eMedicine Specialties > Gastroenterology > Liver

Acute Liver Failure: Differential Diagnoses & Workup

Author: Gagan K Sood, MD, Associate Professor, Department of Medicine and Surgery, Baylor College of Medicine
Contributor Information and Disclosures

Updated: Jun 25, 2009

Differential Diagnoses

Other Problems to Be Considered

Acute fatty liver of pregnancy
Adult-onset Still disease
A phalloides mushroom poisoning
B cereus toxin
Fructose intolerance
Galactosemia
HELLP syndrome of pregnancy
Hemorrhagic viruses (Ebola virus, Lassa virus, Marburg virus)
Idiopathic drug reaction (hypersensitivity)
Neonatal iron storage disease
Paramyxovirus
Primary graft nonfunction (in liver transplant recipients)
Tyrosinemia
Yellow phosphorus poisoning
Acetaminophen poisoning

Workup

Laboratory Studies

• Complete blood cell (CBC) count: Results may indicate thrombocytopenia.
• PT and/or international normalized ratio (INR)
  • These tests are used to determine the presence or severity of coagulopathy.
  • They are sensitive markers of hepatic synthetic failure but rarely in the setting of suspected fulminant hepatic failure.
  • Their laboratory values may be increased because of extrahepatic causes (vitamin K deficiency, disseminated intravascular coagulation [DIC], consumptive coagulopathy).
• Hepatic enzymes
  • Levels of the transaminases (aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase [SGOT] and alanine aminotransferase [ALT]/serum glutamic-pyruvic transaminase [SGPT]) are often elevated dramatically as a result of severe hepatocellular necrosis.
  • In instances of acetaminophen toxicity (especially alcohol-enhanced), the AST level may be well over 10,000 U/L.
  • The alkaline phosphatase (ALP) level may be normal or elevated.
• Serum bilirubin
  • By definition, this value should be elevated in fulminant hepatic failure. It climbs as hepatic dysfunction worsens.
  • Serum bilirubin that is elevated greater than 4 mg/dL suggests a poor prognosis in the setting of acetaminophen poisoning.
• Serum ammonia
  • This level may be elevated dramatically in patients with fulminant hepatic failure. Arterial blood is the best way to measure ammonia.
  • The arterial serum ammonia level is most accurate, but venous ammonia levels are generally acceptable.
  • It does not exclude the possibility of another cause for mental status changes (notably increased ICP and seizures).
• Serum glucose: levels may be very low and pose a serious hazard. This results from impairments in glycogen production and gluconeogenesis.
• Serum lactate
  • Arterial blood lactate levels either at 4 hours (>3.5 mmol/L) or at 12 hours (>3.0 mmol/L) are early predictors of outcome in acetaminophen-induced acute liver failure. levels are often elevated as a result of both impaired tissue perfusion (increases production) and decreased clearance by the liver.
  • An increased anion gap metabolic acidosis is associated with this condition (although it may be accompanied by a respiratory alkalosis as a result of hyperventilation).
• Arterial blood gases (ABGs): These may reveal hypoxemia, which is a significant concern as a result of adult respiratory distress syndrome (ARDS) or other causes (eg, pneumonia).
• Serum creatinine: levels may be elevated, signifying the development of hepatorenal syndrome or some other cause of acute renal failure.
• Blood cultures
  • Most patients develop some sort of infection during or before hospitalization. Patients are at risk of line sepsis and complications from all other invasive procedures.
  • Fungal infections are common, most likely as a result of decreased host resistance and antibiotic treatment.¹⁵
  • Infection may be associated with bacteremia, but identifying and treating it early is important because the mortality from fulminant hepatic failure increases significantly with the development of this serious complication.
• Serum-free copper
  • Serum-free copper studies are important to consider when Wilson disease must be excluded or confirmed. Fulminant hepatic failure from Wilson disease appears to be uniformly fatal without transplantation.
  • The diagnosis may be challenging because serum ceruloplasmin levels may be elevated as an acute phase reactant or depressed in a nonspecific fashion as a result of hepatic failure; therefore, copper studies are preferable but also may be confounded by impaired biliary excretion. This leads to increased urinary copper excretion by way of increased serum copper. In this setting, an increased serum-free (unbound) copper may be more reliable than any other study results.
• Serum phosphate
  • levels of serum phosphate may be low.
  • It has been hypothesized that people whose livers rapidly regenerate will develop hypophosphatemia. Elevated phosphate levels suggest impaired regeneration.
• Viral serologies
  • HAV immunoglobulin M (IgM), hepatitis B surface antigen (HBsAg), and HBV anticore IgM serologies help determine acute infection with HAV or HBV.
  • Hepatitis C virus (HCV) antibody testing may be negative for several weeks or months. Repeat testing may be necessary, but acute HCV infection as a cause of fulminant hepatic failure appears to be exceedingly uncommon. If a strong index of suspicion exists, obtain hepatitis C viral load testing.
  • If HBsAg is positive (especially if the patient is a known intravenous [IV] drug abuser), consider HDV-IgM.
  • Other viral studies may be helpful in the posttransplantation setting or when patients are otherwise heavily immunosuppressed. Other studies include cytomegalovirus viremia and cytomegalovirus antigenemia. Also consider herpes simplex virus (HSV).
• Autoimmune markers: Antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and immunoglobulin levels are important markers for a diagnosis of autoimmune hepatitis.
• Acetaminophen level
  • The acetaminophen level may have decreased by the time a patient presents with fulminant hepatic failure, but it may be helpful for documentation purposes.
  • Acetaminophen-protein adducts are specific biomarkers of drug-related toxicity. These can be measured in blood. It has been shown that measurement of serum adducts improves the diagnostic accuracy in patients with acute liver failure. Measurement of acetaminophen-protein adducts is particularly useful to diagnose cases lacking historical data or other clinical information. Serum acetaminophen-protein adducts decrease in parallel to aminotransferases and can be detected up to 7 days.
• Drug screen: Consider a drug screen in a person who is an IV drug abuser.

Imaging Studies

• Liver ultrasonography (Doppler)
  • This examination may establish the patency and flow in the hepatic vein (allowing exclusion of Budd-Chiari syndrome), hepatic artery, and the portal vein.
  • The examination may not be necessary if an obvious explanation exists for the hepatic failure. However, it may assist the clinician in excluding the presence of a hepatocellular carcinoma or intrahepatic metastases (see Image 1 or below).
    

    

    Ultrasonogram shows a hyperechoic mass representing hepatocellular carcinoma.

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    Ultrasonogram shows a hyperechoic mass representing hepatocellular carcinoma.

  • Liver ultrasonography establishes the presence of ascites.
• Computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the abdomen
  • These may be required for further definition of hepatic anatomy and to help the clinician exclude other intraabdominal processes, particularly if the patient has developed massive ascites, is obese, or if transplantation is being planned (see Image 2 or below).
    

    

    Computed tomography scan in the hepatic arterial phase of contrast enhancement showing neovascularity in a low-density hepatic mass.

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    Computed tomography scan in the hepatic arterial phase of contrast enhancement showing neovascularity in a low-density hepatic mass.

  • Intravenous contrast may compromise renal function. Consider performing a contrast-free study.
• CT scanning of the head helps identify cerebral edema and exclude intracranial mass lesions (especially hematomas) that may mimic edema from fulminant hepatic failure. Also consider and exclude subdural hematomas (see Image 3 or below).
  

  

  Subacute subdural hematoma with extension into the anterior interhemispheric cistern. Note that the sutures do not contain the spread of these hemorrhages.

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  Subacute subdural hematoma with extension into the anterior interhemispheric cistern. Note that the sutures do not contain the spread of these hemorrhages.

Other Tests

• Electroencephalogram: Consider this study in the evaluation of a patient with encephalopathy if seizures must be excluded.

Procedures

• Liver biopsy: A percutaneous liver biopsy is contraindicated in the setting of coagulopathy. However, a transjugular biopsy is helpful for diagnosis if autoimmune hepatitis, metastatic liver disease, lymphoma, or herpes simplex hepatitis is suspected.
• Intracranial pressure monitoring
  • When establishing a diagnosis of ICH or cerebral edema, this approach is frequently necessary and has value in guiding management.
  • Typically, extradural catheters are safer than intradural catheters. Intradural catheters are somewhat more accurate and, in the hands of a neurosurgeon experienced with their use, may be equally safe.

Histologic Findings

Liver biopsy findings may be nonspecific, but, in general, the findings depend on the underlying etiology of the acute liver failure. Panlobular necrosis is generally observed as a result of idiosyncratic medication-induced hepatitis leading to fulminant hepatic failure. Centrilobular necrosis is typical of acetaminophen-induced fulminant hepatic failure, but panlobular injury may also be observed. Viral hepatitis typically shows a panlobular injury and may be difficult to distinguish from medication-induced hepatitis. The presence of microvesicular steatosis suggests certain medications (eg, valproic acid, salicylates in Reye syndrome) as a cause for fulminant hepatic failure, but this finding is also observed in acute fatty liver of pregnancy.

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