Acute Liver Failure Workup
- Author: Gagan K Sood, MD; Chief Editor: BS Anand, MD more...
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 (CBC) count in patients with liver failure may reveal thrombocytopenia.
American College of Gastroenterology guidelines for drug-induced liver injury
In 2014, the American College of Gastroenterology released new guidelines for the diagnosis and management of drug-induced liver injury. Key points include the following[28, 29] :
Drug-induced liver injury is a diagnosis of exclusion; a thorough history-taking and workup should be performed to rule out other possible etiologies
Liver biopsy should be considered to help confirm the presence of drug-induced liver injury, if autoimmune hepatitis may be associated with the condition, and when immunosuppressive agents are being considered
The widely used Roussel Uclaf Causality Assessment Method scale may underestimate the risk of liver injury associated with herbal and dietary supplements
The guidelines also include an algorithm for the diagnosis of patients with suspected drug-induced liver injury and provide separate diagnostic pathways based on the type of liver damage (hepatocellular, mixed, or cholestatic) present.
The PT and/or the international normalized ratio (INR) are used to determine the presence and severity of coagulopathy. These are sensitive markers of hepatic synthetic failure and are usually abnormal in the setting of fulminant hepatic failure. Results may be worsened because of extrahepatic causes (eg, vitamin K deficiency, disseminated intravascular coagulation [DIC], consumptive coagulopathy).
The 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.
Arterial Blood Gases
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.
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.
Serum Free Copper
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 the 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. 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 veins (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).
Computed Tomography Scanning
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.
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.
Intracranial Pressure Monitoring
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.
[Guideline] Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology. 2005 May. 41(5):1179-97. [Medline].
Stravitz RT, Kramer AH, Davern T, Shaikh AO, Caldwell SH, Mehta RL, et al. Intensive care of patients with acute liver failure: recommendations of the U.S. Acute Liver Failure Study Group. Crit Care Med. 2007 Nov. 35(11):2498-508. [Medline].
Bernal W. Intensive care support therapy. Liver Transpl. 2003 Sep. 9(9):S15-7. [Medline].
Jalan R. Acute liver failure: current management and future prospects. J Hepatol. 2005. 42 Suppl(1):S115-23. [Medline].
Sussman NL, Gislason GT, Conlin CA, Kelly JH. The Hepatix extracorporeal liver assist device: initial clinical experience. Artif Organs. 1994 May. 18(5):390-6. [Medline].
Hughes RD, Williams R. Use of bioartificial and artificial liver support devices. Semin Liver Dis. 1996 Nov. 16(4):435-44. [Medline].
Nyberg SL, Misra SP. Hepatocyte liver-assist systems--a clinical update. Mayo Clin Proc. 1998 Aug. 73(8):765-71. [Medline].
Demetriou AA, Brown RS Jr, Busuttil RW, Fair J, McGuire BM, Rosenthal P, et al. Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure. Ann Surg. 2004 May. 239(5):660-7; discussion 667-70. [Medline]. [Full Text].
Jalan R, Olde Damink SW, Deutz NE, Hayes PC, Lee A. Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension. Gastroenterology. 2004 Nov. 127(5):1338-46. [Medline].
Jiang W, Desjardins P, Butterworth RF. Hypothermia attenuates oxidative/nitrosative stress, encephalopathy and brain edema in acute (ischemic) liver failure. Neurochem Int. 2009 Jul-Aug. 55(1-3):124-8. [Medline].
Hoofnagle JH, Carithers RL Jr, Shapiro C, Ascher N. Fulminant hepatic failure: summary of a workshop. Hepatology. 1995 Jan. 21(1):240-52. [Medline].
Lee WM, Schiodt FV. Fulminant hepatic failure. In: Schiff ER, Sorrell, MF, Maddrey WC, eds. Schiff's Diseases of the Liver. 8th ed. Baltimore: Md: Lippincott Williams & Wilkins; 1999.
Lidofsky SD, Bass NM, Prager MC, Washington DE, Read AE, Wright TL, et al. Intracranial pressure monitoring and liver transplantation for fulminant hepatic failure. Hepatology. 1992 Jul. 16(1):1-7. [Medline].
Detry O, Arkadopoulos N, Ting P, Kahaku E, Margulies J, Arnaout W, et al. Intracranial pressure during liver transplantation for fulminant hepatic failure. Transplantation. 1999 Mar 15. 67(5):767-70. [Medline].
Schiødt FV, Rochling FA, Casey DL, Lee WM. Acetaminophen toxicity in an urban county hospital. N Engl J Med. 1997 Oct 16. 337(16):1112-7. [Medline].
Larson AM, Polson J, Fontana RJ, Davern TJ, Lalani E, Hynan LS, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology. 2005 Dec. 42(6):1364-72. [Medline].
Davern TJ 2nd, James LP, Hinson JA, Polson J, Larson AM, Fontana RJ, et al. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology. 2006 Mar. 130(3):687-94. [Medline].
Khandelwal N, James LP, Sanders C, Larson AM, Lee WM. Unrecognized acetaminophen toxicity as a cause of indeterminate acute liver failure. Hepatology. 2011 Feb. 53(2):567-76. [Medline].
Paterson JM, Mamdani MM, Manno M, Juurlink DN. Fluoroquinolone therapy and idiosyncratic acute liver injury: a population-based study. CMAJ. 2012 Aug 13. [Medline].
Notes from the field: acute hepatitis and liver failure following the use of a dietary supplement intended for weight loss or muscle building - may-october 2013. MMWR Morb Mortal Wkly Rep. 2013 Oct 11. 62(40):817-9. [Medline]. [Full Text].
Hand L. CDC: supplement linked to hepatitis, liver failure. Medscape Medical News. October 15, 2013. Available at http://www.medscape.com/viewarticle/812581. Accessed: October 22, 2013.
Lo Re V 3rd, Haynes K, Forde KA, et al. Risk of acute liver failure in patients with drug-induced liver injury: evaluation of Hy's law and a new prognostic model. Clin Gastroenterol Hepatol. 2015 Dec. 13 (13):2360-8. [Medline].
Klein AS, Hart J, Brems JJ, Goldstein L, Lewin K, Busuttil RW. Amanita poisoning: treatment and the role of liver transplantation. Am J Med. 1989 Feb. 86(2):187-93. [Medline].
Hoyer DP, Munteanu M, Canbay A, et al. Liver transplantation for acute liver failure: are there thresholds not to be crossed?. Transpl Int. 2014 Jun. 27 (6):625-33. [Medline].
O'Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989 Aug. 97(2):439-45. [Medline].
Lee WM, Galbraith RM, Watt GH, Hughes RD, McIntire DD, Hoffman BJ, et al. Predicting survival in fulminant hepatic failure using serum Gc protein concentrations. Hepatology. 1995 Jan. 21(1):101-5. [Medline].
Schiødt FV, Rossaro L, Stravitz RT, Shakil AO, Chung RT, Lee WM. Gc-globulin and prognosis in acute liver failure. Liver Transpl. 2005 Oct. 11(10):1223-7. [Medline].
[Guideline] Kelly JC. Drug-Induced Liver Injury Guidelines Released by ACG. Medscape Medical News. Jun 18 2014. [Full Text].
[Guideline] Chalasani NP, Hayashi PH, Bonkovsky HL, et al. ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014 Jun 17. [Medline].
Rolando N, Harvey F, Brahm J, Philpott-Howard J, Alexander G, Casewell M, et al. Fungal infection: a common, unrecognised complication of acute liver failure. J Hepatol. 1991 Jan. 12(1):1-9. [Medline].
Murphy N, Auzinger G, Bernel W, Wendon J. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology. 2004 Feb. 39(2):464-70. [Medline].
Pereira SP, Langley PG, Williams R. The management of abnormalities of hemostasis in acute liver failure. Semin Liver Dis. 1996 Nov. 16(4):403-14. [Medline].
Stine JG, Lewis JH. Current and future directions in the treatment and prevention of drug-induced liver injury: a systematic review. Expert Rev Gastroenterol Hepatol. 2015 Dec 25. 1-20. [Medline].
[Guideline] Murray KF, Carithers RL Jr. AASLD practice guidelines: Evaluation of the patient for liver transplantation. Hepatology. 2005 Jun. 41(6):1407-32. [Medline].
AASLD position paper: the management of acute liver failure. Private Nonprofit Research Organization. American Association for the Study of Liver Diseases - Private Nonprofit Research Organization. 2005 May. 36(1):19 pages.
ClinicalTrials.gov. The Effect of Prometheus (R) Liver Support Dialysis on Cerebral Metabolism in Acute Liver Failure. Available at http://clinicaltrials.gov/ct2/show/NCT00655304.
Fontana RJ, Ellerbe C, Durkalski VE, et al; for the US Acute Liver Failure Study Group. Two-year outcomes in initial survivors with acute liver failure: results from a prospective, multicentre study. Liver Int. 2015 Feb. 35 (2):370-80. [Medline].
Fairfield C, Penninga L, Powell J, Harrison EM, Wigmore SJ. Glucocorticosteroid-free versus glucocorticosteroid-containing immunosuppression for liver transplanted patients. Cochrane Database Syst Rev. 2015 Dec 15. 12:CD007606. [Medline].
|Grade||Level of Consciousness||Personality and Intellect||Neurologic Signs||Electroencephalogram (EEG) Abnormalities|
|Subclinical||Normal||Normal||Abnormalities only on psychometric testing||None|
|1||Day/night sleep reversal, restlessness||Forgetfulness, mild confusion, agitation, irritability||Tremor, apraxia, incoordination, impaired handwriting||Triphasic waves (5 Hz)|
|2||Lethargy, slowed responses||Disorientation to time, loss of inhibition, inappropriate behavior||Asterixis, dysarthria, ataxia, hypoactive reflexes||Triphasic waves (5 Hz)|
|3||Somnolence, confusion||Disorientation to place, aggressive behavior||Asterixis, muscular rigidity, Babinski signs, hyperactive reflexes||Triphasic waves (5 Hz)|
|4||Coma||None||Decerebration||Delta/slow wave activity|