Acute Liver Failure and Hepatitis

Acute liver failure (ALF) is a life-threatening critical illness that occurs in patients without preexisting liver dysfunction. Hepatitis or inflammation of the liver can develop from a wide range of underlying causes, including alcohol-associated hepatitis and viral hepatitis, and some causes of hepatitis may cause ALF. Worldwide, the most common cause of ALF is viral hepatitis (hepatitis A, B, and E) and in the United States, acetaminophen toxicity causes up to 50% of ALF cases. In this section, we focus on the presentation and management of acute liver failure, alcohol-associated hepatitis, and viral hepatitis B and C, acknowledging that this is by no means a comprehensive review of all causes of liver disease.

• Acute Liver Failure

• Alcohol-Associated Hepatitis

• Hepatitis B Virus (HBV)

• Hepatitis C Virus (HCV)

Acute Liver Failure

Acute liver failure (ALF) is a rare, life-threatening condition that can rapidly develop in patients without preexisting cirrhosis or chronic liver disease.

ALF is characterized by:

• illness duration <26 weeks

• impaired hepatic synthetic function as demonstrated by coagulopathy (international normalized ratio [INR] ≥1.5) and encephalopathy

Clinical features: ALF is also associated with a range of clinical features that affect all organ systems, as detailed in the following diagram:

(Source: Acute Liver Failure. N Engl J Med 2013.)

Etiology: Causes of ALF include:

• viral hepatitis (A, B, and E): the most common cause worldwide

• drug- and toxin-induced

  • Acetaminophen toxicity is the leading cause of drug-induced ALF, accounting for as much as half of ALF cases in the United States.

  • Other drug-related causes include antituberculosis drugs (isoniazid and rifampicin), nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics (amoxicillin-clavulanate and ciprofloxacin, among others), and antiepileptic medications (sodium valproate, carbamazepine, and phenytoin). LiverTox is a useful resource to identify medications that cause drug-induced liver injury.

  • acute mushroom poisoning (Amanita phalloides)

• acute ischemic hepatocellular injury from systemic hypotension

  • can be secondary to sepsis or cardiac dysfunction

  • recreational drugs (e.g., cocaine and 3, 4-methylenedioxymethylamphetamine/ecstasy [MDMA]) can cause a similar pattern of liver injury

• pregnancy (acute fatty liver of pregnancy or HELLP [hemolysis, elevated liver enzymes, and low platelet count] is ALF specific to pregnancy)

• autoimmune hepatitis

• Wilson disease (aspartate-aminotransferase [AST]-to-alanine-aminotransferase [ALT] ratio >2.0 and alkaline-phosphatase-to-total-bilirubin ratio <4.0)

• acute Budd-Chiari syndrome (hepatic vein thrombosis)

• heatstroke

• neoplastic infiltration

General management: Patients with ALF are often admitted to the intensive care unit (ICU) at a center with an active liver-transplantation program. Complications and general management considerations for all patients with ALF include the following:

• Cardiorespiratory dysfunction:

  • Intravascular volume depletion, hypotension, and circulatory dysfunction are common and usually multifactorial. Management is focused on correction of volume depletion, administration of vasopressors, and inotropic support as needed.

  • Respiratory dysfunction is more common in the later stages of ALF and may require intubation and ventilation. Patients may also require intubation due to changes in mental status.

  • Systemic vasodilation due to sepsis can exacerbate underlying low systemic vascular resistance in the setting of liver failure and warrants a high level of suspicion and consideration of broad-spectrum antibiotic administration.

• Encephalopathy:

  • Encephalopathy can progress rapidly and lead to cerebral edema and seizures.

  • Early intubation and sedation for airway control and to control oxygen and carbon dioxide levels are recommended if a patient becomes agitated or is in a coma.

  • Lactulose is not routinely used and is controversial for management of ALF as it can increase bowel distention and worsen outcomes.

  • Rifaximin and neomycin may be of limited use in encephalopathy of ALF.

• Cerebral edema and intracranial hypertension:

  • Preventing the progression of encephalopathy and reducing the risk of cerebral edema are the goals of clinical therapy in patients with ALF.

  • Cerebral edema is the main cause of death in patients with ALF.

    • Osmotic agents (e.g., mannitol) are first-line therapy for reducing cerebral edema.

    • Hypertonic saline can also be used to induce hypernatremia in patients with ALF and high-grade encephalopathy to delay the development of intracerebral hemorrhage.

    • Hyperventilation to induce hypocapnia may be used for emergent control of intracranial hypertension.

    • Hypothermia may be used in cases of resistant intracranial hypertension.

    • Use of an intracranial pressure (ICP) monitor may be useful in stages 3-4 hepatic coma but is associated with a higher risk of intracranial hemorrhage.

• Coagulopathy

  • Overt bleeding is uncommon in patients with ALF.

  • Serial evaluation of coagulation variables is important for prognosis, although not helpful in determining a patient’s bleeding risk.

  • Routine administration of fresh frozen plasma (FFP) or platelets is not recommended and is only considered on a case-by-case basis prior to invasive procedures or in case of hemorrhage.

• Renal dysfunction

  • More than 50% of patients with ALF experience substantial renal dysfunction. and renal-replacement therapy is required in some patients.

  • However, resolution of liver failure is generally associated with normalization of renal function to baseline levels.

• Nutritional support

  • Patients with ALF are at risk of hypoglycemia, for which glucose infusion can be administered with careful monitoring of sodium to avoid hyponatremia.

  • Because ALF is a catabolic state, enteral nutrition should be instituted as soon as possible, with careful monitoring of ammonia.

• Irreversible liver injury

  • Begin discussion with liver transplantation specialists regarding transfer to a liver transplantation center.

  • Orthotopic liver transplantation is the only cure for patients with irreversible liver injury. Utilize King’s College Criteria and UNOS Criteria to help determine if patients meet transplantation criteria.

Management of acetaminophen toxicity: Acetaminophen is the most common toxin associated with ALF in the United States. Typically, toxicity is thought to be dose-dependent and rarely occurs at therapeutic doses (defined as up to 4 g/day in a patient without preexisting liver disease). However, ALF can occur at therapeutic doses in patients with history of excess alcohol use, fasting, or underlying liver disease.

• N-acetylcysteine (NAC) is the antidote for acetaminophen toxicity and should be started as soon as possible following overdose. Treatment with NAC during the preclinical phase usually leads to full recovery.

• Patients who are not treated until hepatic injury has developed have variable prognosis.

• The Rumack-Matthew nomogram (see image below) was developed to estimate the likelihood of hepatic injury due to acetaminophen toxicity and to determine which patients are candidates for NAC.

  • Plot the patient’s plasma acetaminophen concentration and time interval since ingestion.

  • If the resulting point is above and to the right of the sloping line, hepatic injury is likely and NAC use is indicated.

  • If the resulting point is below and to the left of the line, hepatic injury is unlikely.

(Source: Acetylcysteine for Acetaminophen Poisoning. N Engl J Med 2008.)

Alcohol-Associated Hepatitis

Alcohol use disorder is a major cause of preventable liver disease worldwide. Alcohol-associated liver disease develops in approximately 35% of patients with alcohol use disorder. Alcohol-associated hepatitis is a specific entity that develops in patients with alcohol-associated liver disease and ongoing heavy alcohol use or binge drinking that is characterized by new onset of jaundice (<8 weeks), malaise, decompensated liver disease, and coagulopathy. This should be suspected in patients with ongoing consumption of more than three drinks (approximately 40 grams) per day for women and four drinks (approximately 50 to 60 grams) per day for men for 6 months or more. A standard serving in the United States (e.g., 12 ounces of beer, 5 ounces of wine, or 1.5 ounces of spirits [gin, vodka, or whiskey]) contains 14 grams of ethanol.

Signs and symptoms: The characteristic clinical features include jaundice, anorexia, muscle wasting, fever, and tender hepatomegaly. Patients can also present with ascites and hepatic encephalopathy, and they may have protein-calorie malnutrition.

Diagnosis: Diagnosis of alcohol-associated hepatitis is made on clinical grounds using clinical history, laboratory data, and in some cases liver biopsy. Other causes of jaundice should be ruled out using laboratory investigations (e.g., viral hepatitis) and imaging (e.g., biliary obstruction).

• Laboratory investigations:

  • serum bilirubin typically ≥3 mg/dL

  • moderately elevated AST and ALT levels, typically AST <400 U/liter

  • AST-to-ALT ratio >1.5

  • Albumin <3 mg/dL

  • gamma-glutamyl transferase (GGT) >100 U/liter

  • INR >1.5

  • platelet count <150,000/mm³

  • moderate leukocytosis

  • the Maddrey Discriminant Function and Model for End-Stage Liver Disease (MELD) scores can be used to assess severity of disease and for consideration for use of glucocorticoids

• Liver biopsy: Although rarely performed, liver biopsy may be required if the diagnosis is uncertain. A transjugular liver biopsy is the preferred route. Characteristic histologic findings include:

  • ballooning of hepatocytes

  • Mallory-Denk bodies

  • neutrophil infiltration

  • cholestasis

  • steatosis

  • fibrosis

Management:

• Immediate and lifetime abstinence from alcohol use is essential to prevent the progression of alcoholic hepatitis. Patient should be referred to addiction specialists where available, and behavioral and/or pharmacotherapy for alcohol use disorder should be considered.

• Glucocorticoids can be used in select populations (maximum benefit in patients with MELD scores of 25-39) after ruling out infections.

• Nutritional status should be assessed in all patients, particularly for adequate protein and caloric intake.

• Infections should be actively ruled out and treated.

• Use of other investigated medications is not recommended (e.g., pentoxifylline, tumor necrosis factor [TNF], alpha-ablating agents, vitamin E, and N-acetylcysteine).

• Early liver transplantation for severe alcoholic hepatitis is performed in selected centers. Transplant referral centers should be contacted to discuss potential referrals.

• Palliative care should be considered in patients who are not transplant candidates and are not responding to medical therapy.

Hepatitis B Virus (HBV)

Hepatitis B virus (HBV): Chronic HBV develops in up to 5% of people infected with HBV in adulthood, as compared with 90% of those infected during infancy and 50% of those who acquire the infection during early childhood. The consequence of greatest concern in chronic HBV infection is progression to liver cirrhosis and hepatocellular carcinoma. In endemic regions, HBV transmission is largely vertical from mother to neonate in the perinatal period. In areas where HBV is not endemic (e.g., the United States), common routes of transmission include percutaneous through intravenous drug use, tattoos, or piercings with contaminated equipment and horizontal via sexual contact with infected individuals.

Screening: Chronic HBV infection is usually asymptomatic.

• The Centers for Disease Control and Prevention (CDC) recommends that all adults should be screened for HBV at least once in their lifetime with a triple panel test consisting of hepatitis B surface antigen (HBsAg), antibody to hepatitis B surface antigen (anti-HBs), and total antibody to hepatitis B core antigen (anti-HBc).

• Serologic markers of HBV include:

  • HBsAg: detection defines infection, used as a screening test for HBV infection

  • anti-HBs: detection indicates immunity

  • HBV DNA

  • anti-HBc: detection indicates exposure to virus

  • hepatitis B e antigen (HBeAg): correlates with infectivity

(Source: New Approaches to Chronic Hepatitis B. N Engl J Med 2023.)

Treatment: Treatment of HBV depends on severity of liver disease and HBV DNA level. However, current guidance statements are nuanced and complex and may differ across regions. Moreover, the paradigms of who is eligible for HBV treatment are shifting.

• Several sources of evidence indicate that HBV DNA >2000 IU/mL is a strong predictor of cirrhosis and hepatocellular carcinoma. Treatment for such patients (regardless of phase) can reduce integration of HBV DNA with hepatocyte genome, decrease covalently closed circular DNA (cccDNA) pool, and prevent transition to active disease and potentially improve outcomes.

  • Nucleos(t)ide analogues are tolerated better than interferon.

  • Entecavir, tenofovir disoproxil, and tenofovir alafenamide are currently considered first-line therapy because they reduce HBV DNA concentration rapidly, have a high genetic barrier to resistance, and are safe.

  • Although interferon is associated with a higher rate of seroconversion and shorter treatment duration than entecavir or tenofovir, interferon is associated with significant adverse effects.

    HBV Management Options

    Medication	Dose Frequency	Notes
    Tenofovir (nucleotide analogue) Tenofovir disoproxil fumarate (TDF) Tenofovir alafenamide (TAF)	Daily oral pill	First-line therapy in treatment-naive patients as well as those who have been exposed to prior nucleos(t)ide therapy TAF associated with lower bone and renal toxicity than TDF TAF safe in pregnancy
    Entecavir (nucleoside analogue)	Daily oral pill	Potent antiviral activity and low rates of resistance in nucleos(t)ide-naive patients Avoid if patient is lamivudine resistant (up to 50% of lamivudine-refractory patients have been noted to develop resistance after 5 years of treatment) Reduce dose in chronic kidney disease Increase dose in those with decompensated liver disease
    Pegylated interferon alfa-2a	Weekly subcutaneous injection	Primarily for patients with well-compensated liver disease without portal hypertension who do not wish to be on long-term treatment Higher rates of HBeAg and HBsAg loss as compared to same duration of nucleos(t)ide analogue therapy Contraindicated in decompensated liver disease and in patients with history of severe psychiatric condition Adverse effects include thrombocytopenia, leukopenia, anemia, flulike symptoms, alopecia

  • Special treatment considerations:

    • Prevention of vertical transmission: When a mother is HbsAg positive, hepatitis B immune globulin is given to the infant at birth and hepatitis B vaccine is administered to the infant at birth and 1 and 6 months.

    • Hepatocellular carcinoma surveillance: Due to the risk of hepatocellular carcinoma, surveillance with 6-monthly liver ultrasound for suspicious features (including new lesions) and alpha-fetoprotein (AFP) screening is indicated in select patients (see the American Association for the Study of Liver Diseases [AASLD] guidelines for further information).

    • Patients on immunosuppressive drug therapy: Due to risk of reactivation of inactive HBV infection with immunosuppressive treatment (e.g., rituximab), patients must first be screened for HBV infection with full serology panel before starting immunosuppressive treatment. See the American Gastroenterological Association (AGA) guidelines for HBV prevention and treatment during immunosuppressive drug therapy.

Hepatitis C Virus (HCV)

Hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, cirrhosis, hepatocellular carcinoma, and liver transplantation worldwide. The United States Preventive Services Task Force (USPSTF) recommends screening for HCV infection in adults aged 18 to 79 years. Among the six main genotypes, genotype 1 accounts for the predominant number of cases in North America, South America, and Europe. After exposure to HCV, 55%-85% of patients develop chronic HCV infection. One-third of patients develop an acute illness with fatigue, arthralgia, and jaundice. In the last decade, effective therapies for HCV have transformed the landscape of cirrhosis and liver transplantation with declining HCV-related deaths and transplant listings.

• Chronic HCV infection is defined as persistence of HCV RNA in the blood for at least 6 months. Following exposure to the virus, it can take a few weeks to develop anti-HCV antibodies, and HCV antibody test will remain positive even if cleared or treated. Assessment of HCV genotype, HIV and hepatitis B status, assessment if the patient has cirrhosis, medication reconciliation, assessment of potential drug-drug interaction, and patient education should be performed before making decisions regarding HCV therapy. Prior to initiation of therapy, basic laboratory testing (including complete blood count, renal function, hepatic function) and serum pregnancy test should be checked.

• Cirrhosis: About 2%-20% of patients with chronic HCV infection develop cirrhosis, usually over a period of 20-25 years, with risk increasing with the duration of infection. Progression to cirrhosis is more rapid in patients with higher-than-moderate alcohol intake and with HIV coinfection.

Management: Direct-acting antivirals (DAAs) have revolutionized HCV treatment. Previously, the mainstay of therapy was interferon-based regimens that were only modestly effective and associated with significant adverse effects that limited tolerability and compliance. Now, short courses of well-tolerated therapy are associated with high cure rates (>95% in some patient populations). All patients with HCV infection should be considered for treatment, except if life expectancy is <12 months due to non-liver- or non-HCV-related comorbidities. Women of childbearing age should be advised to avoid pregnancy during and 4 weeks after DAA treatment.