Acute Liver Failure
Coagulopathy (INR ≥1.5) + hepatic encephalopathy + no prior liver disease + illness <26 weeks. NAC improves transplant-free survival even in non-acetaminophen ALF. Contact transplant center EARLY. Do NOT correct INR prophylactically.
🔍 Overview
Definition
Acute liver failure (ALF) is defined by the triad: (1) Coagulopathy (INR ≥1.5), (2) Hepatic encephalopathy (any grade), and (3) No prior liver disease, with illness duration <26 weeks. It is a medical emergency with mortality >50% without transplant in many etiologies.
Causes
- Acetaminophen (acetaminophen), #1 cause in US/UK. Best prognosis of all causes. Often unintentional (supratherapeutic dosing).
- Viral hepatitis, HAV, HBV (most common worldwide), HEV (especially in pregnancy)
- Autoimmune hepatitis, can present fulminantly
- Wilson disease, suspect in young patients with Coombs-negative hemolytic anemia + ALF
- Budd-Chiari syndrome, hepatic vein thrombosis
- Drug-induced, isoniazid, phenytoin, statins, herbal supplements, anti-TB drugs
- Pregnancy-related, HELLP syndrome, acute fatty liver of pregnancy (AFLP)
- Ischemic hepatitis, "shock liver" from hypoperfusion
- Mushroom poisoning, Amanita phalloides (death cap)
- Indeterminate, ~20% remain without identified cause
Classification by Onset
- Hyperacute: 0-7 days (acetaminophen, ischemic). Often better prognosis with higher chance of spontaneous recovery.
- Acute: 8-28 days
- Subacute: 29 days to 26 weeks (worst prognosis, less cerebral edema but more portal hypertension)
🚨 Management
Immediate Management
Give NAC to ALL acute liver failure, not just acetaminophen. Lee, Gastroenterology 2009 showed improved transplant-free survival in non-acetaminophen ALF (Grades I-II HE).
- N-acetylcysteine (NAC), IV protocol: 150 mg/kg over 1h, then 50 mg/kg over 4h, then 100 mg/kg over 16h. Continue until INR <1.5 or transplant.
- ICU admission, all ALF patients need ICU-level monitoring.
- Contact transplant center EARLY, do not wait for deterioration. Transfer may become impossible once cerebral edema develops.
- Intubate for Grade III-IV encephalopathy, airway protection. Avoid propofol if hemodynamically unstable.
🔄 Updated Practice: Old teaching: N-acetylcysteine (NAC) only for acetaminophen overdose. Current practice: NAC improves transplant-free survival in ALL causes of acute liver failure, not just acetaminophen (Lee, Gastroenterology 2009). The benefit is greatest in early hepatic encephalopathy (grades I-II). Give NAC to every ALF patient regardless of etiology, there is no reason to withhold it.
Do NOT correct INR prophylactically. INR is your prognostic marker. Only give FFP/PCC if actively bleeding. Correcting INR blinds you to the trajectory and removes your ability to assess for improvement or need for transplant.
King's College Criteria (Transplant Listing)
Acetaminophen ALF
- pH <7.3 after resuscitation, OR
- All three: INR >6.5 + Creatinine >3.4 mg/dL + Grade III-IV HE
Non-Acetaminophen ALF
- INR >6.5 alone, OR
- Any 3 of: age <10 or >40, non-A/non-B hepatitis or drug etiology, jaundice >7 days before HE onset, INR >3.5, bilirubin >17.5 mg/dL
Complications Management
- Cerebral edema: Elevate HOB to 30°. Mannitol 0.5-1 g/kg IV (if serum osm <320) or hypertonic saline (23.4%) for acute herniation. Avoid hyperthermia. Target Na 145-155 mEq/L with hypertonic saline prophylaxis.
- Hypoglycemia: D10 continuous drip. Check glucose q1-2h. Common and life-threatening (failed hepatic gluconeogenesis).
- Coagulopathy: Only treat if actively bleeding. Paradoxically balanced hemostasis (low pro- and anti-coagulant factors). Routine FFP is harmful.
- Infection: Low threshold for empiric antibiotics. Surveillance cultures daily. Up to 80% develop bacterial infection, 30% fungal.
- AKI: Common (50-70%). Avoid nephrotoxins. CRRT preferred over intermittent HD (less hemodynamic instability, better ICP control).
🧪 Workup
Diagnostic Workup, Find the Cause
Etiology-specific workup should be sent simultaneously on arrival:
- Acetaminophen level, check even if not suspected (unintentional overdose is common)
- Viral serologies: HAV IgM, HBsAg, HBc IgM, HCV RNA (not just anti-HCV), HEV IgM (if pregnant or endemic area)
- Autoimmune: ANA, anti-smooth muscle antibody (ASMA), IgG levels
- Wilson disease: Ceruloplasmin (low), 24h urine copper, slit-lamp exam (Kayser-Fleischer rings). Alkaline phosphatase:bilirubin ratio <4 + AST:ALT ratio >2.2 suggests Wilson.
- Budd-Chiari: Doppler ultrasound of hepatic veins
- Pregnancy test, HELLP, AFLP
- Drug screen / toxicology, urine drug screen, medication reconciliation
- HSV, HSV PCR if immunocompromised or unexplained (consider empiric acyclovir)
Baseline Labs
- CBC, CMP (LFTs, BMP), coags (INR, PT, fibrinogen), lactate, ammonia level, lipase
- ABG (acid-base status), phosphate (prognostic, rising phosphate in acetaminophen ALF = failure to regenerate)
- Blood type and screen (anticipate possible transplant)
💊 Medications
Medications
| Drug | Indication | Dose | Notes |
|---|---|---|---|
| N-acetylcysteine (NAC) | ALL ALF, first-line | 150 mg/kg IV over 1h → 50 mg/kg over 4h → 100 mg/kg over 16h | Continue until INR <1.5 or transplant. Improves transplant-free survival even in NON-acetaminophen ALF. Lee, Gastroenterology 2009 |
| Mannitol 20% | Cerebral edema / herniation | 0.5-1 g/kg IV bolus | Use if serum osm <320. Can repeat x1. Monitor serum osmolality. |
| Hypertonic saline (3% or 23.4%) | Cerebral edema prophylaxis | 3% NaCl infusion targeting Na 145-155 | Prophylactic hypernatremia reduces cerebral edema incidence. 23.4% (30 mL) for acute herniation. |
| Dextrose 10% (D10) | Hypoglycemia prevention | Continuous drip at 75-100 mL/h | Check glucose q1-2h. Hepatic gluconeogenesis fails, hypoglycemia is common and dangerous. |
| Lactulose | Hepatic encephalopathy | 30 mL PO/NG q2h titrated to 3-4 BMs/day | Role in ALF is less established than in cirrhotic HE, but often given. Avoid excessive diarrhea (volume depletion). |
| Piperacillin-tazobactam | Empiric antibiotics | 4.5 g IV q6h | Low threshold. Infection in up to 80%. Fungal prophylaxis (fluconazole) may be warranted. |
🏥 Rounds
Pimp Questions
❓ Why do we give NAC in non-acetaminophen acute liver failure?
The Lee 2009 study showed that IV NAC improved transplant-free survival in non-acetaminophen ALF, specifically in patients with Grade I-II encephalopathy (52% vs 30% survival). Mechanism likely relates to antioxidant properties and improved hepatic microcirculation.
❓ Why should you NOT correct INR prophylactically in ALF?
INR is your single best prognostic marker in ALF. Giving FFP/PCC masks the trajectory, you cannot tell if the liver is recovering or worsening. Paradoxically, ALF patients have balanced hemostasis (both pro- and anti-coagulant factors are reduced). They are NOT at increased bleeding risk despite high INR. Only give blood products if actively bleeding or before an invasive procedure.
❓ How do you suspect Wilson disease in ALF?
Young patient (<40) + ALF + Coombs-negative hemolytic anemia + very low alkaline phosphatase (AP:bilirubin ratio <4) + AST:ALT ratio >2.2 + low ceruloplasmin. Wilson ALF has a near-100% mortality without transplant, list immediately.
Clinical Examples
📋 Case 1, Acetaminophen-Induced ALF
Patient: 28F presents with 5 days of nausea, vomiting, and jaundice. Reports taking "extra-strength Tylenol" ~4-6 g/day for 10 days for back pain. No prior liver disease.
Key findings: HR 110, BP 95/60, confused with asterixis (Grade II HE). ALT 8,400, AST 10,200, total bilirubin 8.5, INR 4.8, Cr 2.1, pH 7.28, lactate 6.2, acetaminophen level 45 mcg/mL.
Management:
- IV NAC immediately (150 mg/kg over 1h, then 50 mg/kg over 4h, then 100 mg/kg over 16h). Continue until INR < 2 and improving
- Do NOT correct INR prophylactically -- it is the best prognostic marker. Only give FFP/PCC if actively bleeding
- Apply King's College Criteria serially: pH < 7.3 after resuscitation = list for transplant
- ICU admission. Monitor glucose q1-2h (hepatic gluconeogenesis fails). For cerebral edema: hypertonic saline, target Na 145-155
Teaching point: Acetaminophen ALF has the best prognosis if treated promptly with NAC. Unintentional supratherapeutic dosing is more common than intentional overdose. Never correct INR prophylactically -- it masks prognosis.
📋 Case 2, Non-Acetaminophen ALF (Autoimmune Hepatitis)
Patient: 35F with no prior history, presents with 2 weeks of fatigue, jaundice, and dark urine. Now confused and unable to follow commands. PMH: Hashimoto thyroiditis.
Key findings: Jaundiced, Grade III HE. ALT 2,100, AST 1,800, total bilirubin 22, INR 3.6, IgG 3,200 (markedly elevated), ANA 1:640, anti-smooth muscle antibody positive. Viral hepatitis serologies negative.
Management:
- IV NAC for all non-acetaminophen ALF -- improves transplant-free survival in Grade I-II HE Lee, 2009
- Autoimmune hepatitis causing ALF: trial of methylprednisolone 60 mg IV daily. If no improvement in 7 days, proceed to transplant listing
- Transjugular liver biopsy to confirm diagnosis and assess for cirrhosis
- Early transplant hepatology involvement -- autoimmune ALF has worse prognosis than acetaminophen ALF if steroid-unresponsive
Teaching point: NAC benefits ALL causes of ALF, not just acetaminophen. Autoimmune hepatitis causing ALF can receive a steroid trial, but do not delay transplant evaluation. Elevated IgG + autoantibodies in a young woman = think autoimmune.
📋 Case 3, Wilson Disease Presenting as ALF
Patient: 22M presents with acute jaundice, confusion, and dark urine x 1 week. No medications. Sister diagnosed with Wilson disease at age 18.
Key findings: Kayser-Fleischer rings on slit lamp. AST 1,400, ALT 600 (AST:ALT > 2.2), ALP 45 (paradoxically LOW), total bilirubin 32, INR 5.2. Ceruloplasmin 8 (low). Hgb 7.2 with Coombs-negative hemolytic anemia (reticulocytes 8%, haptoglobin < 10, LDH 890). 24h urine copper 1,200 mcg.
Management:
- List for transplant immediately -- Wilson ALF has near-100% mortality without transplant. No medical therapy reverses fulminant Wilson
- Revised Wilson Prognostic Index > 11 = transplant indicated
- D-penicillamine and trientine are NOT effective in fulminant Wilson disease (too slow)
- Supportive: NAC, plasmapheresis or MARS as bridge to transplant to remove copper
Teaching point: Wilson ALF has a classic triad: Coombs-negative hemolytic anemia + very low ALP + AST:ALT > 2.2. The ALP:bilirubin ratio < 4 is highly specific. This is a transplant emergency -- chelation does not work fast enough.
Sample Presentation
Mrs. Patel is a 28-year-old woman presenting with 5 days of nausea, vomiting, and jaundice, now with confusion and asterixis. She reports taking "extra-strength Tylenol" for back pain, approximately 4-6 g/day for the past week. VS: T 37.2, HR 110, BP 95/60, RR 22. Labs: ALT 8,400, AST 10,200, total bilirubin 8.5, INR 4.8, Cr 2.1, acetaminophen level 45 mcg/mL, pH 7.28, lactate 6.2, ammonia 98. Hepatitis serologies pending. NAC drip started immediately. Transplant hepatology notified.
Key Points: ALF from supratherapeutic acetaminophen (unintentional). Meets ALF criteria: INR ≥1.5 + encephalopathy + no prior liver disease. NAC is the priority. Do NOT correct INR unless actively bleeding. Apply King's criteria serially: pH 7.28 (close to 7.3 cutoff), if pH drops below 7.3 after resuscitation, meets criteria for transplant listing. Monitor glucose, ammonia, and neuro status closely. Acetaminophen ALF has the best prognosis of all causes if treated promptly.
Monitoring
- INR, LFTs q6-12h, trending INR is your prognostic window. Rising INR despite NAC = worsening. Falling INR = recovery.
- Glucose q1-2h, hypoglycemia is life-threatening and common. D10 drip.
- Ammonia level q12-24h, levels >150-200 mcmol/L associated with cerebral herniation.
- Neuro checks q1-2h, grade encephalopathy (West Haven criteria). Grade III-IV requires intubation.
- Lactate q6-12h, rising lactate in acetaminophen ALF is a poor prognostic sign.
- BMP q6h, K+, Na+, creatinine, phosphate trending.
- Urine output, target >0.5 mL/kg/h. AKI develops in 50-70%.
- King's College Criteria, reassess at least daily for transplant listing urgency.
- ICP monitoring, controversial. Consider in Grade III-IV HE if transplant candidate. Target CPP >60 mmHg, ICP <20 mmHg.
📋 Summary
Summary
The Definition Is Precise
Coagulopathy with INR 1.5 or above, plus hepatic encephalopathy, in a patient with no prior liver disease and an illness lasting under 26 weeks. Encephalopathy is what separates acute liver failure from severe acute hepatitis, and its appearance is the moment the transplant center should be called.
Call the Transplant Center Early
Before the patient looks like they need it. Deterioration is measured in hours, and cerebral edema and hemodynamic instability make transfer progressively more dangerous. A patient who becomes too unstable to move has lost the option.
Give NAC to Everyone
N-acetylcysteine is no longer just for acetaminophen. It improves transplant-free survival in non-acetaminophen acute liver failure (Lee, Gastroenterology 2009), with the benefit concentrated in grade I to II encephalopathy. Start it while the cause is still being worked up.
Do Not Correct the INR Prophylactically
The INR is the prognostic marker and the transplant listing criterion. Correcting it blinds you to the trajectory and removes the ability to tell improvement from deterioration. Give plasma or PCC only for active bleeding or before an invasive procedure. These patients are not truly auto-anticoagulated: pro- and anticoagulant factors fall together, so the INR overstates the bleeding risk.
Work the Cause Systematically
Acetaminophen is the commonest cause in the United States, including staggered supratherapeutic dosing in a patient who never took an overdose. Also viral hepatitis (A, B, E, HSV), drug-induced liver injury, autoimmune hepatitis, Budd-Chiari, Wilson disease, ischemic hepatitis and pregnancy-related (HELLP, acute fatty liver). Send the acetaminophen level even without a history, plus viral serologies, autoimmune markers, ceruloplasmin in anyone under 40, and a Doppler ultrasound of the hepatic vessels.
Cerebral Edema Is What Kills
It is the leading cause of death and it tracks the grade of encephalopathy and the ammonia level. Head of bed at 30 degrees, minimize stimulation, avoid sedation that clouds the neurologic exam, and intubate at grade III to IV encephalopathy for airway protection. Treat surges with hypertonic saline or mannitol, and use renal replacement therapy to clear ammonia, which also handles the acute kidney injury these patients develop. Lactulose does not have the same role here as in cirrhotic encephalopathy and risks ileus and distension before transplant.
Know the King's College Criteria
Acetaminophen: arterial pH below 7.3 after resuscitation, or the triad of INR above 6.5, creatinine above 3.4 mg/dL and grade III to IV encephalopathy. Non-acetaminophen: INR above 6.5 alone, or any 3 of unfavorable etiology, age under 10 or over 40, jaundice-to-encephalopathy interval over 7 days, INR above 3.5, bilirubin above 17.5 mg/dL. These identify who will die without a transplant, and they are highly specific but insensitive, so failing to meet them is not reassurance.
Manage the Other Organs Deliberately
Check glucose every 1 to 2 h and run a dextrose infusion, because a failing liver stops making glucose and hypoglycemia is common and easily mistaken for worsening encephalopathy. Watch for infection without fever, since these patients are functionally immunosuppressed and sepsis often presents as a deepening encephalopathy. Start stress ulcer prophylaxis, correct electrolytes and phosphate, and avoid nephrotoxins.
Related Topics
Acute Alcoholic HepatitisAutoimmune HepatitisBowel ObstructionCholangitis & CholecystitisCirrhosis & AscitesClostridioides difficile (C. diff)