Definition of disease

• ALF is a rare condition in which severe hepatic injury leads to rapid deterioration in liver function resulting in altered mental status and coagulopathy (INR ≥1.5) in a patient with no pre-existing liver disease.
  
• The illness is considered acute if less than 26 weeks in duration.

Disease classification

• ALF can be further divided into subgroups based on the length of illness: hyperacute (<7 days); acute (7–21 days); subacute (>21 days and <26 weeks).

Incidence

• ALF is rare. In the USA, there are about 2000 cases/year.
  
• Overall global incidence in developed countries is between one and five cases per million people every year.

Economic impact

• Based on the ALF Study Group database, the average age of presentation for ALF in the USA is between 37 and 40 years.
  
• As this disease affects younger patients, there is a significant economic impact both by the early loss of life in those who don’t survive and the cost of life-long immunosuppression in those who were successfully transplanted.

Etiology

• The most common cause of ALF in the USA and UK is acetaminophen poisoning, both intentional and unintentional. Idiosyncratic drug reactions are the next most common cause.
  
• In countries where viral hepatitis is endemic such as South East Asia, hepatitis viruses (hepatitis B±D, E and A) are the most common causes.
  
• Other causes of ALF are listed in the Table: etiologies of ALF.

Pathology/pathogenesis

• In ALF, there are two competing intrahepatic processes. On the one hand, there is overwhelming hepatocellular injury and on the other there is hepatocellular regeneration in an effort to compensate for the acute loss of hepatocyte function. The abrupt loss in hepatic metabolic and immunologic functions, leads to encephalopathy, coagulopathy, and in many cases results in multi-organ failure.
  
• While disease-specific etiologies have unique pathophysiologic features which require specific intervention, there are general features common to ALF regardless of the etiology and they are outlined here.
  
  
  
  • Cerebral edema and ICH:
    
    
    
    • Cerebral edema and ICH are the most serious complications of ALF.
      
    • The pathogenic mechanisms leading to cerebral edema and ICH are not completely understood but result from a combination of osmotic disturbances in the brain and increased cerebral blood flow due to loss of cerebrovascular autoregulation.
    
    
  • Coagulopathy:
    
    
    
    • Loss of hepatocellular function results in decreased synthesis of Factor II, V, VII, IX, and X.
      
    • Abnormalities in platelet count, function, and morphology.
    
    
  • Infection/sepsis:
    
    
    
    • Kupffer cell malfunction – resident macrophages in the liver provide an important function in the clearance of gut-derived bacteria and endotoxin. In FHF, impaired uptake has in part been ascribed to decreased fibronectin, an important co-factor made by the liver which is needed for opsonization.
      
    • Neutrophil malfunction – phagocytosis, opsonization and mobility are all decreased. May be related to decreased serum complement levels.
      
    • Cell-mediated immunity – defective lymphocyte function.
    
    
  • Cardiovascular dysfunction and tissue oxygen debt:
    
    
    
    • Low systemic and pulmonary vascular resistance.
      
    • Compensatory increase in cardiac output.
      
    • Increased metabolic rate.
      
    • Abnormal oxygen transport and uptake.
      
    • Pathologic state is similar to that seen in septic shock.
    
    
  • Renal failure:
    
    
    
    • Depending on the etiology of ALF, direct nephrotoxicity can be seen, such as the case for acetaminophen.
      
    • Hepatorenal syndrome can be seen which is due to intense renal vasoconstriction secondary to the systemic vasodilation. The etiology of specific hemodynamic changes is incompletely understood but renal function recovers fully after liver transplant.
      
    • Impaired hepatic urea production results in underestimation of renal impairment.
    
    
  • Metabolic derangements:
    
    
    
    • Hypoglycemia is observed due to both defective gluconeogenesis and inadequate hepatic uptake of insulin.
      
    • Acidosis and alkalosis may both occur and should be managed by identifying and treating underlying cause.

Predictive/risk factors

• Since there are numerous etiologies for ALF, risk factors vary depending on the etiology.
  
• Acetaminophen poisoning: use of multiple medications containing acetaminophen, history of depression/suicidal behavior, chronic alcohol consumption, narcotic use.
  
• Amanita phalloides toxicity: ingestion of wild mushrooms.
  
• Fulminant hepatitis E: most common in women in third trimester of pregnancy. Limit travel to endemic areas during pregnancy.
  
• Reactivation of hepatitis B: chemotherapy or other immunosuppression.

Screening

• Hepatitis B status in cancer patients to undergo chemotherapy or immunosuppressive therapy: check HBsAg and HBcAb. If either positive check HBeAg and HBV DNA levels.

Primary prevention

• Prophylactic oral nucleoside or nucleotide antiviral therapy should be administered to HBsAg-positive individuals several weeks before the onset of chemotherapy or immunosuppressive therapy. Antiviral therapy should be maintained for 6 months after completion of the chemotherapy or immunosuppressive therapy in patients with HBV DNA levels <2000 IU/mL. If HBV DNA >2000 IU/mL, continue antiviral therapy until HBV DNA is undetectable and ALT levels are normalized.
  
• Limiting availability of bulk acetaminophen: restriction in package size and use of blister packaging begun in 1998 in the UK to combat impulsive suicide overdose has had some benefit. Similar strategies are currently being considered by the FDA.

Secondary prevention

• Psychiatric assistance for those with depression and have attempted suicide.
  
• Patient education in those with accidental overdose.

Differential diagnosis

• If there is evidence of acute hepatitis associated with INR >1.5 and altered mental status, the patient has ALF.
  
• Initially upon presentation before laboratory studies are available, the differential is broad to include anything that causes acute mental status changes such as drug overdose, psychosis, primary CNS pathology, sepsis, electrolyte/metabolic disturbances. Prior history and physical examination may help clarify differential.

Typical presentation

• The typical patient with acute liver failure has no history of liver disease or abnormal liver tests. Patients are either brought in by family members due to acute change in mental status or the patient is noted to be jaundiced without obvious mental status changes. Jaundice is often but not always seen at presentation.
  
• The patient may also report RUQ tenderness, nausea and vomiting.
  
• For intentional acetaminophen overdose, the patient will often admit to family members that they took acetaminophen and are brought in prior to the development of either jaundice or acute mental status changes.

Clinical diagnosis

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