Acute Liver Failure Workup

The most important step in patients with acute liver failure is to identify the cause. Prognosis in acute liver failure is dependent on etiology. Acute liver failure from certain causes demands immediate and specific treatment. It is also critical to identify those patients who will be candidates for liver transplantation.

All patients with clinical or laboratory evidence of moderate or severe acute hepatitis should have immediate measurement of prothrombin time (PT) and careful evaluation of mental status. Prolongation of the PT or alteration in mental sensorium is grounds for hospital admission.

A complete blood cell count in patients with liver failure may indicate thrombocytopenia.

The PT and/or the international normalized ratio (INR) are used to determine the presence or severity of coagulopathy. They are sensitive markers of hepatic synthetic failure but are rarely abnormal in the setting of fulminant hepatic failure. Results may be increased because of extrahepatic causes (eg, vitamin K deficiency, disseminated intravascular coagulation [DIC], consumptive coagulopathy).

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 and ALT level may be well over 10,000 U/L. The alkaline phosphatase (ALP) level may be normal or elevated.

By definition, the serum bilirubin level should be elevated in fulminant hepatic failure. It climbs as hepatic dysfunction worsens. A serum bilirubin that is elevated to greater than 4 mg/dL suggests a poor prognosis in the setting of acetaminophen poisoning.

The serum ammonia level may be elevated dramatically in patients with fulminant hepatic failure. The arterial serum ammonia level is most accurate, but venous ammonia levels are generally acceptable. An elevated serum ammonia level does not exclude the possibility of another cause for mental status changes (notably, increased intracranial pressure and seizures).

Serum glucose levels may be dangerously low. This decrease results from impairments in glycogen production and gluconeogenesis.

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. Blood lactate levels are often elevated as a result of both impaired tissue perfusion, which increases production, and decreased clearance by the liver.

Patients with elevated lactate levels may have an associated metabolic acidosis due to an increased anion gap. Alternatively, this condition may be accompanied by a respiratory alkalosis as a result of hyperventilation.

Like pulse oximetry, arterial blood gas evaluation is valuable for identifying acid-base imbalances. However, because of significant disturbances in the acid-base balance, which are usually progressive, arterial blood gas evaluation is required, rather than only monitoring pulse oximetry. Placement of an arterial line is recommended.

Additionally, arterial blood gases 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.

Most patients develop infection during or before hospitalization. Patients are at risk of catheter sepsis and complications from all other invasive procedures. Fungal infections are common, most likely as a result of decreased host resistance and antibiotic treatment.^[17]

Infection may be associated with bacteremia. Early identification and treatment of bacteremia is important because the mortality from fulminant hepatic failure increases significantly with the development of this serious complication.

Patients with Wilson disease have low ceruloplasmin and total serum copper levels. However, ceruloplasmin acts as an acute-phase reactant as well as a copper transporter, and levels may be increased (eg, from active inflammation, pregnancy, or estrogen treatment) or depressed in a nonspecific fashion as a result of hepatic failure. Thus, determination of serum free copper (ie, non-ceruloplasmin–bound copper) is important when Wilson disease must be excluded or confirmed. Fulminant hepatic failure from Wilson disease appears to be uniformly fatal without transplantation.

The free copper level is determined by subtracting 3 times the ceruloplasmin level (mg/dL) from the total serum copper level (µg/dL). Normal free copper levels range from 1.3 to 1.9 µmol/L (8-12 µg/dl); in Wilson disease, levels exceed 3.9 µmol/L (>25 µg/dL).

Levels of serum phosphate may be low. It has been hypothesized that hypophosphatemia develops in people whose livers regenerate rapidly. Elevated phosphate levels suggest impaired regeneration.

Hepatitis A virus (HAV) immunoglobulin M (IgM), hepatitis B surface antigen (HBsAg), and hepatitis B virus (HBV) anticore IgM serologies help identify acute infection with HAV or HBV.

Hepatitis C virus (HCV) antibody test results may remain 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 the HBsAg assay is positive, consider testing for hepatitis D virus (HDV) IgM. This test is particularly advisable if the patient is a known intravenous (IV) drug abuser.

Other viral studies may be helpful in the posttransplantation setting or when patients are otherwise heavily immunosuppressed. Such studies include cytomegalovirus viremia and cytomegalovirus antigenemia. Also consider herpes simplex virus (HSV).

Antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and immunoglobulin levels are important markers for a diagnosis of autoimmune hepatitis.

In patients with liver failure from acetaminophen toxicity, the acetaminophen level may have decreased by the time a patient presents with fulminant hepatic failure. Nevertheless, this assay may be helpful for documentation purposes.

Acetaminophen-protein adducts are specific biomarkers of acetaminophen-related toxicity. These can be measured in blood. Measurement of acetaminophen-protein adducts is particularly useful for diagnosis in cases lacking historical data or other clinical information.^[10] Serum acetaminophen-protein adducts decrease in parallel to aminotransferases and can be detected up to 7 days.

Consider a drug screen in a patient who is an IV drug abuser.

A Doppler scan of the liver establishes the presence of ascites and may establish the patency and flow in the hepatic vein (allowing exclusion of Budd-Chiari syndrome), hepatic artery, and the portal vein.

Liver ultrasonography 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 the image below).

CT scanning (or magnetic resonance imaging) of the abdomen may be required for further definition of hepatic anatomy and to help the clinician exclude other intra-abdominal processes, particularly if the patient has developed massive ascites, if the patient is obese, or if transplantation is being planned (see the image below).

Intravenous contrast may compromise renal function. Consider performing a contrast-free study.

CT scanning of the head may help identify cerebral edema, although CT scans do not reliably demonstrate evidence of edema, especially at early stages. Head imaging with CT scanning is also used to exclude other causes of decline in mental status, such as intracranial mass lesions (especially hematomas) that may mimic edema from fulminant hepatic failure. It can also exclude subdural hematomas (see the image below).

Consider electroencephalography in the evaluation of a patient with encephalopathy if seizures must be excluded.

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. Liver biopsy findings may be nonspecific, but in general, the findings depend on the underlying etiology of the acute liver failure.

When establishing a diagnosis of intracranial hypertension or cerebral edema, intracranial pressure monitoring is frequently necessary. Monitoring also has value in guiding management.

Typically, extradural catheters are safer than intradural catheters. On the other hand, intradural catheters are somewhat more accurate and, in the hands of a neurosurgeon experienced with their use, may be equally safe.

Liver biopsy in patients with idiosyncratic medication-induced hepatitis leading to fulminant hepatic failure generally shows panlobular necrosis. In patients with acetaminophen-induced fulminant hepatic failure, centrilobular necrosis is typical but panlobular injury may also be observed.

Viral hepatitis typically produces 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.