When Does Transaminitis Become Acute Hepatic Failure? What Is the Management of Transaminitis and Acute Hepatic Failure?

  • Michelle A. HiegerEmail author


The non-toxicological causes for elevated transaminases include infection, ischemia, metabolic derangements, malignancy, autoimmune disease, and primary graft failure after transplant. Acute liver failure is a common pathway for many conditions and insults, leading to massive hepatic necrosis or loss of normal hepatic function. Acute liver failure can be described in different subgroups by acuity of encephalopathy onset. Tools exist to aid in the prognostication of acute liver failure. Treatment of transaminitis and disposition of the patient are guided by the underlying diagnosis.


Transaminases Liver function tests LFTs Drug toxicity Hepatitis 

Pearls and Pitfalls

  • Acute liver failure is a common pathway for many conditions and insults, leading to massive hepatic necrosis and/or loss of normal hepatic function.

  • Transaminases can be elevated secondary to many intra- and extrahepatic causes.

  • The level of transaminitis should not be the sole determinant in management and disposition.

  • Patients with acute liver failure should be considered for early transfer to a liver transplant center, ideally prior to elevation in intracranial pressure or the development of severe coagulopathy.

When Does Transaminitis Become Acute Hepatic Failure?

Transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) are frequently obtained in the acute care setting [1, 2, 3]. Non-toxicological causes of elevated transaminases include infection, ischemia, metabolic derangement, malignancy, autoimmune disease, and primary graft failure after transplant [1].

Acute Hepatic Failure

Non-toxicological causes of acute liver failure are listed in Table 69.1 [1]. Toxicological causes of acute liver failure are listed in Table 69.2 [1]. Viral hepatitis is the most common cause of acute liver failure worldwide, while acetaminophen is the most common cause of acute liver failure in the United States [3]. Acute liver failure is a common pathway for many conditions and insults, leading to massive hepatic necrosis and/or loss of normal hepatic function.
Table 69.1

Non-toxicological causes of acute liver failurea



Metabolic derangements


Autoimmune problems

Primary graft failure after transplant

Viral hepatitis (hepatitis A&E most common)

Disruption of portal vein or hepatic artery

Acute fatty liver of pregnancy

Any malignancy causing obstruction or liver damage

Autoimmune hepatitis

Liver transplant failure

Herpes simplex, EBV, varicella zoster, CMV, parvovirus (usually immunocompromised if acute liver failure occurs from these)

Prolonged hypotension (overdose, cardiac arrest, intraoperative, AMI, PE)

HELLP syndrome


Rare: Coxiella burnetii, Plasmodium falciparum, amebic abscesses, disseminated TB, Bacillus cereus

Veno-occlusive disease (chemotherapy or bone marrow transplant related)

Reye’s syndrome


Budd-Chiari syndrome

Wilson’s disease


Exertional heat stroke


EBV Epstein-Barr virus, CMV cytomegalovirus, TB tuberculosis, AMI acute myocardial infarction, PE pulmonary embolism, HELLP hemolysis, elevated liver enzymes, low platelets

aNot an all-inclusive list

Table 69.2

Toxicological causes of acute liver failurea


Drugs of abuse


Biologic agents




Sea anemone sting

Rare/idiosyncratic/unpredictable (valproic acid, troglitazone, amiodarone)



Mushrooms (cyclopeptides)

Hypersensitivity reactions (phenytoin, para-aminosalicylate, chlorpromazine, sulfonamides)




Halogenated anesthetics (enflurane, methoxyflurane, isoflurane, halothane): toxic hepatitis, rare FHF

TCE (inhaled)

Cleaning solvents with fluorinated or halogenated hydrocarbons


NSAIDs: sulindac, diclofenac

Toluene (inhaled)


Macrolides (erythromycin, clarithromycin): cholestasis, rare hepatic necrosis



Other medications: aspirin, amoxicillin-clavulanate, azathioprine, infliximab, carbamazepine, captopril, tetracycline, zidovudine, dantrolene, herbal meds (kava), dapsone, diltiazem, statins, methimazole, MAOIs, methotrexate, nitrofurantoin, TCAs, phenothiazines, gold, propylthiouracil, isoniazid, rifampin, ketoconazole, methyldopa


FHF fulminant hepatic failure, NSAIDs nonsteroidal anti-inflammatory drugs, MAOIs monoamine oxidase inhibitors, TCAs tricyclic antidepressants, MDMA 3,4-methylenedioxymethamphetamine, PCP phencyclidine, TCE trichloroethylene

aNot an all-inclusive list

Acute liver failure can be classified into subgroups by acuity of encephalopathy. Hyperacute liver failure is encephalopathy within 1 week of jaundice onset. Acute liver failure is encephalopathy within 8–28 days of jaundice onset. Subacute liver failure is encephalopathy within 5–12 weeks of jaundice onset [4, 5].


Each subgroup has its own set of complications. Hyperacute and acute liver failure have an increased incidence of cerebral edema, but hyperacute liver failure patients are more likely to survive with supportive care, and acute liver failure patients are more likely to die without liver transplant. Subacute liver failure patients have increased mortality, less cerebral edema, and increased likelihood of portal hypertension, leading to ascites and renal failure [5].

Other complications from acute liver failure include [5]:
  • Bleeding (including exsanguination)

  • Cardiovascular derangements

  • Pulmonary and ventilatory derangements

  • Central nervous system dysfunction (temperature dysregulation causing hypothermia, disruption of the blood-brain barrier, and increased intracranial pressure leading to encephalopathy)

  • Metabolic derangements

  • Infection

The higher the number of complications, the more likely the patient will not survive [1].

Overall, outcomes have improved due to earlier identification of causes, earlier initiation of treatment, improved intensive care, and improved transplant science. Formerly, mortality was 55–95%, and now mortality is 30–40% [4, 6].

Laboratory Abnormalities

Liver failure generally results in laboratory abnormalities beyond transaminitis. Blood work in acute liver failure may show [1, 7]:
  • Synthetic dysfunction, which is usually the first sign of impending liver failure – decreased albumin and clotting factor levels, increased coagulation profiles

  • Defects in gluconeogenesis – decreased serum glucose

  • Worsening toxicant metabolism – increased ammonia

  • Decreased hepatic excretory function – increased bilirubin

  • Decreased renal function – elevated creatinine from prerenal azotemia, acute tubular necrosis, and/or hepatorenal syndrome

Table 69.3 reviews the utility of labs , imaging, and other ancillary tests in the evaluation of potential acute hepatic failure [1, 3, 8].
Table 69.3

Initial diagnostic testing in fulminant hepatic failure



Electrolytes and minerals

Imbalances are common. Abnormalities can cause arrhythmias and worsen encephalopathy. Hypophosphatemia is common in acetaminophen overdose


Renal failure is frequent and affects management and prognosis. Etiology (e.g., toxic effect of ingested substances) may alter therapy (e.g., hemodialysis)


Hypoglycemia is common and can produce permanent neurologic sequelae

CBC with platelets

Assess for sepsis (leukocytosis), GI bleeding (anemia), and risk of hemorrhage (thrombocytopenia)

Liver profile

Assess for degree of damage and follow course of illness. Elevated transaminases are generally due to hepatocyte damage. Increase in alkaline phosphatase is usually due to cholestasis or biliary obstruction. Increased bilirubin with indirect/direct can guide differential


Increased in hepatic metabolic failure. Poor prognosis if significantly increased in fulminant hepatic failure

Coagulation profile

Serve as prognostic indicators (protime, factor V level) and assess risk of hemorrhage

Arterial blood gases

Prognostic significance (lactic acidosis). Derangements are common

Blood group

Preparation for transplantation. Type and crossmatch in anticipation of bleeding

Toxicology, virology, autoimmune panel, ceruloplasmin, medication history

Etiology affects management (e.g., NAC for acetaminophen, charcoal for Amanita) and prognosis

Blood and urine cultures

Surveillance for sepsis; aggressive treatment warranted if positive


May affect management. Preparation for transplantation

Chest radiograph

Sepsis surveillance. Evaluate for ARDS and pulmonary edema

Abdominal ultrasound

Evaluate for vascular thrombosis and infection. Preparation for transplantation

Intracranial pressure

Assess ICP if stage III–IV encephalopathy present. Cerebral edema is the most common cause of death

ARDS adult respiratory distress syndrome, BUN blood urea nitrogen, CBC complete blood count, ECG electrocardiogram, ALF acute liver failure, GI gastrointestinal, ICP intracranial pressure, NAC N-acetylcysteine, PT prothrombin time

Non-hepatic Transaminitis

In the appropriate clinical setting , elevations in AST and ALT should prompt the clinician to consider rhabdomyolysis and order a creatinine kinase level. Rhabdomyolysis-induced transaminitis occurs secondary to AST (and some ALT) release from muscle breakdown. In the past, ALT was considered liver-specific, but ALT elevations may occur in patients with myopathy but no liver disease [9]. Hypoperfusion from other medical issues can lead to transaminitis as well.


The King’s College Criteria is used to determine potential for liver transplant in both acetaminophen toxicity and other causes of acute liver failure.

The King’s College Criteria for acetaminophen toxicity suggests transplant if [4, 10]:
  • pH <7.3 (irrespective of other factors)

  • Grade III–IV encephalopathy (Table 69.4) and protime >100 s and serum creatinine >3.4 mg/dL

Table 69.4

Stages of clinical hepatic encephalopathy


Level of consciousness

Neuromuscular changes

Behavioral/intellectual changes


Reversal of sleep pattern

Mild confusion

Mild asterixis

Impaired handwriting


Short-term memory lapses


Slow responses

Increasing drowsiness


Slurred speech

Inappropriate behavior

Loss of time/amnesia





Loss of continence


Marked confusion/paranoia



A: Responds to pain

B: No response to pain

Decorticate/decerebrate posturing



The King’s College Criteria for non-acetaminophen toxicity suggests transplant if [4, 10]:
  • PT >35 s

  • INR >7.7

  • Any three of the following:
    • Age <10 or >40 years old

    • Unfavorable etiology (non-A and non-B hepatitis, idiosyncratic drug reaction, halothane hepatitis, Wilson’s disease)

    • Serum bilirubin >17 mg/dL

    • Time from jaundice to encephalopathy >7 days

    • INR >4

The Acute Physiology and Chronic Health Evaluation III Score (APACHE III Score) may also identify those in need of liver transplant [11].

What Is the Management of Transaminitis and Acute Hepatic Failure?


Initial management of acute transaminitis includes fluid resuscitation, pain management, and nausea management. Generally, the cause of transaminitis will determine treatment and disposition. Transaminase values alone do not determine disposition. Admission is recommended for higher-risk (elderly and pregnant) patients or when there is no response or poor response to supportive care. It is also recommended for bilirubin ≥20 mg/dL, PT >50% above normal, hypoglycemia, spontaneous bacterial peritonitis, new or worsening hepatic encephalopathy, hepatorenal syndrome, or coagulopathy with bleeding. Additionally, the patient should be admitted if the he or she cannot ambulate safely or if there is an unsafe home condition. Any patient with acetaminophen toxicity (using the Rumack-Matthew nomogram) should be admitted, even if the transaminases and coagulation factors are normal [8].

Acute Hepatic Failure

Patients with acute liver failure should be considered for early transfer to a liver transplant center, ideally prior to intracranial pressure elevation or development of severe coagulopathy [1]. Prophylactic treatment of coagulopathy is unnecessary. Fresh frozen plasma or factor VII should be given if there is active bleeding or before invasive procedures [12]. Patients with grade IV encephalopathy generally require intubation. Providers should elevate the head of bed to 10–20 ° and consider avoiding positive end-expiratory pressure if possible (grade III recommendation) [13]. With cerebral edema, intracranial pressure monitoring and decompression may be necessary.

Antidotes and Specific Treatments

Specific antidotes exist for acetaminophen toxicity (n-acetylcysteine) and for Amanita mushroom poisoning (silibinin and intravenous penicillin G). Shock liver will improve with the restoration of perfusion. Herpes causing transaminitis can be treated with acyclovir. Acute Budd-Chiari syndrome (thrombosis of the hepatic veins) can be treated with transjugular intrahepatic portosystemic shunt (TIPS), surgical decompression, or thrombolysis. Autoimmune hepatitis can be treated with steroids. Idiosyncratic drug-induced transaminitis can be treated with withdrawal of the drug. Rechallenge of the drug should not be performed unless there is no alternate therapy [1].

Suggested Resources

  • Interpretation of liver function tests. (2013).

  • Bernal W, Wendon J. Acute liver failure. N Engl J Med. 2013;369:2525–34.

  • Farkas S, Hackl C, Schlitt HJ. Overview of the indications and contraindications for liver transplantation. Cold Spring Harb Perspect Med. 2014;4


  1. 1.
    Dalhoff K. Toxicant-induced hepatic failure. In: Brent J, et al., editors. Critical care toxicology. Cham: Springer International Publishing; 2016. p. 385–408.Google Scholar
  2. 2.
    Moore P, Burkhart K. Adverse drug reactions in the ICU. In: Brent J, et al., editors. Critical care toxicology. Cham: Springer International Publishing; 2016. p. 693–741.Google Scholar
  3. 3.
    Aghababian RV. Essentials of emergency medicine. Hepatitis. Sudbury: Jones & Bartlett Learning; 2010.Google Scholar
  4. 4.
    O’Grady JG, et al. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989;97(2):439–45.CrossRefGoogle Scholar
  5. 5.
    O'Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet. 1993;342(8866):273–5.CrossRefGoogle Scholar
  6. 6.
    Murali AR, Narayanan Menon KV (2017) Acute liver failure [cited 4 Mar 2018]; Available from:
  7. 7.
    O’Grady JG, Williams R. Management of acute liver failure. Schweiz Med Wochenschr. 1986;116(17):541–4.PubMedGoogle Scholar
  8. 8.
    Susan R, O’Mara KG. Hepatic disorders. In: Tintinalli JE, et al., editors. Tintinalli’s emergency medicine: a comprehensive study guide. New York: McGraw-Hill Education. p. 525–33.Google Scholar
  9. 9.
    Delaney KA. Hepatic principles. In: Hoffman RS, editor. Goldfrank’s toxicologic emergencies. New York: McGraw-Hill Education. p. 302–11.Google Scholar
  10. 10.
    McPhail MJ, Wendon JA, Bernal W. Meta-analysis of performance of Kings’s college hospital criteria in prediction of outcome in non-paracetamol-induced acute liver failure. J Hepatol. 2010;53(3):492–9.CrossRefGoogle Scholar
  11. 11.
    Fikatas P, et al. APACHE III score is superior to King's college hospital criteria, MELD score and APACHE II score to predict outcomes after liver transplantation for acute liver failure. Transplant Proc. 2013;45(6):2295–301.CrossRefGoogle Scholar
  12. 12.
    Shami VM, et al. Recombinant activated factor VII for coagulopathy in fulminant hepatic failure compared with conventional therapy. Liver Transpl. 2003;9(2):138–43.CrossRefGoogle Scholar
  13. 13.
    Muñoz SJ. Difficult management problems in fulminant hepatic failure. In:Seminars in liver disease. New York: Thieme Medical Publishers; 1993.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Section of Toxicology, Department of Emergency MedicineWellSpan Health, York HospitalYorkUSA

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