04. Acute Liver Failure

Definition

  • Triad of abnormal liver tests + encephalopathy + coagulopathy (INR>1.5) in a patient without known liver disease, with onset of symptoms occurring within 26 weeks.
  • No pre-existing cirrhosis.
  • If no encephalopathy, then termed acute liver injury.

Etiology/Risk Factors

  • Etiologies include:
    • Drugs/toxin: acetaminophen (causes >40% in USA), Amanita mushrooms, antibiotics, antiepileptics, herbs/OTC, CCl­4, fluorinated hydrocarbons, isoniazid.
    • Viral: HBV, HAV, HEV; rarely EBV, CMV, HSV, VZV. Hepatitis C does not result in acute liver failure (although it does cause acute liver injury).
    • Autoimmune hepatitis: usually initial presentation, more common in women.
    • Vascular: Budd-Chiari, ischemic hepatitis, hypotension (not always documented), other venoocclusive disease.
    • Wilsons disease: associated with renal failure, psychiatric co-morbidities, hemolysis.
    • Acute fatty liver of pregnancy/HELLP: usually in late pregnancy.
    • Malignancy: tumor infiltration.
    • Idiopathic.
  • The following are NOT causes of ALF but may increase risk: alcohol, malnutrition, underlying chronic liver disease (e.g., chronic hepatitis C, iron overload/hemochromatosis, fatty liver disease, alpha-1-antitrypsin deficiency, PBC, PSC).
  • Prognosis: high mortality without transplant. Most important factor for prognosis is etiology.
    • Better prognosis: acetaminophen, hepatitis A, AFLP, ischemia. If time from symptoms to encephalopathy is less than 7 days, almost always related to acetaminophen.
    • Bad prognosis: Wilson’s disease, drugs other than acetaminophen, autoimmune, HBV, idiopathic.
    • When compared to those transplanted for chronic liver disease, patients transplanted for ALF have increased mortality after 1 year but do better in the long term.
    • Degree of encephalopathy is most predictive of spontaneous recovery. Grade I to II – 65 to 70 percent, Grade III – 40 to 50 percent, Grade IV – <20 percent.

Diagnostics

Broad diagnostic workup targeting the most likely etiologies: 

  • Drug/toxin: acetaminophen level, urine and serum tox screen. 1 year medication/toxin/ingestion history including OTC, supplements, herbals, wild mushrooms, weight loss drugs.
  • Viral: HAV IgM, HBsAg, HBcAb, HBV DNA, HCV Ab, HCV RNA. Also consider: Hep E IgM, HSV DNA, EBV DNA, CMV DNA, VZV DNA, Anti HDV (only in known/suspected HBV). 
  • Autoimmune: ANA, anti-smooth muscle/anti actin antibody, IgG levels.
  • Vascular: abdominal ultrasound with Doppler. Also consider: CT/MRI, hypercoagulability workup, IR consult, TTE/EKG.
  • Wilson’s: ceruloplasmin. Often associated with low alk phos and a bilirubin/alk phos ratio of >2 and hemolytic anemia. Also consider: 24h urine copper, slit lamp eval for KF rings, liver copper levels if biopsy.
  • AFLP/HELLP: HCG, OB-GYN consult.
             
    Malignancy: abdominal ultrasound, CT, liver biopsy.
  • Idiopathic: liver biopsy.

Management

  • If suspect ALF, IMMEDIATELY contact liver transplant team.
  • Consider ICU-level care for neurologic monitoring, hemodynamic and ventilator support, and renal replacement therapy with CVVH. Management centers on supportive care particularly to reduce cerebral edema and infections (the two most common immediate causes of death in ALF patients), with preparation for liver transplantation if necessary.
  • Start NAC in all patients with acute liver injury and coagulopathy regardless of etiology, and in every patient with APAP-induced acute liver injury regardless of degree of encephalopathy. Increases transplant-free survival especially in grade 1-2 encephalopathy.
  • Initiate specific treatment if specific cause is known or highly suspected (i.e., initiate therapy while work-up pending and then stop if testing is negative -- see table).
  • Intracranial hypertension: pathogenesis unclear, thought to be due to systemic/local inflammation leading to “leaky” blood-brain barrier, circulating neurotoxins (ammonia), hyponatremia decreasing oncotic pressure. Cerebral uncal herniation is the cause of death in many patients with ALF.
  • King’s College Criteria: can be used to determine likelihood of transplant-free survival. Takes into account age, cause, encephalopathy, coagulopathy. Degree of encephalopathy is most predictive of spontaneous recovery. Grade I to II – 65 to 70 percent, Grade III – 40 to 50 percent, Grade IV – <20 percent.
  • ALFSG Prognostic Score: uses encephalopathy severity, etiology, vasopressor use, bilirubin, and INR to predict transplant-free survival at 21 days.
  • Refer to the ALF checklist (alfchecklist.com or app available) for a detailed guide to management.

General Management Strategies in all Patients with Acute Liver Failure

System

Pathophysiology

Management

Neurologic
  • Cerebral edema with elevated intracranial pressure, risk of herniation. Common cause of death in ALF
  • Intracranial hemorrhage secondary to coagulopathy
  • Progressive encephalopathy

 

Hepatic Encephalopathy

Grade I: mild confusion, euphoria, slurred speech, sleep disturbance. May or may not have asterixis

Grade II: lethargy, moderate confusion, asterixis present

Grade III: marked confusion, incoherent, sleepy but arousable, asterixis present

Grade IV: coma, no asterixis

In all patients:

  • Check serum ammonia level upon admission (>200 increases likelihood of intracranial hypertension)
  • Frequent neuro checks
  • Hypertonic saline as needed for goal sodium >145 mmol/L (esp if high risk for increase ICP – renal failure, pressors, ammonia >150)
  • Prevent hyperthermia  
  • Do not warm patient if hypothermic
  • Elevate bed to 30 degrees
  • Minimize excess IV fluid administration

 

If altered:

  • Lactulose is not very helpful in ALF, may be used in early encephalopathy but avoid diarrhea
  • CT to evaluate degree of cerebral edema and to rule out intracranial hemorrhage
  • Intubate if grade III-IV encephalopathy. No specific ventilatory strategy recommended, but can try to keep PEEP low (can increase ICP) & allow hyperventilation (can decrease ICP)
  • Avoid sedatives unless required to control seizure activity. Steroids not useful in ALF even if ICP elevated
  • Mannitol 0.5-1.0 g/kg Q6H if documented or high concern for increased ICP
  • Goal ICP <25 mmHg, CPP 50-80 mmHg (although ICP monitoring is no longer commonly used). Use systemic MAP >75 as a surrogate
  • Can consider hypothermia or barbiturates if ICP intractable

CV

Splanchnic vasodilation causes a low SVR
  • MAP goal generally >75
  • Liberal use of vasopressors (norepinephrine, inotropy if needed)
    • Adding vasopressin to norepi is still recommended but controversial since some studies have shown increases in ICP
  • Replete intravascular volume with IV fluids but avoid excess IVF for resuscitation once euvolemic (can increase ICP)

GI
  • Malnutrition associated with worse outcomes
  • GIB most common site of hemorrhage
  • Early enteral nutrition
  • PPI for stress ulcer prophylaxis
  • Liver transplant evaluation

Metabolic/Renal
  • Hypoglycemia (from liver failure)
  • Hypophosphatemia (from rapid liver regeneration)
  • Hypokalemia (from high sympathetic tone)
  • Hyponatremia (from renal dysfunction/increased ADH)
  • Lactic acidosis (from liver necrosis)
  • Frequent glucose checks. Start dextrose drip if glucose <80
  • Aggressive phosphorus and potassium repletion (note: hypokalemia can lead to increased ammonia levels)
  • Hypertonic saline as needed for goal Na >145 (see “Neurologic”)
  • Avoid nephrotoxic drugs and IV contrast
  • Consider renal consult/early RRT if 1) oliguric, 2) new AKI, 3) serum ammonia >150 (somewhat dialyzable), 4) volume overload and 5) known or suspected increased ICP (if HE grade 3/4)
    • CVVH has better outcomes than iHD even if hemodynamically stable

Hematologic
  • Coagulopathy from acute liver failure
  • DIC

All patients:

  • High risk for DVT-- use lower extremity sequential compression device
  • Avoid anti-platelet agents. Continuation of prior anticoagulation is case by case but unless high thrombotic risk it is generally held
  • Frequent monitoring of INR, fibrinogen and CBC. In the absence of bleeding transfuse for plt <10, fibrinogen <100. Do not correct INR with FFP but can give Vitamin K—discuss with LTU

If bleeding:

  • Transfuse platelets to >50K and fibrinogen to >100 with cryoprecipitate. Can also correct INR with FFP

If procedure:

  • Typically, INR does not predict bleeding risk. It may not be necessary to correct even for invasive procedures, but the risks/benefits of correction need to be discussed with proceduralist. FFP unlikely to correct INR under 1.7
  • Platelets and fibrinogen likely predict bleeding risk and should be corrected for invasive procedures. Discuss goals with proceduralist but generally at least plt >50K and fibrinogen >100

Immunologic/Infectious
  • High risk of sepsis – clinical signs often absent. Common cause of death in ALF.
  • High risk of fungal infections, esp if prolonged hospitalization, immunocompromised, recent steroids or antibiotics, or on CRRT
  • Pan culture with surveillance cultures Q24-48h (blood, sputum, urine)
  • Antibiotic prophylaxis not generally recommended if no evidence of infection and cultures negative
  • Guide antibiotic choice by symptoms and culture results
  • Consider IV broad spectrum antibiotics & antifungal coverage if 1) critically ill, 2) deteriorating, 3) progressive encephalopathy, or 4) listed for transplant

 

Etiology Specific Management

Etiology

Management

Drug/Toxin
  • Acetaminophen: activated charcoal if ingestion within 4 hours, NAC, APAP levels q1-2 hours until peak
  • Amanita mushroom: toxicology consult; activated charcoal, NAC, silibinin*, penicillin G if silibinin not available
  • Drug induced liver injury: NAC, discontinue all non-essential medications

Viral
  • HBV: entecavir or tenofovir
  • HSV/VZV: acyclovir

Autoimmune
  • Corticosteroids (at least prednisone 40-60 mg daily)

Vascular
  • Budd Chiari: anticoagulation, IR TIPS procedure, also consider thrombolysis and surgical decompression
  • “Shock liver”: avoid hypotension

Wilson’s
  • Liver transplantation
  • Chelation with trientine
  • Consider plasmapheresis, early CRRT, exchange transfusion

AFLP/HELLP
  • Early delivery

*Not FDA approved

Key Points

  • The patient should be evaluated by a liver transplant team as early as possible. If not at a transplant center, discuss the patient with a liver transplant center and consider early transfer before progression to stage III/IV encephalopathy.  
  • Often critically ill requiring ICU level care and monitoring.
  • Start NAC in all patients and follow both etiology-specific and general management principles.
  • High risk for cerebral edema and herniation.

 

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