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 |
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System |
Pathophysiology |
Management |
Neurologic |
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:
If altered:
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CV |
Splanchnic vasodilation causes a low SVR |
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GI |
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Metabolic/Renal |
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Hematologic |
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All patients:
If bleeding:
If procedure:
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Immunologic/Infectious |
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Etiology Specific Management |
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Etiology |
Management |
Drug/Toxin |
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Viral |
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Autoimmune |
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Vascular |
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Wilson’s |
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AFLP/HELLP |
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*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.
Acute liver failure in adults: Management and prognosis - UpToDate
Amatoxin-containing mushroom poisoning (eg, Amanita phalloides): Clinical manifestations, diagnosis, and treatment - UpToDate
Bernal W, Wendon J. Acute liver failure. N Engl J Med. 2013 Dec 26;369(26):2525-34.
Fix OK, Liou I, Karvellas CJ, et al. Development and Pilot of a Checklist for Management of Acute Liver Failure in the Intensive Care Unit. PLOS ONE. 2016;11(5):e0155500. doi:10.1371/journal.pone.0155500
Frontera JA, Kalb T. Neurological Management of Fulminant Hepatic Failure. Neurocrit Care. 2011; 14((2):318-27.
Gupta S, Fenves AZ, Hootkins R. The Role of RRT in Hyperammonemic Patients. Clin J Am Soc Nephrol. 2016;11(10):1872-1878. doi:10.2215/CJN.01320216
Harrison MF. The Misunderstood Coagulopathy of Liver Disease: A Review for the Acute Setting. West J Emerg Med. 2018;19(5):863-871. doi:10.5811/westjem.2018.7.37893
Hemostatic abnormalities in patients with liver disease - UpToDate.
Lee WM. AASLD Position Paper: The Management of Acute Liver Failure: Update 2011. Published online 2011:88.
Lee WM et al. Intravenous N-Acetylcysteine Improves Transplant-Free Survival in Early Stage Non-Acetaminophen Acute Liver Failure. Gastroenterology 2009;137:856-864.
Sass DA, Shakil O. Fulminant hepatic failure. Liver Transpl 2005;11:594-605.