with liver disease. It most often results from high gut protein or acute metabolic stress (eg, gastrointestinal... read more ) and jaundice Jaundice Jaundice is a yellowish discoloration of the skin and mucous membranes caused by hyperbilirubinemia. Jaundice becomes visible when the bilirubin level is about 2 to 3 mg/dL (34 to 51 micromol/L)... read more Jaundice . Manifestations of chronic liver disease such as ascites Ascites Ascites is free fluid in the peritoneal cavity. The most common cause is portal hypertension. Symptoms usually result from abdominal distention. Diagnosis is based on physical examination and... read more argue against the acuity of the condition but can be present in subacute liver failure. Other symptoms may be nonspecific (eg, malaise, anorexia) or result from the causative disorder. Fetor hepaticus (a musty or sweet breath odor) and motor dysfunction are common. Tachycardia, tachypnea, and hypotension may occur with or without sepsis. Signs of cerebral edema can include obtundation, coma, bradycardia, and hypertension. Patients with infection sometimes have localizing symptoms (eg, cough, dysuria Dysuria Dysuria is painful or uncomfortable urination, typically a sharp, burning sensation. Some disorders cause a painful ache over the bladder or perineum. Dysuria is an extremely common symptom... read more ), but these symptoms may be absent. Despite prolonged international normalized ratio (INR) , bleeding is rare unless patients are in disseminated intravascular coagulation Disseminated Intravascular Coagulation (DIC) Disseminated intravascular coagulation (DIC) involves abnormal, excessive generation of thrombin and fibrin in the circulating blood. During the process, increased platelet aggregation and coagulation... read more (DIC). This is because patients with acute liver failure have a re-balanced distribution of pro- and anticoagulant factors and, if anything, these patients are more frequently hypercoagulable (1, 2 Symptoms and signs references Acute liver failure is caused most often by drugs and hepatitis viruses. Cardinal manifestations are jaundice, coagulopathy, and encephalopathy. Diagnosis is clinical. Treatment is mainly supportive... read more ).

Symptoms and signs references

  • 1. Hugenholtz GC, Adelmeijer J, Meijers JC, et al: An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: Implications for hemostasis and clinical outcome. Hepatology 2013;58:752–761.

  • 2. Lisman T, Bakhtiari K, Adelmeijer J, et al: Intact thrombin generation and decreased fibrinolytic capacity in patients with acute liver injury or acute liver failure. J Thromb Haemost10(7):1312–1319, 2012. doi: 10.1111/j.1538-7836.2012.04770.x.

Diagnosis of Acute Liver Failure

Acute liver failure Acute Liver Failure Acute liver failure is caused most often by drugs and hepatitis viruses. Cardinal manifestations are jaundice, coagulopathy, and encephalopathy. Diagnosis is clinical. Treatment is mainly supportive... read more should be suspected if patients without underlying chronic liver disease or cirrhosis have acute onset of jaundice and/or elevated transaminases that is accompanied by coagulopathy and mental status changes. Patients with known liver disease who acutely decompensate are not considered to have acute liver failure but rather acute-on-chronic liver failure, which has different pathophysiology from that of acute liver failure.

Laboratory tests to confirm the presence and severity of liver failure include liver enzyme and bilirubin levels and PT. Acute liver failure is usually considered confirmed if sensorium is altered or PT is prolonged by > 4 seconds or if INR is > 1.5 in patients who have clinical and/or laboratory evidence of acute liver injury. Evidence of cirrhosis suggests that liver failure is chronic.

Patients with acute liver failure should be tested for complications. Tests usually done during the initial evaluation include complete blood count (CBC), serum electrolytes (including calcium, phosphate, and magnesium), renal function tests, and urinalysis. If acute liver failure is confirmed, arterial blood gases (ABGs), amylase and lipase, and blood type and screen should also be done. Plasma ammonia is sometimes recommended for diagnosing encephalopathy or monitoring its severity. If patients have hyperdynamic circulation and tachypnea, cultures (blood, urine, ascitic fluid) and chest x-ray should be done to rule out infection. If patients have impaired or worsening mental status, particularly those with coagulopathy, head CT should be done to rule out cerebral edema or less likely intracranial bleeding.

To determine the cause of acute liver failure, clinicians should take a complete history of toxins ingested, including prescription and over-the-counter drugs, herbal products, and dietary supplements. Tests done routinely to determine the cause include

Other testing is done based on findings and clinical suspicion, as for the following:

Patients should be monitored closely for complications (eg, subtle changes in vital signs compatible with infection), and the threshold for testing should be low. For example, clinicians should not assume worsening mental status is due to encephalopathy; in such cases, head CT and often bedside glucose testing should be done. Because of the high risk of infection, the American Association for the Study of Liver Diseases (AASLD) suggests considering surveillance blood cultures every 48 hours. Routine laboratory testing (eg, daily PT, serum electrolytes, renal function tests, blood glucose, and ABGs) should be repeated frequently in most cases. However, testing may need to be more frequent (eg, blood glucose every 2 hours in patients with severe encephalopathy).

Prognosis for Acute Liver Failure

Prediction of prognosis can be difficult. Important predictive variables include

Various scores (for example, King's College criteria or Acute Physiologic Assessment and Chronic Health Evaluation II [APACHE II] score) can predict prognosis in populations of patients but are not highly accurate for individual patients.

Treatment of Acute Liver Failure

(See also the American Association for the Study of Liver Diseases [AASLD] practice guideline Management of Acute Liver Failure: Update 2011 and the European Association for the Study of the Liver Practical Guidelines on the Management of Acute [Fulminant] Liver Failure.)

Whenever possible, patients should be treated in an intensive care unit at a center capable of liver transplantation Liver Transplantation Liver transplantation is the 2nd most common type of solid organ transplantation. (See also Overview of Transplantation.) Indications for liver transplantation include Cirrhosis (70% of transplantations... read more . Patients should be transported as soon as possible because deterioration can be rapid and complications (eg, bleeding, aspiration, worsening shock) become more likely as liver failure progresses.

Intensive supportive therapy is the mainstay of treatment. Drugs that could worsen manifestations of acute liver failure (eg, hypotension, sedation) should be avoided or used in the lowest possible doses.

For hypotension and acute kidney injury, the goal of treatment is maximizing tissue perfusion. Treatment includes IV fluids and usually, until sepsis is excluded, empiric antibiotics. If hypotension is refractory to about 20 mL/kg of crystalloid solution, clinicians should consider measuring pulmonary capillary wedge pressure to guide fluid therapy. If hypotension persists despite adequate filling pressures, clinicians should consider using pressors (eg, dopamine, epinephrine, norepinephrine).

For encephalopathy, the head of the bed is elevated 30° to reduce risk of aspiration; intubation should be considered early. When selecting drugs and drug doses, clinicians should aim to minimize sedation so that they can monitor the severity of encephalopathy. Propofol is the usual induction drug for intubation because it protects against intracranial hypertension and has a brief duration of action, allowing rapid recovery from sedation. There is no evidence that treatments such as lactulose or rifaximin help alleviate encephalopathy in acute liver failure, although they are useful in portosystemic encephalopathy Portosystemic Encephalopathy Portosystemic encephalopathy is a neuropsychiatric syndrome that can develop in patients with liver disease. It most often results from high gut protein or acute metabolic stress (eg, gastrointestinal... read more . Also, lactulose can cause ileus Ileus Ileus is a temporary arrest of intestinal peristalsis. It occurs most commonly after abdominal surgery, particularly when the intestines have been manipulated. Symptoms are nausea, vomiting... read more and produce gas that distends the intestines, which can be problematic if laparotomy is needed (eg, for liver transplantation) (1 Treatment references Acute liver failure is caused most often by drugs and hepatitis viruses. Cardinal manifestations are jaundice, coagulopathy, and encephalopathy. Diagnosis is clinical. Treatment is mainly supportive... read more ). Measures are taken to avoid increasing intracranial pressure (ICP) and avoid decreasing cerebral perfusion pressure:

  • To avoid sudden increases in ICP: Stimuli that could trigger a Valsalva maneuver are avoided (eg, lidocaine is given before endotracheal suctioning to prevent the gag reflex).

  • To temporarily decrease cerebral blood flow: Mannitol (0.5 to 1 g/kg, repeated once or twice as needed) can be given to induce osmotic diuresis, and possibly brief hyperventilation can be used, particularly when herniation is suspected. (However, mannitol is contraindicated with acute kidney injury and serum osmolality must be checked before giving a second dose.)

  • To monitor ICP: It is not clear whether or when the risks of ICP monitoring (eg, infection, bleeding) outweigh the benefits of being able to detect cerebral edema early and being able to use ICP to guide fluid and pressor therapy; some experts recommend such monitoring if encephalopathy is severe. However, no data indicate that ICP monitoring impacts mortality (2 Treatment references Acute liver failure is caused most often by drugs and hepatitis viruses. Cardinal manifestations are jaundice, coagulopathy, and encephalopathy. Diagnosis is clinical. Treatment is mainly supportive... read more ). Goals of treatment are an ICP of < 20 mm Hg and a cerebral perfusion pressure of > 50 mm Hg.

Seizures are treated with phenytoin; benzodiazepines are avoided or used only in low doses because they cause sedation.

Infection is treated with antibacterial and/or antifungal drugs; treatment is started as soon as patients show any sign of infection (eg, fever; localizing signs; deterioration of hemodynamics, mental status, or renal function). Because signs of infection overlap with those of acute liver failure, infection is likely to be overtreated pending culture results.

Electrolyte deficiencies may require supplementation with sodium, potassium, phosphate, or magnesium.

Hypoglycemia is treated with continuous glucose infusion (eg, 10% dextrose), and blood glucose should be monitored frequently because encephalopathy can mask the symptoms of hypoglycemia.

Coagulopathy is treated with fresh frozen plasma if bleeding occurs, if an invasive procedure is planned, or possibly if coagulopathy is severe (eg, international normalized ratio [INR] > 7). Fresh frozen plasma is otherwise avoided because it may result in volume overload and worsening of cerebral edema. Also, when fresh frozen plasma is used, clinicians cannot follow changes in PT, which are important because PT is an index of severity of acute liver failure and is thus sometimes a criterion for transplantation. Recombinant factor VII is sometimes used instead of or with fresh frozen plasma in patients with volume overload. Its role is evolving. H2 blockers may help prevent gastrointestinal bleeding.

Nutritional support may be necessary if patients cannot eat. Severe protein restriction is unnecessary; 60 g/day is recommended.

Acute acetaminophen toxicity Treatment Acetaminophen poisoning can cause gastroenteritis within hours and hepatotoxicity 1 to 3 days after ingestion. Severity of hepatotoxicity after a single acute overdose is predicted by serum... read more is treated with N-acetylcysteine. Because chronic acetaminophen toxicity can be difficult to diagnose, use of N-acetylcysteine should be considered if no cause for acute liver failure is evident. Whether N-acetylcysteine has a slight beneficial effect on patients with acute liver failure due to other conditions is under study.

Liver transplantation Liver Transplantation Liver transplantation is the 2nd most common type of solid organ transplantation. (See also Overview of Transplantation.) Indications for liver transplantation include Cirrhosis (70% of transplantations... read more results in average 1-year survival rates of about 80%. Transplantation is thus recommended if prognosis without transplantation is worse. However, prediction is difficult and scores, such as King's College criteria and the APACHE II (Acute Physiologic Assessment and Chronic Health Evaluation II) score, are not sufficiently sensitive and specific to be used as the only criteria for transplantation; thus, they are used as adjuncts to clinical judgment (eg, based on risk factors).

Further information regarding acute liver failure can be found in the European Association for the Study of the Liver (EASL) guidelines.

Treatment references

Key Points

  • The most common causes of acute liver failure are viral hepatitis (in developing countries) and drugs and toxins (in developed countries).

  • Acute liver failure is characterized by jaundice, coagulopathy, and encephalopathy.

  • Confirm the diagnosis by finding prolongation of PT or clinical manifestations of encephalopathy in patients with hyperbilirubinemia and elevated aminotransferase levels.

  • Determine the cause by assessing history of drug use and exposure to toxins and doing hepatitis virus serologic tests, autoimmune markers, and other tests based on clinical suspicion.

  • Acute liver failure should be managed in the intensive-care setting and referral to a transplant center should be promptly initiated.

  • Consider N-acetylcysteine for acetaminophen-induced liver failure and liver transplantation for patients with poor prognostic factors (eg, age < 10 or > 40, severe encephalopathy, severe prolongation of PT, idiosyncratic drug reaction, Wilson disease).

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