Acute Liver Failure

Overall, the most common causes of acute liver failure are:

• Viruses, primarily hepatitis B

• Medications (most commonly acetaminophen), other substances, and toxinsMedications (most commonly acetaminophen), other substances, and toxins

In countries with poor sanitation, viral hepatitis is usually considered the most common cause; in countries where there is effective sanitation, toxins are usually considered the most common cause (1).

Overall, the most common viral cause is hepatitis B, often with hepatitis D coinfection; hepatitis C is not a common cause. Other possible viral causes of acute liver failure include:

• Cytomegalovirus

• Epstein-Barr virus

• Herpes simplex virus

• Human herpesvirus 6

• Parvovirus B19

• Varicella-zoster virus

• Hepatitis A virus

• Hepatitis E virus (especially if contracted during pregnancy)

• Viruses that cause hemorrhagic fever (eg, Ebola, Marburg, and other viruses)

The most common toxin is acetaminophen; toxicity is dose-related. Predisposing factors for acetaminophen-induced liver failure include: ; toxicity is dose-related. Predisposing factors for acetaminophen-induced liver failure include:

• Preexisting liver disease

• Chronic alcohol use

• Medications that induce the cytochrome P-450 enzyme system (eg, anticonvulsants)

Other toxins include:

• Antibiotics (notably amoxicillin/clavulanate)

• Halothane

• Iron compounds

• IsoniazidIsoniazid

• Nonsteroidal anti-inflammatory drugs (NSAIDs)

• Some compounds in herbal products

• Amanita phalloides mushrooms

(See Liver Injury Caused by Drugs).

Less common causes include:

• Vascular disorders

• Metabolic disorders

• Autoimmune hepatitis

Vascular causes include:

• Hepatic vein thrombosis (Budd-Chiari syndrome)

• Ischemic hepatitis

• Portal vein thrombosis

• Hepatic sinusoidal obstruction syndrome (also called hepatic veno-occlusive disease), which is sometimes medication- or toxin-induced

Metabolic causes include:

• Acute fatty liver of pregnancy

• HELLP syndrome (Hemolysis, Elevated values on Liver tests, and Low Platelets)

• Reye syndrome

• Wilson disease

Other causes include autoimmune hepatitis, metastatic liver infiltration, heatstroke, and sepsis. The cause is not determined in 5 to 70% of cases, varying by geographic region (1).

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: Systemic vascular resistance and blood pressure decrease, causing hyperdynamic circulation with increased heart rate and cardiac output. The hemodynamic profile is similar to "warm" septic shock.

• 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:Acute kidney injury occurs in up to 70% of patients, and up to 30% require renal replacement therapy (1). 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)., 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.

Characteristic manifestations are altered mental status (usually part of portosystemic encephalopathy), coagulopathy, and jaundice. Manifestations of chronic liver disease such as ascites 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), but these symptoms may be absent.

Despite coagulopathy due to hepatic synthetic dysfunction (with prolonged international normalized ratio [INR]), bleeding is rare unless patients are in disseminated intravascular coagulation (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).

• Prolongation of international normalized ratio (INR) to ≥ 1.5 and clinical manifestations of encephalopathy in patients without a prior history of chronic liver disease

• To determine the cause: History of illicit drug use, misuse of prescription medications, or exposure to toxins, hepatitis virus serologic tests, autoimmune markers, and other tests based on clinical suspicion

Acute liver failure 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 (1).

Tests usually performed during the initial evaluation of acute liver failure include:

• Complete blood count (CBC)

• INR

• Serum electrolytes (including calcium, phosphate, and magnesium)

• Renal function tests

• Urinalysis

Liver enzyme, bilirubin levels, and INR confirm the presence and severity of liver failure. Acute liver failure is usually considered confirmed if sensorium is altered and INR is > 1.5 in patients who have clinical and/or laboratory evidence of acute liver injury. INR is used as an index of severity of acute liver failure and sometimes as a criterion for transplantation. Evidence of cirrhosis suggests that liver failure is chronic.

Patients with acute liver failure should then be tested for complications. If acute liver failure is confirmed, arterial blood gases (ABGs) should be performed to evaluate acid-base status, and blood type and screen should also be performed in case blood products are necessary. If patients have hyperdynamic circulation and tachypnea, cultures (blood, urine, ascitic fluid) and chest radiograph should be performed to exclude infection. Plasma ammonia is recommended to help predict prognosis because higher ammonia levels (> 150 to 200 μg/dL [> 107-143 μmol/L] ) predict increased risk of cerebral edema (2). If patients have impaired or worsening mental status, particularly those with coagulopathy, head CT should be performed to exclude 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 medications, herbal products, and dietary supplements. Tests performed routinely to determine the cause include:

• Viral hepatitis serologic tests (eg, IgM antibody to hepatitis A virus [IgM anti-HAV], hepatitis B surface antigen [HBsAg], IgM antibody to hepatitis B core antigen [IgM anti-HBcAg], antibody to hepatitis C virus [anti-HCV])

• Autoimmune markers (eg, antinuclear antibodies, anti–smooth muscle antibodies, immunoglobulin levels)

• Possible additional viral testing, for herpes simplex virus (nucleic acid amplification testing), cytomegalovirus (antibody testing), or Ebstein-Barr virus (antibody testing).

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

• Recent travel to countries where sanitation is poor: Expanded testing for viral hepatitis D and E

• Females of child-bearing age: Pregnancy testing

• Age < 40 years, hemolytic anemia, and a pattern showing a low alkaline phosphatase level with alkaline phosphatase/total bilirubin ratio < 4 and the aspartate aminotransferase (AST) level greater than the alanine aminotransferase (ALT) level, with elevations in ALT and AST (although usually < 2000): check ceruloplasmin level for Wilson disease

• Suspicion of a disorder with structural abnormalities (eg, Budd-Chiari syndrome, portal vein thrombosis, liver metastases): Ultrasound and sometimes other imaging

Over time, patients should be monitored closely for complications such as cerebral edema and infection (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 to evaluate for cerebral edema and often bedside glucose testing should be performed. Infection should also be considered in patients with acute liver failure as infections are more common and associated with higher mortality in this population (3, 4). Further, it can be more challenging to diagnosis infection in the acute liver failure population as up to 30% of patients lack the usual signs (4). Conversely, many patients meet systemic inflammatory response system (SIRS) criteria in the absence of infection related to the hyperinflammatory cytokine state of acute liver failure. Thus blood cultures and/or studies for infectious sources should be obtained at admission and frequently thereafter (1, 5). Routine laboratory testing (eg, INR, CBC, CMP, blood glucose, and ABGs) should be repeated frequently in most cases every 4 to 6 hours.

• Supportive measures

• N-Acetylcysteine for -Acetylcysteine foracetaminophen toxicity

• Sometimes liver transplantation

Whenever possible, patients should be treated in an intensive care unit at a center capable of liver transplantation. 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. Medications 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 volume challenge, clinicians should consider noninvasive or, if needed, invasive measures of volume status to guide fluid therapy. If hypotension persists despite adequate filling pressures, norepinephrine is recommended as the first-line vasopressor with vasopressin as the second agent (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 volume challenge, clinicians should consider noninvasive or, if needed, invasive measures of volume status to guide fluid therapy. If hypotension persists despite adequate filling pressures, norepinephrine is recommended as the first-line vasopressor with vasopressin as the second agent (1).

For encephalopathy, the head of the bed is elevated 30° to reduce risk of aspiration; intubation should be considered early. When selecting medications and medication doses, clinicians should aim to minimize sedation so that they can monitor the severity of encephalopathy. Propofol is the usual induction medication for intubation because it protects against intracranial hypertension and has a brief duration of action, allowing rapid recovery from sedation. the head of the bed is elevated 30° to reduce risk of aspiration; intubation should be considered early. When selecting medications and medication doses, clinicians should aim to minimize sedation so that they can monitor the severity of encephalopathy. Propofol is the usual induction medication 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 There is no evidence that treatments such as lactulose or rifaximin help alleviate encephalopathy in acute liver failure, although they are useful inportosystemic encephalopathy (1). Also, lactulose can cause ). Also, lactulose can causeileus and produce gas that distends the intestines, which can be problematic if laparotomy is needed (eg, for liver transplantation) (2).

Measures are taken to avoid increasing intracranial pressure (ICP) and avoid decreasing cerebral perfusion pressure:

• To reduce cerebral edema: Renal replacement therapy helps clear ammonia and reduces mortality if initiated early. Guidelines recommend renal replacement therapy in patients with liver failure and markedly elevated ammonia or progressive encephalopathy, even if there are no other indications for renal replacement therapy (1, 2).

• 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 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, 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 (3). 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.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 medications; treatment is started as soon as patients show any sign of infection (eg, fever; localizing signs; deterioration of hemodynamics, systemic inflammatory response system [SIRS] criteria, refractory hypotension mental status, or renal function). Empiric antimicrobial therapy is not routinely recommended (1) given limited data on efficacy which suggests that prophylaxis decreases infection rates but does not impact mortality (4). However, given the challenges of diagnosing infection in the acute liver failure population and risk that infection could jeopardize a patients ability to receive a liver transplant, some societies including EASL recommend prophylaxis in a subset of patients with acute liver failure. This pertains specifically to patients who are listed urgently for liver transplantation with SIRS criteria, refractory hypotension, or unexplained progression to stage 3 or 4 encephalopathy (2).

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.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 or if an invasive procedure is planned. Fresh frozen plasma for correction of coagulopathy is otherwise avoided because it may result in volume overload and worsening of cerebral edema (1). Also, when fresh frozen plasma is used, clinicians cannot follow changes in INR, which are important because INR 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. 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 is treated with N-acetylcysteine. -acetylcysteine.

Administration of N-acetylcysteine is also recommended by professional societies for -acetylcysteine is also recommended by professional societies forother causes of acute liver failure, although the supporting evidence is less definitive than for its use in acetaminophen toxicity (of acute liver failure, although the supporting evidence is less definitive than for its use in acetaminophen toxicity (1, 2). Antiviral therapy is recommended for patients with liver failure due to reactivation of hepatitis B, and IV silibinin or penicillin may be considered for liver failure due to mushroom poisoning (1).

Liver transplantation for acute liver failure results in average 1-year survival rates of approximately 84 to 90% and 5 year survival of 80% (1,5). Transplantation is thus recommended for patients with acute liver failure who score poorly on prognostic risk scores like the King's College criteria and continue to show signs of clinical evolution of acute liver failure (2).

Prediction of prognosis can be difficult. Important predictive variables include:

• Degree of encephalopathy: Worse when encephalopathy is severe

• Patient age: Worse when age is < 10 years or > 40 years

• Prothrombin time: Worse when INR is prolonged

• Cause of acute liver failure: Better with acetaminophen toxicity, hepatitis A, or hepatitis B than with idiosyncratic drug reactions or Wilson disease (1, 2, 3)

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.