Acute Liver Failure (ALF), previously fulminant hepatic failure, is the syndrome of severe hepatocyte injury leading to the rapid onset of altered coagulation (elevated INR), jaundice, and hepatic encephalopathy with NO prior history of liver disease within 8 weeks. There are 3 exceptions to “no prior liver injury” – Wilson disease, autoimmunity and reactivation of chronic hepatitis B (1,2).
Time of Onset
- Hyperacute: Encephalopathy and liver injury developing within 7 days (most frequently caused by acetaminophen and ischemia).
- Acute (8-28 days) and Subacute (4-8 weeks) are more frequently caused by viral hepatitis, non-acetaminophen drug induced liver injury, autoimmune hepatitis and Wilson disease (1,2).
More Common Etiologies
- Drug induced liver injury (DILI): Drug induced liver injury is the most common cause of acute liver failure with acetaminophen accounting for the vast majority of cases. Antibiotics, anticonvulsants and NSAIDs are also frequently implicated. Cocaine and MDMA have been associated with acute liver failure but these cases are rare (2,3).
- Many other medications have been implicated outside these categories – see livertox.nih.gov for a comprehensive database (4).
- Viral Hepatitis (A,B,E): Are the predominant causes of acute liver failure in the developing world where vaccination and effective sanitation are less widespread.
- Hepatitis B reactivation can cause acute liver failure in the setting of immunosuppression (i.e. chemotherapy), and is a more common cause of ALF than other viral infections in developed nations.
- Disseminated HSV, verissela, EBV, parvovirus infections are far less common but cases have been reported (1,2).
- Ischemia: Shock, prolonged hypoxia, severe heart failure leading to ischemia can cause acute liver failure. Unlike other causes of acute liver failure, this carries a relatively good prognosis if hemodynamic collapse is rapidly corrected and if the underlying cause of shock is reversible.
- Autoimmune hepatitis: Not as uncommon as one might think and should be considered if other known culprits are excluded (though workup will most likely take place once admitted) (1,2).
Less Common Etiologies
- Budd Chiari (hepatic venous outflow occlusion). Consider RUQ doppler imaging if a patient has RUQ pain, ascites, hepatomegaly, lower extremity edema in the setting of markedly elevated LFTs as this is potentially reversible.
- Pregnancy (acute fatty liver of pregnancy and HELLP) – emergent delivery often indicated.
- Hyperthermia severe hyperthermia
- Wilson disease (2)
- CBC (thrombocytopenia, evidence of bleeding)
- LFT’s (How high are the transaminases, what is the ratio, how high is the alkaline phosphatase and how high is the bilirubin). There is no exact correlation but this can be diagnostically helpful.
- Acetaminophen level
- Coags (remember that elevated INR does NOT help you assess bleeding risk in a patient with liver failure because both pro and anti coagulant factors made by the liver are lost and not in exact proportions across all patients. Thromboelastography (TEG) or rotational thromboelastography (ROTEM) are needed to determine coagulopathy and are not universally available (5).
- Ammonia: Good to know, especially if extremely elevated, but very prone to lab error and not the sole cause of encephalopathy. Ammonia samples must be drawn perfectly to be reliable (lavender tube, placed on ice immediately, no prolonged tourniquet time, must be sent to the lab immediately).
- BMP, Phos: Creatinine elevation / decreased GFR may indicate hepatorenal syndrome. Sodium, phos, glucose and potassium may all be low in acute liver failure.
- Viral Hepatitis Labs
- Hepatitis A IgG/IgM
- Hepatitis B Surface Ag, Surface Ab, Core IgG, Core IgM
- Hepatitis C antibody (very unlikely to be the cause of acute liver failure but should be sent for a full evaluation).
- Can consider hepatitis E IgG/IgM if readily available, especially if there was recent travel, undercooked meat or shellfish.
- Ascitic Fluid: If ascites is present and a pocket can safely be accessed, diagnostic paracentesis is indicated in all patients who will be admitted to the hospital. Patients admitted with ascites who had routine paracentesis performed were found to have a lower mortality rate due to increased detection of SBP. It is furthermore indicated in all cases of new ascites to determine the etiology (6,7). A cell count, gram stain and culture should be performed at minimum though routine standard testing is as follows:
- Cell Count
- Gram Stain + Culture
- Albumin – SAAG (Serum to Ascites Albumin Gradient) > 1.1 indicates the ascites is likely the result of portal hypertension
- Total Protein (if >2.5, may have exudative effusion)
- Additional tests can be added to evaluate for TB, malignancy, etc.
- CT Head: Consider head imaging if there is severe encephalopathy. High grade encephalopathy is sometimes associated with cerebral edema which can lead to herniation. Mannitol or hypertonic saline can be considered if there is severe cerebral edema or risk for herniation (2).
Managing Hepatic Encephalopathy
The exact cause of hepatic encephalopathy is not fully understood. While it is likely that ammonia plays a role, it has been postulated that other unmeasured neurotoxins, cytokines and nitrogenous wastes likely do as well. For that reason, ammonia levels do not always correlate perfectly with the degree of encephalopathy observed. The treatment if suspected, however, is as follows:
- Lactulose: Given orally (preferably) or through a nasogastric or PEG tube. Decreases enteral absorption of ammonia, improves encephalopathy. This is the FIRST LINE treatment for hepatic encephalopathy.
- Rifaximin: An antibiotic given orally with broad spectrum activity against enteric bacteria which can serve as an ADJUNCT to lactulose. Start with lactulose first, rifaximin can be added if the patient fails to respond.
- Avoid sedation unless absolutely needed for severe agitation. Sedatives are frequently slower to clear in patients with severe liver disease. While benzodiazepines and opiates should be minimized, choosing a benzodiazepine without hepatically cleared metabolites such as lorazepam or an opiate such as fentanyl which has a similar bolus elimination time in patients with liver disease is advisable (8,9).
Managing Massive Ascites
- SBP (spontaneous bacterial peritonitis; >250 ascitic PMN’s) is associated with a high risk of hepatorenal syndrome (up to 30%) and HRS has a very high mortality rate. Large volume paracentesis, especially when done without appropriate albumin repletion can also cause large volume shifts and precipitate HRS. The presence of SBP makes the decision to do a large volume paracentesis far more nuanced. Current best practices are to evaluate for SBP first through diagnostic paracentesis and if present, to treat with antibiotics and to approach any LVP with caution. There is, however, a paucity of data with regards to LVP performed in SBP patients so look out for newer data going forward (10).
- When ascites decompression is required, can remove up to 5L without giving albumin. When removing >5L, 6-8 grams per liter removed of 25% albumin should be replaced during the procedure to minimize large volume shifts.
- Peritoneal catheters should be removed immediately following the paracentesis to minimize the risk of secondary bacterial peritonitis.
N-Acetylcysteine (NAC) for acute liver failure
- There is clear evidence for preventing acute liver failure in patients with acute acetaminophen overdose.
- There is less clear evidence that NAC may be helpful in patients with acute liver failure from non-acetaminophen related causes (though there is also little harm in giving it). In one randomized placebo controlled trial with 173 patients (exclusion criteria included pregnancy, cancer, shock liver, APAP), transplant free survival was significantly better for NAC patients than for those given placebo (40% vs. 27%) though the paper was not powered to detect (and did not detect) any overall survival benefit. Avoiding liver transplant, however, is a worthy goal and giving NAC for acute liver failure can be discussed with the accepting liver transplant service (11).
Transferring to a transplant center
- If transplant surgery is not available in-house, acute liver failure patients should be transferred immediately. A MELD score may be requested.
- Bernal W, Wendon J. Acute Liver Failure. New England Journal of Medicine. 2013;369(26):2525-2534. doi:10.1056/nejmra1208937.
- Stravitz RT, Lee WM. Acute liver failure. The Lancet. 2019;394(10201):869-881. doi:10.1016/s0140-6736(19)31894-x.
- Reuben A, Koch DG, Lee WM. Drug-induced acute liver failure: Results of a U.S. multicenter, prospective study. Hepatology. 2010;52(6):2065-2076. doi:10.1002/hep.23937.
- LiverTox. National Institutes of Health. http://livertox.nih.gov/.
- Harrison M. The Misunderstood Coagulopathy of Liver Disease: A Review for the Acute Setting. Western Journal of Emergency Medicine. 1996;19(5):863-871. doi:10.5811/westjem.2018.7.37893.
- EASL clinical practice guidelines on the management of ascites, spontaneous bacterial peritonitis, and hepatorenal syndrome in cirrhosis. Journal of Hepatology. 2010;53(3):397-417. doi:10.1016/j.jhep.2010.05.004.
- Gaetano JN, Micic D, Aronsohn A, et al. The benefit of paracentesis on hospitalized adults with cirrhosis and ascites. Journal of Gastroenterology and Hepatology. 2016;31(5):1025-1030. doi:10.1111/jgh.13255.
- Lee WM, Stravitz RT, Larson AM. Introduction to the revised American Association for the Study of Liver Diseases position paper on acute liver failure 2011. Hepatology. 2012;55(3):965-967. doi:10.1002/hep.25551.
- Kornerup LS, Gluud LL, Vilstrup H, Dam G. Update on the Therapeutic Management of Hepatic Encephalopathy. Current Gastroenterology Reports. 2018;20(5). doi:10.1007/s11894-018-0627-8.
- Chitsaz E, Nunes D. Risks and Benefits of Large Volume Paracentesis in Spontaneous Bacterial Peritonitis With Tense Ascites: Where is the Clinical Evidence? American Journal of Gastroenterology. 2014;109. doi:10.14309/00000434-201410002-02307.
- Lee WM, Hynan LS, Rossaro L, et al. Intravenous N-Acetylcysteine Improves Transplant-Free Survival in Early Stage Non-Acetaminophen Acute Liver Failure. Gastroenterology. 2009;137(3). doi:10.1053/j.gastro.2009.06.006.