Acute liver failure (ALF) is a rare and often heterogeneous presentation of severe liver dysfunction in a patient with otherwise no pre-existing liver disease. Though it has high morbidity and mortality, its overall survival has improved through advancements in intensive care management and emergency liver transplantation.[1][2][3] A high index of suspicion, early referral to a specialist liver transplantation center, and adequate supportive management remains the cornerstone for the management of ALF. Future better understanding and knowledge of the pathophysiology of liver injury and management of multi-organ failure will help improve outcomes.
ALF is defined as the development of severe acute liver injury with encephalopathy and impaired synthetic function (INR of 1.5 or higher) in a patient without cirrhosis or preexisting liver disease and with an illness of fewer than 26 weeks duration.[4][5]
An extensive workup for the etiology of ALF is recommended, as this guides directed therapy and helps determine the outcome. Viral hepatitis and drug-induced hepatitis are the 2 most common causes of ALF worldwide. Other causes include hypoxia-induced liver injury, acute Budd-Chiari syndrome, veno-occlusive disease, Wilson disease, mushroom ingestion, sepsis, autoimmune hepatitis, acute fatty liver of pregnancy, HELLP (hemolysis, elevated liver enzymes, low platelet) syndrome, heat stroke, and malignant infiltration (with metastasis from breast cancer, small cell lung cancer and lymphoma) of the liver.[6][7]
Drug-induced hepatitis accounts for almost half the cases of ALF in the United States, of which acetaminophen is the most common cause. Acetaminophen toxicity is dose-dependent. Drug-induced hepatotoxicity could be idiosyncratic, but this is usually rare. Unintentional ingestion of acetaminophen-induced hepatoxicity leading to liver failure is more common in patients with concomitant alcohol abuse and malnourishment.[8]
Hepatitis A and E are the leading causes of liver failure, most of which are reported from the developing countries. Hepatitis B infection could cause liver failure from both acute infections, as well as, from reactivation of hepatitis B following initiation of immunosuppressive therapy. Co-infection with both hepatitis B and C could lead to ALF, although it is rarely seen with hepatitis C alone. Other viral etiologies of ALF include herpes simplex virus, cytomegalovirus CMV), Epstein-Barr virus EBV), Parvoviruses, adenovirus and varicella zoster virus.
The etiology and the incidence of ALF vary in developed countries as compared to developing countries. Hepatitis A, B, and E are the leading causes of ALF worldwide and are mostly seen in the developing countries compared to drug-induced liver injury in developed countries.[9] A recent review of the epidemiology of ALF over the past 50 years reveals the relative incidence of ALF secondary to hepatitis A and B to have declined, while that of acetaminophen to have increased, mainly in the United States and Western Europe.
The pathophysiology depends on the etiology of the ALF. Most cases of ALF (except acute fatty liver of pregnancy and Reye syndrome) will have massive hepatocyte necrosis and/or apoptosis leading to liver failure. Hepatocyte necrosis occurs due to ATP depletion causing cellular swelling and cell membrane disruption. The pathophysiology of cerebral edema and hepatic encephalopathy is seen in ALF is multi-factorial and includes altered blood-brain barrier (BBB) secondary to inflammatory mediators leading to microglial activation, accumulation of glutamine secondary to ammonia crossing the BBB and subsequent oxidative stress leading to depletion of adenosine triphosphate (ATP) and guanosine triphosphate (GTP). This ultimately leads to astrocyte swelling and cerebral edema.
Only if the clinical interpretation through history, examination, laboratory and imaging modalities are inconclusive, a transjugular liver biopsy could be performed to ascertain the specific etiology of the ALF.
Any viral hepatitis would show inflammatory cells (neutrophils and lymphocytes), along with hepatic necrosis (especially in herpes simplex hepatitis). The histology is specifically helpful in infiltrative conditions like malignancies and lymphomas. Special stains for hepatitis B, CMV, EBV, adenovirus hepatitis and herpes simplex, along with immune-histopathological stains could be considered.
A comprehensive history helps to delineate possible etiologies. The following information could be obtained from the patient's chart, the patient, or the family:
Physical exam findings of hypotension, altered mental status, fever (with infectious etiology), right upper quadrant discomfort, pain, and tenderness with nausea and features of jaundice and fluid overload may be included.
Prolonged INR greater than or equal to 1.5, often elevated bilirubin and aminotransferases, thrombocytopenia, with anemia, hypoglycemia, elevated ammonia and features of acute renal injury (with elevated serum creatinine), and dyselectrolytemia (hypokalemia, hypophosphatemia) is common.
Imaging of the abdomen, pelvis, brain, and chest should be considered. Abdominal imaging to determine the presence of cirrhosis, features of portal hypertension, hepatocellular carcinoma, vascular thrombosis, lymph nodes, and spleen is vital. Abdominal sonogram with Doppler could be considered in patients with concomitant renal injury and vascular thrombosis. Brain imaging (CT or an MRI) is helpful to rule out organic etiology of altered mental status while chest imaging will help rule out pulmonary edema or pneumonia.
The management of ALF consists of supportive care, prevention, and management of complications, specific treatment when the exact etiology is known, and determination of prognosis and the need for liver support including possible liver transplantation. [10][11][12]All patients should be hospitalized, preferably at a center which has facilities and expertise for a liver transplant.
Supportive and Preventive Care
Specific Treatment When the Exact Etiology is Known
For patients with known or suspected acetaminophen-induced ALF, activated charcoal (if presented within 4 hours of ingestion) and prompt administration of N-acetyl cysteine (NAC) is indicated. Rising serum aminotransferases or falling serum aminotransferases along with progressively worsening coagulopathy indicates hepatic necrosis and progression of ALF with likely need for liver transplantation. NAC is also indicated for patients with ALF due to other causes except perhaps ischemic hepatitis and is particularly useful in those with early grades of encephalopathy.
Patients with hepatitis A and E associated ALF should receive supportive care as no specific anti-virals are known to be effective. Patients with acute or reactivation of hepatitis B should receive nucleus(t)ide analogs. Patients with suspected autoimmune hepatitis may benefit from intravenous methylprednisolone at a dose of 60 mg/day. In patients with suspected Amanita phalloides poisoning, gastric lavage, activated charcoal, and intravenous penicillin G at a dose of 1 g/kg/day may be administered.
Patients with identifiable Wilson disease or known hepatic vein thrombosis as the etiology for ALF should be considered for a liver transplant. Those with Budd-Chiari syndrome should be considered for TIPS placement as well as anticoagulation therapy.
Patients with herpes hepatitis or varicella zoster-related ALF should receive acyclovir (5 to 10 mg/kg IV every 8 hours). Patients with hepatitis due to Cytomegalovirus should be given intravenous ganciclovir at a dose of 5 mg/kg every 12 hours.
In pregnant patients with ALF likely secondary to the acute fatty liver of pregnancy or HELLP syndrome, prompt delivery of the fetus is recommended. Also, should the ALF does not resolve, we should again consider possible liver transplantation.
Management of Complications
Every attempt should be made to avoid the development of multi-organ dysfunction.
Liver Support and Liver Transplantation
The etiology of ALF and the hospital prognosis could help physicians ascertain whether a particular patient is likely to improve or not, and hence need a liver transplant. Those several selection criteria for patients with ALF, to determine the need for liver transplantation exists, it is neither universally accepted, nor fully endorsed by the AASLD as the sole criteria to decide on liver transplantation.
Extracorporeal liver-assist devices have been used in clinical trials in patients with ALF with the aim of detoxification and restore synthetic functions. Recent multicenter trials involving the molecular adsorbent recirculating system and the porcine hepatocyte-based HepaAssist device have both shown to be of no survival benefit.
Liver transplantation, though not readily available is an option for selected patients. Because these patients are critically ill, they are at increased risk of graft complications, most commonly from infections and sepsis, which seems to be the most common etiology of liver graft failure in patients transplanted following ALF.
The expected clinical outcomes have drastically changed since ALF was first defined approximately 50 years ago. The current 1-year survival rate of patients, including those undergoing liver transplantation, is greater than 65%. In the past, studies from the United States and Europe had indicated a lower 1-year survival rate of patients with ALF receiving a liver transplant when compared to their counterparts in patients with cirrhosis. However, the 2012 registry from the United States and Europe indicate a higher survival rate up to 79% at 1 year and 72% at 5 years. The most widely used criteria for determining the prognosis of ALF are the King's College Criteria for ALF due to acetaminophen overdose and ALF not associated with acetaminophen. Other useful prognostic criteria include Clichy criteria (presence of hepatic encephalopathy along with a factor V level lower than 20% to 30% of normal, MELD score higher than 30, and Acute Physiology and Chronic Health Evaluation (APACHE) II score higher than 15.[13][14]
Patients with acute liver failure and fulminant Wilson disease receive the highest priority for liver transplantation in the United States and are assigned Status 1A category on the liver transplant wait list due to their risk for the highest mortality in the absence of liver transplantation. Contraindications to liver transplantation in ALF include multiorgan failure or severe cardiopulmonary disease, septic shock, extrahepatic malignancy, irreversible brain injury or brain death, severe thrombotic disorder, active substance abuse, multiple suicide attempts, and lack of social support.
Because there are many causes of ALF and its management is complex, the disorder is best managed by an interprofessional team that includes a dietitian, hematologist, liver specialist, gastroenterologist, surgeon, radiologist, pathologist, and an intensivist.
The management of ALF consists of supportive care, prevention, and management of complications, specific treatment when the exact etiology is known, and determination of prognosis and the need for liver support including possible liver transplantation. All patients should be hospitalized, preferably at a center which has facilities and expertise for a liver transplant. The pharmacist should ensure that the patient is on no medication that can worsen liver function and should continuously monitor the medications for drug-drug interactions.
The treatment of ALF depends on the cause but at the same time, all patients need aggressive hydration. Since these patients develop a range of complications, the relevant specialist should be consulted promptly. Some patients may benefit from a liver transplant or Extracorporeal liver-assist device.
The outlook for patients with ALF depends on the cause, extent of liver damage, comorbidity, response to treatment, the age of patient, and number of organs involved.[15][16]
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