Acute Liver Injury and Failure

Background

• Acute liver injury (ALI): elevated liver enzymes + INR ≥1.5 without encephalopathy 
• Tylenol accounts for most of the cases with most patients achieving full recovery

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: review patient’s med list with NIH Liver Tox Database, paying close attention to recently started medications or any antibiotics they recently received

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

*May present with chronic liver injury as well; $May present with AST/ALT >100

Cholestatic Injury: R Factor < 2 (Primarily elevated Alkaline phosphatase)

*May present with chronic liver injury as well; $May present with AST/ALT >100

Prognostication

• King’s College Criteria (KCC) and Model for End Stage Liver Disease (MELD) scores help prognosticate ALI and guide transplant decisions 
• KCC used in acetaminophen-induced ALI and MELD used in non-acetaminophen induced ALI 
• Development of encephalopathy should trigger ICU level care as it is progression to acute liver failure

Acute Liver Failure

• Acute liver failure (ALF): elevated liver enzymes + encephalopathy (any degree of AMS or asterixis) in the absence of pre-existing liver disease* + <26 weeks duration 
• 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) 
  • (*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)

Evaluation

• As HE Grade increases, the risk of cerebral edema increases 
• Signs of increased intracranial pressure: Pupillary changes, Cushing’s triad (HTN, bradycardia, respiratory depression, seizures, increased muscle tone and hyperreflexia, abnormal brainstem reflexes 
• 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) 
  • 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 1/2, 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 U/S 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 assess for cardiac dysfunction and aid in transplantation consideration 
  • Consider CTH or MRI to assess for cerebral edema 
  • 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 (for q1h monitoring even if mild change in mental status given high-risk for neurological decline with cerebral edema and they die acutely from hypoglycemia, cerebral edema, and infection) 
• Monitoring: Q1-2h neuro checks, Q1-2h glucose checks 
• Closely monitor CMP, Magnesium, phosphorus, INR q6-8 hrs

Treatment of Primary Injury

• Early hepatology consult for liver transplant evaluation and assistance in management 
• IV N-acetylcysteine: May improve transplant-free survival even in patients WITHOUT nonacetaminophen drug induced acute liver failure 
• Initial loading dose = 150mg/kg over 1 hour, then 12.5mg/kg/hr for 4 hours for second phase, then 6.25mg/kg/hr for 72-hour portocol for maintenance

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: consult neurology; phenytoin (no evidence to support seizure ppx), short acting benzodiazepines if refractory 
• Renal Failure: early CRRT if persistent metabolic acidosis, volume overload, 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-Mattew Nomogram and consult with toxicology 
  • In Epic: search “N-acetylcysteine” and select order set “Acetaminophen overdose” 
• 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, consider administering prophylactically until excluded based on lab work

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