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Acute Liver Injury and Failure

Hannah Lomzenski, and Lauren Chan


  • Acute liver injury (ALI): elevated liver enzymes + INR ≥1.5 but NO encephalopathy

  • Acute liver failure (ALF): elevated liver enzymes + encephalopathy/AMS in the absence of pre-existing liver disease*

    • *Chronic autoimmune hepatitis, HBV, Wilson disease, and Budd-Chiari syndrome can have ALF if they develop new AMS, despite the presence of a pre-existing liver disease
  • Alcohol-associated hepatitis (AH) is not ALF (see above)


  • R-factor (if history, exam, and diagnostic data are inconclusive i.e. R-factor is not a replacement to clinical judgement) = (ALT/uln ALT) / (ALP/uln ALP); See chart below

    • R > 5 = hepatocellular injury; R<2 = cholestatic injury; R 2-5 = mixed injury
  • Isolated hyperbilirubinemia: Differentiate direct versus indirect

    • Direct: Refer to cholestatic pattern
    • Indirect: Gilbert vs hemolysis
  • Drugs Associated with liver injury

    • Hepatocellular pattern: acarbose, Acetaminophen, Allopurinol, Amiodarone, Baclofen, Bupropion, Fluoxetine, HAART (Nevirapine), Kava kava, Isoniazid, Ketoconazole, Lisinopril, Losartan, Methotrexate, NSAIDs, Omeprazole, Oxacillin/Nafcillin, Paroxetine, Pyrazinamide, Propylthiouracil, Rifampin, Risperidone, Sertraline, Statins, Tetracycline, Trazodone, Valproic Acid

    • Mixed pattern: Amitriptyline, Azathioprine, Captopril, Carbamazepine, Clindamycin, Cyproheptadine, Enalapril, Flutemide, Nitrofurantoin, Phenobarbital, Phenytoin, Sulfonamides, Trazodone, Verapamil

    • Cholestatic pattern: Amoxicillin-clavulanic acid, Anabolic steroids, Chlorpromazine, Clopidogrel, Oral contraceptives, Erythromycins, Estrogens, Irbesartan, Mirtazapine, Phenothiazines, Terbinafine, Tricyclics

Hepatocellular Injury: R factor > 5 (Primary elevation of AST/ALT)
Acetaminophen intoxication$

Acetaminophen lvl

Aspirin lvl

Acute Viral Hepatitis

Hep A$, B*$, C*, D, E


Viral serologies (see below), hx of tattoos, IVDU, piercings, blood transfusion prior to 1990s, intranasal cocaine use and mass vaccinations (in 3rd world countries)
Autoimmune hepatitis\* Autoantibodies and high serum globulins Anti-smooth muscle (f-actin), ANA, ANCA, anti-liver kidney microsome (anti-LKM-1), anti-soluble liver antigen/liver-pancreas IgG
Budd-Chiari Syndrome\* Hepatic vein obstruction Ultrasound of abdomen w/ doppler, CT w/ contrast
DILI – Drug Induced Liver Injury\*$ Many drugs See above
\*Query NIH Liver Tox database:
HELLP Syndrome, Acute Fatty Liver of Pregnancy Pregnancy Requires urgent delivery regardless of gestational age
Ischemic Liver Injury (Shock Liver)$ Shock (can be of any variety) AST and ALT can be in the thousands, high LDH, history of hypotension
Toxins Ethanol, cocaine, mushroom (Amanita phalloides) UDS, ethanol level, PEth lvl
Wilson’s Disease\* Copper overload Ceruloplasmin level (screening), 24h urine copper (confirmation), quantitative copper on liver biopsy
\*May present with chronic liver injury as well; $May present with AST/ALT >100
Cholestatic Injury: R Factor \< 2 (Primarily elevated Alkaline phosphatase)
Acute biliary obstruction Gallstones Abdominal ultrasound, MRCP, ERCP
DILI – Drug-induced liver injury*$ Many drugs, consult livertox website Common: Augmentin, Bactrim, amiodarone, Imuran
Malignancy* Pancreas, cholangiocarcinoma CT abdomen, ERCP
Primary Biliary Cirrhosis* Autoimmune Anti-mitochondrial antibody
Primary Sclerosing Cholangitis* Autoimmune, associated with IBD MRCP, ERCP
Critical illness or COVID cholangiopathy Hypotension, COVID MRCP with biliary stenosis, appropriate history
*May present with chronic liver injury as well; $May present with AST/ALT >100


  • Consult hepatology early! (to assist with workup AND for transplant evaluation)
  • Labs:

    • CBC w/diff, CMP, Dbili, Mg, Phos, T&S, BCx, UCx, PT/INR, aPTT, fibrinogen
    • Amylase, lipase
    • Beta-hCG for females of reproductive age
    • ABG with arterial lactate, ammonia (arterial >124 predicts mortality and CNS complications e.g. need for intubation, seizures, cerebral edema, <75 very unlikely to develop ICH)
    • Viral etiologies: Virtal hepatitis serologies (HAV panel, HBV panel, HCV IgG ± PCR quant, HDV if known HBV (with low or undetectable HBV load as Misc Reference Test, Hepatitis E PCR ent as miscellaneous if pregnant or travel to southeast Asia), HIV p24 Ag and HIV Ab, EBV Qt, CMV Qt, HSV ½ Qt, VZV IgM/IgG
    • Toxins: UDS, ethanol level ± Peth, acetaminophen level (drawn > 4 hours after last known ingestion), Salicylate level
    • Autoimmune / genetic: ANA, ASMA, IgG, AMA (if predominantly elevated ALP), ceruloplasmin
  • Imaging:

    • RUQ abdominal ultrasound with doppler (important to assess vasculature!)
    • Consider CT with contrast in patients with normal renal function and high suspicion of Budd-Chiari syndrome or malignancy with negative ultrasound  (better for assessing the hepatic veins) and helps with transplant evaluation
    • Consider TTE to rule out cardiac dysfunction; helpful for transplant consideration

Criteria for Transplantation:

  • King’s College criteria: helps identify patients needing transplant referral/consideration
    • ALF due to acetaminophen:
      • Arterial pH \<7.3 after resuscitation and >24 hr since ingestion, OR
      • Arterial Lactate >3 after adequate fluid resuscitation, OR
      • Grade III-IV HE, SCr >3.4, and INR >6.5 all within 24h period
  • ALF not due to acetaminophen: INR > 6.5 OR 3 of the 5 following criteria:
    • Indeterminate etiology, drug-induced hepatitis
    • Age \<10 or >40
    • Interval of jaundice to encephalopathy >7 days
    • Bilirubin > 17.5 mg/dl (300 micromol/L)
    • INR >3.5


  • Any pt with concern for ALF should be cared for in MICU (even if mild change in mental status)
  • Pts with ALF die acutely from hypoglycemia, cerebral edema, and infection
  • ABC’s:
    • Intubate for GCS \<8, Grade 3 or 4 HE
    • IVF resuscitation with isotonic crystalloid (most pts are volume deplete; avoid hypotonic fluids due to risk of cerebral edema)
    • Vasopressive agents for persistent hypotension (norepinephrine preferred)
  • Monitoring:
    • Q1-2h neuro checks, Q1-2h glucose checks
    • Closely monitor CMP, INR q6-8 hrs
  • Treatment of Primary Injury
    • IV N-acetylcysteine - improves transplant-free survival even in patients WITHOUT acetaminophen induced acute liver failure
      • Initial loading dose = 150mg/kg over 1 hour, then 50mg/kg/hr for 4 hours, then 100mg/kg/hr for 16 hours ​​​​​​​
      • Patients with early stage hepatic encephalopathy (grade I/II) have increased transplant free survival, while those with grade III/IV do not
    • See below for etiology-specific treatment; hepatology consult for LT eval
    • Early toxicology consultation if suspected ingestion/overdose
      • For acute management contact Poison Control 800-222-1222
  • Treatment of Secondary Complications
    • Infection: abx only if progressing HE, signs of infection, or development of SIRS; ppx abx do not reduce mortality
    • Cerebral edema/increased ICP:  elevated HOB to 30 degrees, quiet and dimly lit room, minimize IVF, goal Na 145-155, hyperventilation if concern for impending herniation. Consider 3% saline (500mL) and/or mannitol (1g/kg, 20%) for pt at highest risk (serum ammonia >150, grade III/IV HE, ARF, vasopressor support
    • Seizures: phenytoin (no evidence to support seizure ppx)
    • Renal Failure: early CRRT if persistent Metabolic Acidosis, Volume Overload, Hyperammonemia, falling UOP
    • Coagulopathy: IV Vit K; products for invasive procedures or active bleeding only
  • Additional Supportive Care
    • PPI for bleeding ppx
    • Enteral nutrition within 2-3 days; avoid TPN if possible; avoid NG feeds if progressive HE; NG should only be placed w/ intubation as gagging increases ICP
    • Prefer propofol for sedation for better neuro exams and may reduce cerebral blood flow

Specific Management by Etiology:

  • Acetaminophen
    • Early toxicology consultation if suspected ingestion/overdose
    • For acute management contact Poison Control 800-222-1222
    • Activated charcoal within 4 hours of ingestion, most effective within 1 hour
    • IV N-acetylcysteine per protocol, look up Rumack-Matthew Nomogram and consult with toxicology
      • In Epic: search “N-acetylcysteine” and select order set “Acetaminophen overdose”
  • AFLP/HELLP – delivery

  • Amanita phalloides – IV fluid resuscitation, PO charcoal, IV penicillin, IV acetylcysteine

  • Autoimmune – IV steroids following approval by hepatology (and typically post biopsy). Azathioprine generally deferred until cholestasis resolved (Mycophenolate can be used instead)

  • Budd-Chiari – anticoagulation, IR-guided endovascular therapy, transplant (must rule out underlying malignancy and evaluate for thrombotic disorders)

  • HAV/HEV – supportive care, consider ribavirin for ALF due to HEV

  • HBV – nucleos(t)ide analogue; orthotopic liver transplant

  • HSV – acyclovir

Last update: 2022-06-21 11:43:15