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Gastroenterology - Acute Liver Failure and Hepatitis - Fast Facts | NEJM Resident 360

Acute liver failure (ALF) and hepatitis can develop from a wide range of underlying causes, including alcoholic hepatitis and viral hepatitis. Worldwide, the most common cause of ALF is viral hepatitis (hepatitis A, E, and B) and in the United States, up to 50% of ALF cases are due to acetaminophen toxicity. In this section, we focus on the presentation and management of acute liver failure, alcoholic 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

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:

Clinical Features of Acute Liver Failure

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

Etiology

Causes of ALF include:

• viral hepatitis: 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 U.S. 

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

  • Acute mushroom poisoning (Amanita phalloides)

• acute or chronic alcoholic hepatitis

• acute ischemic hepatocellular injury from systemic hypotension (can be secondary to sepsis or cardiac dysfunction)

• pregnancy-specific ALF: acute fatty liver of pregnancy or HELLP (hemolysis, elevated liver enzymes, and low platelets)

• 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)

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.

  • Focus of management is 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 for acute liver failure and is controversial as it can increase bowel distension and may worsen outcomes.

• Cerebral edema and intracranial hypertension

• • 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 is useful in stage 3–4 hepatic coma

• Coagulopathy

• • Overt bleeding may occur due to simultaneous loss of procoagulant factors and hepatically derived anticoagulants.

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

  • Clinically significant bleeding can be managed with clotting factor replacement and platelet transfusion if platelet count <50,000 cells/mm³. Routine administration of fresh frozen plasma (FFP) is not recommended and is only considered in cases of intracranial hemorrhage.

• Renal dysfunction

• • Substantial renal dysfunction occurs in more than 50% of patients.

  • Renal-replacement therapy is required in some patients. However, resolution of the liver failure is generally associated with normalization of renal function to baseline levels.

• Irreversible liver injury

• • Begin discussion with liver transplant specialists regarding transfer to a liver transplant 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.

Etiology-Specific Management

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 pre-existing liver disease). However, ALF can occur at therapeutic doses in patients with histories of alcohol abuse or underlying liver disease as well as in patients with histories of excess drinking or fasting.

• 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.

The Rumack–Matthew Nomogram

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

Alcoholic Hepatitis

Alcohol use is a major cause of preventable liver disease worldwide. Alcoholic hepatitis is the result of chronic alcohol use and should be suspected in patients with known alcoholic liver disease or longterm heavy alcohol use (>100 g/day for more than 6 months). Ongoing heavy alcohol intake or recent heavy binge drinking in addition to other features, such as new-onset jaundice (<8 weeks), should raise concern for alcoholic hepatitis. An average serving (e.g., 12 ounces of beer, 4–5 ounces of wine, or 1 ounce of spirits [gin, vodka, or whiskey]) contains 10 grams of ethanol.

• Signs and symptoms: The characteristic clinical features to be aware of include jaundice, anorexia, muscle wasting, fever and tender hepatomegaly. Patients can also present with ascites. 

• Laboratory investigations:

  • serum bilirubin typically ≥3 mg/dL

  • moderately elevated AST and ALT, typically <300 U/liter

  • AST-to-ALT ratio >1.5

  • moderate leukocytosis 

  • INR can be elevated in moderate-to-severe disease

  • the Maddrey Discriminant Function and MELD scores can be used to assess severity of disease

• Liver biopsy is rarely performed but may be required if the diagnosis is uncertain; history and laboratory results can often establish the diagnosis. Characteristic histological findings include ballooning of hepatocytes, neutrophil infiltration, cholestasis, and varying degree of steatosis and fibrosis.

• Management: Immediate and lifetime abstinence from alcohol use is essential to prevent the progression of alcoholic hepatitis. Corticosteroids can be used in select populations. However, other investigated medications such as pentoxifylline, tumor necrosis factor (TNF) alpha ablating agents, and vitamin E are not used clinically.

Hepatitis B virus (HBV)

Chronic HBV develops in up to 5% of people infected 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.

• Screening**:** Chronic HBV infection is usually asymptomatic. Therefore, screening should be considered in all patients in endemic regions where transmission largely occurs vertically from mother to neonate in the perinatal period. In areas where HBV is not endemic (e.g., the U.S.), common routes of transmission include percutaneous transmission through intravenous drug use or tattoos/piercings with contaminated equipment, or horizontal transmission via sexual contact with infected individuals.

• Diagnosis: Diagnosis of HBV is made using the following serologic markers:

  • hepatitis B surface antigen (HBsAg): detection defines infection, used as a screening test for HBV infection

  • hepatitis B surface antibody (anti-HBs): detection indicates immunity

  • HBV DNA

  • hepatitis B core antibody (anti-HBc): detection indicates exposure to virus

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

Expected Serology at Different Phases of HBV Infection and Immunity

Phase of HBV	HBsAg	Anti-HBs	Anti-HBc	HBV DNA	Comments
Acute infection	Positive	Negative	Positive
(IgM)	Detected
Chronic infection	Positive	Negative	Positive
(IgG)	Detected	Presence of HbsAg for >6
months defines chronic
infection
Resolved infection	Negative	Negative	Positive
(IgG)	Negative	Presence of anti-HBs
without HBsAg defines
resolution
Vaccinated	Negative	Positive	Negative	Negative
Isolated core	Negative	Negative	Positive
(IgG)	May be detected	Detection of HBV DNA
suggests possible acute
infection

• Chronic HBV infection consists of four phases:

  • Phase I: immune tolerance, without significant viral replication

  • Phase II: HBeAg-positive immunoactive disease, high viral replication

  • Phase III: HBeAg-negative inactive disease, without significant viral replication

  • Phase IV: immune escape

• Treatment: Patients in phase II or phase IV should be treated, because high viral replication is associated with hepatocyte damage. Nucleos(t)ide analogues are tolerated better than interferon. Entecavir or tenofovir disoproxil are currently considered first-line therapy because they reduce HBV DNA concentration rapidly and have a high genetic barrier to resistance. 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
Pegylated interferon alfa-2a	Weekly	Contraindicated in decompensated liver disease and in
patients with history of severe psychiatric condition

Adverse effects include thrombocytopenia, leukopenia,
anemia, flu-like symptoms, alopecia | | Entecavir
(nucleoside analogue) | Daily | Avoid if patient is lamivudine-resistant (57% of
lamivudine-resistant patients develop new entecavir
resistance at 6 years [vs. 1% in nonresistant patients])

Adverse effect: lactic acidosis

Test for HIV before commencing treatment | | Tenofovir
(nucleotide analogue) | Daily | Virologic results are better with tenofovir than with
adefovir after 48 weeks’ treatment

Monitor for renal impairment and reduction in bone
mineral density

Adverse effect: lactic acidosis

Test for HIV prior to starting

Safe in pregnancy |

• Prevention of vertical transmission: When a mother is HbsAg positive, hepatitis B immunoglobulin is given to the infant at birth and hepatitis B vaccine is administered to the infant at birth and 1 and 6 months. Due to the risk of hepatocellular carcinoma, surveillance with 6-monthly liver ultrasound for suspicious features (including new lesions) is indicated in select patients (see 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 AGA guidelines for HBV prevention and treatment during immunosuppressive drug therapy. 

Hepatitis C virus (HCV)

HCV infectionis 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.

• 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 should be considered before making decisions regarding HCV therapy. Serum aminotransferases, especially ALT, can be used to measure disease activity.

• 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 (DAA) 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 DAA treatment and the 4 weeks afterward.

Common Treatment Regimens for HCV Infection

Treatment Regimen	Treatment Duration
	HCV Genotype
Sofosbuvir + velpatasvir	1, 2, 3, 4, 5, 6
Glecaprevir + pibrentasvir	1, 2, 3, 4, 5, 6
Elbasvir + grazoprevir	1, 4
Sofosbuvir + ledipasvir	1

*Addition of ribavirin may be considered for patients with genotype 3 HCV and compensated cirrhosis.

†If HCV RNA level is <6 x 10⁶  IU/mL and patient is treatment naïve and does not have cirrhosis, 8 weeks can be considered.

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