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Acute Liver Injury and Failure

Wrinn Alexander

Background

  • Acute liver injury (ALI): elevated liver enzymes + INR ≥1.5 without encephalopathy
  • Acute liver failure (ALF): elevated liver enzymes + encephalopathy (any degree of AMS or asterixis) in the absence of pre-existing liver disease*
    • *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
    • Hyperacute (< 7 d): most often seen with acetaminophen toxicity, Hepatitis A & E, Ischemic; high risk for cerebral edema
    • Acute (7-21 d): Hepatitis B
    • Subacute (> 21 d and < 26 wk): most often non-acetaminophen DILI
  • Alcohol-associated hepatitis (AH) is not ALF (see above)
  • Duration of <26 weeks is a commonly used cut-off

Etiology

  • 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

EBV, CMV, HSV, VZV

 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: https://www.livertox.nih.gov
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

Evaluation

  • Neurologic Exam:
    • See Hepatic Encephalopathy section for grading of HE based on PE/Hx
      • Grade I and II HE: cerebral edema uncommon
      • Grade III HE: Cerebral Edema in 25-35% of patients
      • Grade IV HE: Cerebral Edema in 75% of patients
    • Signs of increased intracranial pressure:
      • Pupillary changes, Cushing’s triad (HTN, bradycardia, respiratory depression, seizures, increased muscle tone and hyperreflexia, abnormal brainstem reflexes
  • Consult hepatology once you suspect ALF! (to assist with workup AND for transplant evaluation)

  • Labs:

    • CBC w/diff, CMP, Dbili, Mg, Phos, T&S, BCx, UCx, PT/INR, aPTT, fibrinogen
    • Ferritin, Iron, transferrin (HFE gene mutation testing if Tsat ≥45% and/or elevated ferritin) o Amylase, lipase
    • Beta-hCG for females of childbearing age; UA to assess for proteinuria if pregnant
    • 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: Viral 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 sent 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, anti-liver/kidney microsomal antibody type 1, anti-liver soluble antigen, alpha-1 antitrypsin
    • *You may not order all the workup included above; hepatology will guide you on what exactly will need to be ordered.

  • 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
    • Consider CTH or MRI to assess for cerebral edema (findings include decrease in ventricular size, flattening of cerebral convolutions, reduction in signal intensity of brain parenchyma)
    • Consider ERCP/MRCP for cholestatic etiologies

  • Discuss possible liver biopsy if etiology unclear

    • Transjugular approach preferred with clinically demonstrable ascites; a known or suspected hemostatic defect; a small, hard, cirrhotic liver; morbid obesity with a difficult- to-identify flank site; or those in whom free and wedged hepatic vein pressure measurements are additionally being sought.

Management

  • 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
    • Early hepatology consult for liver transplant evaluation and assistance in management
    • 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: Rule out infection with CXR, Blood cultures, UA/UCx for every ALF. Antibiotics only if progressing HE, signs of infection, or development of SIRS
    • Cerebral edema/increased ICP:
      • No role for lactulose in the setting of acute liver failure
      • Grade III-IV hepatic encephalopathy: elevated HOB to 30 degrees, quiet and dimly lit room, should be intubated, avoid sedating medications as feasible, and ICP monitor are recommended (if not feasible, hourly neuro checks can be an alternative). If ICP becomes elevated start targeted therapies to reduce intracranial pressure.
      • Mannitol or hypertonic saline should be administered for surges of ICP with consideration for short-term hyperventilation
      • If high ICP is refractory to osmotic agents, consider phenobarbital, indomethacin, and/or cooling to 33-34 degrees Celsius if awaiting LT
    • Seizures: phenytoin (no evidence to support seizure ppx), short acting benzodiazepines if refractory
    • Renal Failure: early CRRT if persistent Metabolic Acidosis, Volume Overload, Hyperammonemia, falling UOP
    • Coagulopathy: IV Vit K (at least one dose) routinely to rule out Vit K deficiency, products for invasive procedures or active bleeding only
      • If trying to differentiate from DIC, can order Factor VIII level (should be normal/high in ALF; low in DIC)
  • Metabolic: Correction of hypoglycemia (continuous D20) and electrolyte abnormalities
  • Circulatory dysfunction/shock: Goal MAP >75 mmHg. Ensure intravascularly replete, add norepinephrine first line, vasopressin can be used second line but may increase ICP. Consider stress dose steroids for refractory shock
  • Additional Supportive Care
    • PPI for bleeding ppx
    • Enteral nutrition EARLY; avoid TPN if possible
    • 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

Criteria for Transplantation:

  • King’s College criteria: helps identify patients needing transplant referral/consideration
  • A) 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, and SCr >3.4, and INR >6.5 all within 24h period
  • B) ALF not due to acetaminophen: INR > 6.5 OR 3 of the 5 following criteria:
    • Etiology: Indeterminate etiology, idiosyncratic drug- induced hepatitis
    • Age <10 or >40
    • Interval of jaundice to onset of encephalopathy >7 days
    • Bilirubin > 17.5mg/dl (300mmol/L)
    • INR >3.5
  • Other predictors of poor prognosis in absence of transplant:
    • Hyperlactatemia: lactate >3.5 after 4 hours of IVF or >3 after 12 hours IVF
    • Hyperphosphatemia: Phosphate >3.75 at 48-96 hours