Acute and Acute-on-Chronic Liver Failure

Liver failure is a life-threatening condition with high mortality rates characterized by the rapid deterioration of liver function. Liver failure is acute, acute-on chronic, or chronic in nature.  Distinguishing between the types of liver failure is important due to significant differences in treatment and overall prognosis.

Acute liver failure (ALF)

Acute liver failure (ALF) is an uncommon condition in which rapid deterioration of the liver function occurs in a previously healthy individual.  It is defined by the development of coagulopathy, usually with an international normalized ratio (INR) of greater than 1.5, and hepatic encephalopathy (HE) precipitated by an illness of less than 26 weeks' duration. ^[1]

There are multiple etiologies with a variety of clinical presentations.  In general, ALF is caused by medications, toxins, infections, metabolic disorders, vascular disorders, trauma and malignancies.

ALF can be further subdivided based on the rapidity of the onset of HE:

• Hyperacute - less than 7 days
• Acute - onset within 7–21 days
• Subacute - onset more than 21 days and less than 26 weeks

Hyperacute ALF has the best prognosis and is most often caused by acetaminophen toxicity or hepatitis A or hepatitis E infection.  Causes of acute ALF include hepatitis B infection, toxic mushrooms, ischemic liver injury and malignancies.  Subacute infections are usually caused by metabolic disorders (ie Wilson disease), vascular disorders (ie, Budd-Chiari syndrome) or autoimmune hepatitis. ^[1]

Acute-on-chronic liver failure (ACLF)

Acute on chronic liver failure (ACLF) is a distinct syndrome in individuals with chronic liver disease (with or without cirrhosis).  ACLF carries a very high short-term (<28 days) mortality but may be reversible if diagnoses and treated quickly.  It can at times be difficult to distinguish ACLF from ALF if the underlying liver disease is unknown or unrecognized. For example, patients with Wilson disease, vertically acquired hepatitis B, or autoimmune hepatitis may have ALF in spite of the presence of cirrhosis, if their disease has been manifesting for less than 26 weeks. Understanding this overlap is important because of significant differences in management. ^{[1, 2]}

There is considerable variation in the exact definition of acute-on-chronic liver failure (ACLF) due to the differences in epidemiology of chronic liver disease globally.  In 2024, American Association for the Study of Liver Diseases (AASLD) sought to reconcile the three most widely used definitions from North America, Europe and the Asian Pacific. The AASLD definition requires the following be present in an individual with chronic kidney disease for a diagnosis of ACLF ^[3] :

• Acute onset with rapid deterioration in clinical condition
• Liver failure defined by elevated bilirubin and elevated INR
• At least one extrahepatic (neurologic, circulatory, respiratory, or renal) organ failure

Chronic liver failure

Chronic liver failure, also known as end-stage liver disease, is the final, irreversible stage of progressive liver damage called liver decompensation.  Liver decompensation is typically defined as the new onset of:

• GI bleeding related to portal hypertension (eg, variceal bleeding)
• Clinically detectable ascites (ie, diagnosed by physical examination or by paracentesis)
• Grade 2 or higher hepatic encephalopathy

There is a difference between nonacute decompensation (NAD) and acute decompensation (AD) in management and prognosis.  For example, a patient with NAD might experience the slow onset of ascites or hepatic encephalopathy and could be managed in an outpatient setting. Patients with AD require hospitalization to address acute GI bleeding, the rapid recurrence of moderate or massive ascites, the acute onset of hepatic encephalopathy, or acute bacterial infection.  AD presents with ACLF in 16% of cases. ^[4]   AD without ACLF is usually reversible with treatment and has a low short-term mortality rate (5%) but median survival decreases significantly compared to patients with NAD. ^[5]

For more information on chronic liver failure and acute decompensation, see Cirrhosis.

Acute liver failure (ALF)

Numerous causes of acute liver failure (ALF) exist, but hepatotoxicity due to acetaminophen and idiosyncratic drug reactions is the most common cause in the United State and may occur with virtually any medication. Drug-induced liver injury (DILI) is a leading cause of emergent liver transplantation ^[6] ; in Western nations, DILI is the primary cause of acute liver failure in adults. ^[7]   See Drug-Induced Hepatotoxicity

Viral hepatitis may lead to ALF. Hepatitis A and B account for most of these cases. In the developing world, acute hepatitis B virus (HBV) infection dominates as a cause of ALF because of the high prevalence of the disease. See Viral Hepatitis.

Atypical causes of viral hepatitis causing ALF include the following:

• Cytomegalovirus
• Hemorrhagic fever viruses
• Herpes simplex virus
• Paramyxovirus
• Epstein-Barr virus
• Dengue virus ^[8]

Autoimmune hepatitis may also result in ALF.

The most common cause of acute jaundice in pregnancy is acute viral hepatitis, but most of these patients do not develop ALF.  The one major exception is pregnant patients who develop hepatitis E. The case fatality rate is 20%, and this rate increases during the second and third trimesters. The exposure history in patients with hepatitis E is usually remarkable for travel and/or residence in the Middle East, India and the subcontinent, Mexico, or other endemic areas. In the United States, hepatitis E is relatively uncommon but must be considered in the appropriate setting. ^[9]

Acute fatty liver of pregnancy (AFLP) frequently culminates in ALF. ^[10]  AFLP typically occurs in the third trimester; preeclampsia develops in approximately 50% of these patients. AFLP has been estimated to occur in 0.008% of pregnancies.  See Liver Disease and Pregnancy.

The following toxins are associated with dose-related toxicity:

• Amanita phalloides mushroom toxin
• Bacillus cereus toxin
• Cyanobacteria toxin
• Organic solvents (eg, carbon tetrachloride)
• Yellow phosphorus

A phalloides mushroom intoxication is much more common in Europe and in California than in the remainder of the United States. See Mushroom Toxicity.

Vascular causes of ALF include:

• Ischemic hepatitis (consider especially in the setting of severe hypotension or recent hepatic tumor chemoembolization)
• Hepatic vein thrombosis (Budd-Chiari syndrome)
• Hepatic veno-occlusive disease
• Portal vein thrombosis
• Hepatic arterial thrombosis (consider posttransplant)

Metabolic diseases causing ALF include:

• Alpha1-antitrypsin deficiency
• Fructose intolerance
• Galactosemia
• Lecithin-cholesterol acyltransferase deficiency
• Reye syndrome
• Tyrosinemia
• Wilson disease

Primary liver tumor (usually hepatocellular carcinoma, rarely cholangiocarcinoma) and secondary malignancies (extensive hepatic metastases or infiltration from adenocarcinoma, such as breast and lung, and melanoma primaries; lymphoma; leukemia) are also responsible for causing ALF.

For nearly 15% of patients, the cause remains indeterminate.

Acute-on-chronic liver failure (ACLF)

Up to 97% of acute decompensation (AD) and ACLF cases are precipitated by bacterial infections or severe alcoholic hepatitis, alone or in combination. Successful first-line antibiotic treatment of bacterial infections in patients with AD is associated with a lower rate of development of ACLF. ^[4]  Metabolic-associated steatotic liver disease (MASLD)-associated cirrhosis remains a chief risk factor for ACLF.

Acute liver failure (ALF)

The development of cerebral edema is the major cause of morbidity and mortality in patients with acute liver failure (ALF). ^[11]  The etiology of this intracranial hypertension (ICH) is not fully understood, but it is considered to be multifactorial. Briefly, hyperammonemia may be involved in the development of cerebral edema. Brain edema is thought to be both cytotoxic and vasogenic in origin.

Cytokine profiles are also deranged. Elevated serum concentrations of bacterial endotoxins, tumor necrosis factor–alpha (TNF-α), interleukin (IL)–1, and IL-6 have been found in ALF. 

Cytotoxic edema is the consequence of impaired cellular osmoregulation in the brain, resulting in astrocyte edema. Cortical astrocyte swelling is the most common observation in neuropathologic studies of brain edema in ALF.

In the brain, ammonia is detoxified to glutamine via amidation of glutamate by glutamine synthetase. The accumulation of glutamine in astrocytes results in astrocyte swelling and brain edema. 

An increase in intracranial blood volume and cerebral blood flow is a factor in acute liver failure. The increased cerebral blood flow results because of the disruption of cerebral autoregulation. The disruption of cerebral autoregulation is thought to be mediated by elevated systemic concentrations of nitric oxide, which acts as a potent vasodilator.

Acute-on-chronic liver failure (ACLF)

Although acute decompensation (AD) and acute-on-chronic liver failure (ACLF) share precipitating events, ACLF has a more severe and rapidly progressive course. In patients with advanced cirrhosis, portal hypertension impairs immune activation and suppression which increases susceptibility to infection, systemic inflammation and multiorgan failure.  A cytokine storm, characterized by elevated levels of interleukin (IL)-6, IL-1, tumor necrosis factor alpha (TNF-α), and IL-8 drives severe systemic inflammation, immune exhaustion, impaired phagocytic function, ultimately leading to organ failure. ^[12]

Risk factors for organ failure include:

• Alcoholic hepatitis
• Hepatitis B or Hepatitis C
• Previous acute decompensation

United States data

Acute liver failure (ALF) is rare. In the United States, the incidence is estimated to be 2,000–3,000 cases per year with approximately 550 attributable to drug-related hepatotoxicity. ^[1]

More than 40% of US adults are affected by some type of chronic liver disease, including ^[13] :

• Alcohol-associated liver disease (ALD) (4.7%)
• Hepatitis C (1%)
• Hepatitis B (0.35%)

Reported prevalence of acute-on-chronic liver failure (ACLF) in patients with chronic liver disease varies from 7% to 54%, depending on diagnostic criteria and study population. ^[12]

International data

In developed nations, ALF has an estimated incidence of fewer than 10 cases per million people per year. ^[14]   In population-based cohorts in the United Kingdom the incidence is up to 0.8 per 100,000 while in Germany the incidence has been estimated as 1.13 per 100,000. ^[1]   Hepatitis E virus (HEV) is associated with a high incidence of ALF in women who are pregnant and is of concern in pregnant patients living in or traveling through endemic areas which include, but are not limited to, Mexico and Central America, India and the subcontinent, and the Middle East. ^[9]

A meta-analysis of 43,206 patients with ACLF reported a global prevalence of 35% among patients admitted to the hospital with decompensated cirrhosis. The highest prevalence was 65% in South Asia. ^[15]

Racial distribution

Acute liver failure is seen among all races. In a US multicenter study of acute liver failure, the ethnic distribution included white persons (74%), Hispanics (10%), black persons (3%), Asians (5%), and Latin Americans (2%). ^{[16, 17, 18]}

Sex and age -related demographics

Viral hepatitis E and autoimmune liver disease are more common in women than in men. ^[9] In a US multicenter study group, acute liver failure was seen more often in women (73%) than in men, and women with acute liver failure were older (39 y) than men (32.5 y).

Age may be pertinent to morbidity and mortality in those with acute liver failure. Patients younger than 10 years and older than 40 years tend to fare relatively poorly.

Acute liver failure (ALF)

Before the introduction of orthotopic liver transplantation (OLT) for acute liver failure, mortality was generally greater than 80%. However, with improved intensive care, the prognosis is much better now than in the past, with One-year and five-year post-OLT patient survival of approximately 80% and 75%, respectively. ^[1]

The etiologic factor and the development of complications are the main determinants of outcome in acute liver failure. Patients with acute liver failure caused by acetaminophen have a better prognosis than those with an indeterminate form of the disorder. Patients with stage 3 or 4 encephalopathy have a poor prognosis. The risk of mortality increases with the development of any complications, which include cerebral edema, renal failure, adult respiratory distress syndrome (ARDS), coagulopathy, and infection.

Paradoxically, rapid progression from the onset of jaundice (usually the first unequivocal sign of liver disease recognized by the patient or family) to encephalopathy is associated with improved survival. When this interval is less than 2 weeks, patients have hyperacute liver failure. Although the grade of encephalopathy is a prognostic factor in cases of acetaminophen overdose, it does not correlate with outcome in other settings.

Preoperative prognostic factors for liver transplantation survival in patients with acute liver failure appear to include the recipient's pretransplantation lowest pH and body mass index.  According to Hoyer et al, the recipient's lowest preoperative pH is also independently associated with inpatient mortality, in which the calculated cutoff is a pH of 7.26. ^[19]

Acute-on-chronic liver failure (ACLF)

The 28-day mortality in patients with ACLF ranges from 30% to 50% depending on the definition used and geographical location. ^[3]   A meta-analysis of 43,206 patients with ACLF reported a global 90-day mortality rate of 58% with a significantly higher mortality rate of 74% in South America. ^[15] The outcome of patients with ACLF is often driven by the number and severity of organ failures.