Acute Liver Failure

Etiology

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, heatstroke, 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 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.  

Epidemiology

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.

Pathophysiology

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.

Histopathology

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. Therefore, special stains for hepatitis B, CMV, EBV, adenovirus hepatitis, and herpes simplex, along with immune-histopathological stains, could be considered.

History and Physical

A comprehensive history helps to delineate possible etiologies. For example, the following information could be obtained from the patient's chart, the patient, or the family:

• Any history of hepatic disease or hepatic decompensation
• Any concomitant relevant chronic health conditions
• The timeline of symptoms with which the patient has presented. This is particularly important in patients with acetaminophen toxicity.
• Toxic habits or high-risk behavior
• Any recent medications or recent ingestion of hepatotoxins, including herbal products
• Family history: always ask for Wilson disease and thrombotic disorders.
• Any recent surgeries where anesthetic agents could be implicated as the possible etiology of the ALF.

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.

Evaluation

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.

Treatment / Management

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.(B3)

Supportive and Preventive Care

1. Access hemodynamic stability and the need for intravenous fluids and maintenance of acid-base levels and normal electrolytes. Vasopressors are indicated to maintain a mean arterial pressure of 75 mm Hg or higher to ensure adequate renal and cerebral perfusion.
2. Monitor hematocrit for any bleeding, as the patients have coagulopathy and poor platelet functions. Blood products of platelets and fresh frozen plasma for coagulopathy is only indicated in patients with active bleeding or before an invasive procedure. Patients should be empirically started on proton pump inhibitors for prophylaxis of gastrointestinal bleed.
3. Consider a fever workup including blood and urine cultures and start empirical antibiotics when required.
4. Monitor hepatic encephalopathy and protect airway (aspiration risk) should the patient show signs of worsening encephalopathy. These patients should be intubated and should be on a protocol to avoid cerebral edema.
5. Adequate nutrition with 1.0 to 1.5 gm of protein per kilogram per day should be administered.
6. Monitor for hypoglycemia and maintain blood glucose between 160 to 200.
7. Discontinue all home medications except the ones we identify essential to continue.

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.

1. Renal failure: It may occur due to hypovolemia, acute tubular necrosis or hepatorenal syndrome. Vasopressor therapy with norepinephrine or dopamine is indicated in severe hypotension. Renal-replacement may be considered as a bridge for a possible liver transplant. Continuous renal replacement therapy is preferred to hemodialysis in critically ill patients.
2. Sepsis, including aspiration pneumonia and fever, should be covered with broad-spectrum antibiotics. Surveillance cultures of blood, sputum, and urine should be obtained in all patients with ALF.
3. Metabolic disorders: Hypoglycemia occurs due to impaired glycogen production and gluconeogenesis, and will need continuous infusions of 10% to 20% glucose. Hypophosphatemia occurring due to ATP consumption in the setting of hepatocyte necrosis requires aggressive repletion. Alkalosis in ALF is due to hyperventilation, and acidosis with a pH less than 7.3 portends 95% mortality in acetaminophen overdose if the patient does not undergo a liver transplant. Hypoxemia may occur due to aspiration, acute respiratory distress syndrome, or pulmonary hemorrhage. Patients with encephalopathy greater than grade 2 should undergo endotracheal intubation for airway protection. Seizure-like activity may be treated with phenytoin or benzodiazepines.
4. Cerebral edema: The most common cause of death in ALF is cerebral edema which leads to intracranial hypertension, ischemic brain injury and herniation. Patients with arterial ammonia levels higher than 200 micromoles per liter are at an increased risk for intracranial hypertension. Triggers for cerebral edema include hypoxia, systemic hypotension, decreased cerebral perfusion pressure (CPP) and astrocyte swelling which occurs due to increased ammonia levels and glutamine production in the brain. Abnormal pupillary reflexes, muscular rigidity and decerebrate posturing when present indicate the onset of intracranial hypertension. Measures to keep the intracranial pressure (ICP) below 25 mm Hg and CPP above 50 mm Hg, if an ICP monitoring device is placed, should be undertaken. Such measures include elevation of the head of the bed to 30 degrees, avoiding unnecessary stimulation such as suctioning of the oropharynx and background noise, endotracheal intubation, and sedation in a patient with grade 3 encephalopathy and above,  prompt initiation of vasopressor therapy and renal replacement therapy, hyperventilation, and intravenous mannitol therapy.
5. Encephalopathy: Encephalopathy is a key feature of ALF. CT of the head should be done in patients with grade 3 encephalopathy and above to assess for intracranial bleeding and cerebral edema.
6. Coagulopathy: Like encephalopathy, coagulopathy is also a defining feature of ALF.  Bleeding events are rare despite the presence of severe coagulopathy. Hence routine correction of coagulopathy is not recommended unless in the setting of overt bleeding or before invasive procedures. Transfusions of platelets, plasma, and cryoprecipitate, may be given if indicated. Recombinant factor VII an administration can cause thrombus;  parenteral vitamin K therapy (slow intravenous infusion) may be considered if a nutritional deficiency is suspected or in cases of prolonged cholestasis.

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.

Differential Diagnosis

• Acute fatty liver of pregnancy
• Amanita phalloidesmushroom poisoning
• Bacillus cereus toxin
• Fructose intolerance
• Galactosemia
• HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome of pregnancy
• Hemorrhagic viruses ( Ebola virus, Lassa virus, and Marburg virus)
• Idiopathic drug reaction (hypersensitivity)
• Neonatal iron storage disease
• Tyrosinemia

Prognosis

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 indicates a higher survival rate up to 79% at 1 year and 72% at 5 years. The most widely used criteria for determining ALF prognosis 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]