Fulminant hepatic failure

Fulminant hepatic failure also known as acute liver failure, is usually defined as the development of severe acute liver injury or severe necrosis of hepatocytes causing encephalopathy and coagulopathy (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 ¹.

The cause of fulminant hepatic failure refers to a wide variety of causes, of which toxin-induced or viral hepatitis are most common. Hepatitis A, B, and E are the leading causes of fulminant hepatic failure worldwide and are mostly seen in the developing countries compared to drug-induced liver injury in developed countries ². A recent review of the epidemiology of fulminant hepatic failure over the past 50 years reveals the relative incidence of fulminant hepatic failure secondary to hepatitis A and B to have declined, while that of acetaminophen to have increased, mainly in the United States and Western Europe.

In spite of specific therapeutic options in distinctive etiologies, orthotopic liver transplantation is the only therapy proven to improve patient survival in the majority of patients. The outcome is determined by the complications like severe coagulopathy, infections, renal impairment or increased intracranial pressure. The decision for transplantation depends on the possibility of spontaneous hepatic recovery, which may be estimated by several factors. The most important variables for predicting the need of transplantation in fulminant hepatic failure are the degree of encephalopathy, patients age and the underlying cause of liver failure.

Though it has high morbidity and mortality, its overall survival has improved through advancements in intensive care management and emergency liver transplantation 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 fulminant hepatic failure. Future better understanding and knowledge of the pathophysiology of liver injury and management of multi-organ failure will help improve outcomes.

Fulminant hepatic failure causes

The cause and the incidence of fulminant hepatic failure vary in developed countries as compared to developing countries. Viral hepatitis and drug-induced hepatitis are the 2 most common causes of fulminant hepatic failure worldwide ⁴. 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 ⁵.

Drug-induced hepatitis accounts for almost half the cases of fulminant hepatic failure 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 ⁶.

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 fulminant hepatic failure, although it is rarely seen with hepatitis C alone. Other viral etiologies of fulminant hepatic failure include herpes simplex virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), Parvoviruses, adenovirus and varicella zoster virus.

Fulminant hepatic failure causes ¹:

• Viral Hepatitis
  • Hepatitis A,B ,C ,D and E
  • Cytomegalovirus (CMV)
  • Herpes simplex virus (HSV)
  • Epstein-Barr virus (EBV)
  • Varicella zoster virus (VZV)
  • Human Herpesvirus 6 (HHV-6)
  • Parvo-virus B19
  • Parainfluenza
  • Yellow Fever
  • Others
• Idiosyncratic
  • Halogenated hydrocarbons
  • Coumarins
  • Methyldopa
  • Phenytoin
  • Carbamazepin
  • Valproic acid
  • Rifampicin
  • Penicillin
  • Sulfonamides
  • Chinolones, etc.
• Toxic Dose-dependent
  • Acetaminophen (Paracetamol)
  • Isoniazid
  • Tetracycline
  • Methotrexate
  • Carbon tetrachloride
  • Amphetamins
  • Amanita phalloides-toxin
• Toxic synergistic
  • Ethanol + Acetaminophen,
  • Barbiturate + Acetaminophen,
  • Isoniazid + Rifampicin
• Metabolic
  • Wilson’s disease
  • Alpha-1 antitrypsin deficiency
  • Galactosemia
  • Tyrosinemia
  • Reye-Syndrome
  • Non-Alcoholic SteatoHepatitis (NASH)
• Associated with pregnancy
  • Acute fatty liver of pregnancy,
  • HELLP syndrome (Hemolysis, Elevated Liver enzyme levels, and Low Platelet levels)
• Vascular
  • Budd-Chiari-Syndrome
  • veno-occlusive disease
  • shock
  • heart failure
• Miscellaneous
  • Autoimmune-hepatitis
  • malignant infiltration
  • hyperthermia
  • sepsis

Fulminant hepatic failure pathophysiology

The pathophysiology depends on the cause of the fulminant hepatic failure. Most cases of fulminant hepatic failure (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 adenosine triphosphate (ATP) depletion causing cellular swelling and cell membrane disruption. The pathophysiology of cerebral edema and hepatic encephalopathy is seen in fulminant hepatic failure 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.

Fulminant hepatic failure symptoms

The term fulminant hepatic failure is generally used to describe the development of encephalopathy within 8 weeks of the onset of symptoms in a patient with a previously healthy liver.

Signs and symptoms of acute failure may include the following:

• Encephalopathy
• Cerebral edema: May lead to signs of increased intracranial pressure (ICP) (eg, papilledema, hypertension, bradycardia)
• Jaundice: Often present but not always
• Ascites: Potential for hepatic vein thrombosis with rapid development in the presence of fulminant hepatic failure accompanied by abdominal pain
• Right upper quadrant tenderness: Variably present
• Change in liver span: May be small due to hepatic necrosis or may be enlarged due to heart failure, viral hepatitis, or Budd-Chiari syndrome
• Hematemesis or melena: Due to upper gastrointestinal (GI) bleeding
• Hypotension and tachycardia: Due to reduced systemic vascular resistance

Fulminant hepatic failure complications

Potential complications of fulminant hepatic failure include seizures, hemorrhage, infection, renal failure, and metabolic imbalances.

Seizures

Seizures, which may be seen as a manifestation of the process that leads to hepatic coma and intracranial hypertension (ICH), should be controlled with phenytoin. The use of any sedative is discouraged in light of its effects on the evaluation of the mental status. Only minimal doses of benzodiazepines should be used, given their delayed clearance by the failing liver. Seizure activity may acutely elevate the intracranial hypertension and may also cause cerebral hypoxia and, thus, contribute to cerebral edema.

Hemorrhage

Hemorrhage develops as a result of the profoundly impaired coagulation that manifests in patients with fulminant hepatic failure. Gastrointestinal bleeding may develop from esophageal, gastric, or ectopic varices as a result of portal hypertension. Portal hypertensive gastropathy and stress gastritis may also develop. Any minor trauma may result in extensive percutaneous bleeding or internal hemorrhage.

The first step in management is to correct coagulopathy. The transfusion requirements for coagulation products (fresh frozen plasma [FFP], platelets) may be enormous. Multiple transfusions with packed red blood cells may be needed. Consider retroperitoneal hemorrhage if large transfusion requirements are not matched by an obvious blood loss.

Infection

Periodic surveillance cultures should be performed to detect bacterial and fungal infections. Empiric broad-spectrum antibiotics and antifungals should be given in the following circumstances:

Progressive encephalopathy (start antibiotics in all patients listed for transplantation)

Signs of systemic inflammatory response syndrome (SIRS) (temperature, >38°C or < 36°C; white blood cell [WBC] count, >12,000/μL or < 4,000/μL; pulse rate, >90 bpm)

Persistent hypotension

Piperacillin/tazobactam (Zosyn) and fluconazole should be the initial antimicrobial choice. In hospital-acquired intravenous (IV) catheter infections, consider vancomycin.

Renal failure

Acute renal failure is a frequent complication in patients with fulminant hepatic failure and may be due to dehydration, hepatorenal syndrome, or acute tubular necrosis ⁷. To preserve renal function, maintain adequate blood pressure, avoid nephrotoxic medications and nonsteroidal anti-inflammatory agents (NSAIDs), and promptly treat infections.

When dialysis is needed, continuous (ie, continuous venovenous hemodialysis) rather than intermittent renal replacement therapy is preferred. Hemodialysis may significantly lower the mean arterial pressure such that cerebral perfusion pressure is compromised.

Metabolic imbalances

Alkalosis and acidosis occur in fulminant hepatic failure. Identify and treat the underlying cause. Base deficits can be corrected by THAM solution (tromethamine injection), which prevents a rise in carbon dioxide, osmolality, and serum sodium.

Severe hypoglycemia occurs in approximately 40% of patients with fulminant hepatic failure. Although hypoglycemia occurs more frequently in children, blood sugar needs to be monitored in adult patients as well. Blood sugars should be maintained in the range of 60-200 mg/dL, using 10% dextrose solution.

Phosphate, magnesium, and potassium levels tend to be low in fulminant hepatic failure. Frequent supplementation is required.

Fulminant hepatic failure diagnosis

The most important step in patients with fulminant hepatic failure is to identify the cause ⁷. Prognosis in fulminant hepatic failure is dependent on the cause. Fulminant hepatic failure from certain causes demands immediate and specific treatment. It is also critical to identify those patients who will be candidates for liver transplantation ⁷.

All patients with clinical or laboratory evidence of moderate or severe acute hepatitis should have immediate measurement of prothrombin time (PT) and careful evaluation of the mental status. Prolongation of the PT, an international normalized ratio (INR) above 1.5, or alteration in mental sensorium is grounds for hospital admission or transfer to a specialized unit ⁷.

A complete blood cell (CBC) count in patients with liver failure may reveal thrombocytopenia.

Consider electroencephalography in the evaluation of a patient with encephalopathy if seizures must be excluded.

American College of Gastroenterology guidelines for drug-induced liver injury

In 2014, the American College of Gastroenterology released new guidelines for the diagnosis and management of drug-induced liver injury ⁷. Key points include the following ⁸:

• Drug-induced liver injury is a diagnosis of exclusion; a thorough history-taking and workup should be performed to rule out other possible etiologies
• Liver biopsy should be considered to help confirm the presence of drug-induced liver injury, if autoimmune hepatitis may be associated with the condition, and when immunosuppressive agents are being considered
• The widely used Roussel Uclaf Causality Assessment Method (RUCAM) scale may underestimate the risk of liver injury associated with herbal and dietary supplements

These guidelines also include an algorithm for the diagnosis of patients with suspected drug-induced liver injury and provide separate diagnostic pathways based on the type of liver damage (hepatocellular, mixed, or cholestatic) present.

Medical history

A comprehensive medical history helps to delineate possible causes. 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 fulminant hepatic failure.

Physical examination

Physical examination includes careful assessment and documentation of the patient’s mental status and search for stigmata of chronic liver disease. Jaundice is often but not always present. Right upper quadrant tenderness is variably present. The liver span may be small, indicative of significant loss of volume due to hepatic necrosis. An enlarged liver may be seen with heart failure, viral hepatitis, or Budd-Chiari syndrome.

The development of cerebral edema may ultimately give rise to manifestations of increased intracranial pressure (ICP), including papilledema, hypertension, and bradycardia.

The rapid development of ascites, especially if observed in a patient with fulminant hepatic failure accompanied by abdominal pain, suggests the possibility of hepatic vein thrombosis (Budd-Chiari syndrome).

Hematemesis or melena as a result of upper gastrointestinal bleeding may complicate fulminant hepatic failure.

Typically, patients are hypotensive and tachycardic as a result of the reduced systemic vascular resistance that accompanies fulminant hepatic failure, a pattern that is indistinguishable from septic shock. Although this presentation may be intrinsic to hepatic failure, it is important to consider the possibility of a superimposed infection (especially spontaneous bacterial peritonitis).

Assess the patient for signs of encephalopathy.

Table 1. Grading of Hepatic Encephalopathy

Grade	Level of Consciousness	Personality and Intellect	Neurologic Signs	Electroencephalogram (EEG) Abnormalities
0	Normal	Normal	None	None
Subclinical	Normal	Normal	Abnormalities only on psychometric testing	None
1	Day/night sleep reversal, restlessness	Forgetfulness, mild confusion, agitation, irritability	Tremor, apraxia, incoordination, impaired handwriting	Triphasic waves (5 Hz)
2	Lethargy, slowed responses	Disorientation to time, loss of inhibition, inappropriate behavior	Asterixis, dysarthria, ataxia, hypoactive reflexes	Triphasic waves (5 Hz)
3	Somnolence, confusion	Disorientation to place, aggressive behavior	Asterixis, muscular rigidity, Babinski signs, hyperactive reflexes	Triphasic waves (5 Hz)
4	Coma	None	Decerebration	Delta/slow wave activity

Laboratory studies

Prothrombin time (PT)

The PT and/or the international normalized ratio (INR) are used to determine the presence and severity of coagulopathy. These are sensitive markers of hepatic synthetic failure and are usually abnormal in the setting of fulminant hepatic failure. Results may be worsened because of extrahepatic causes (eg, vitamin K deficiency, disseminated intravascular coagulation [DIC], consumptive coagulopathy).

Viral serologies

Hepatitis A virus (HAV) immunoglobulin M (IgM), hepatitis B surface antigen (HBsAg), and hepatitis B virus (HBV) anticore IgM serologies help identify acute infection with HAV or HBV.

Hepatitis C virus (HCV) antibody test results may remain negative for several weeks or months. Repeat testing may be necessary, but acute HCV infection as a cause of fulminant hepatic failure appears to be exceedingly uncommon. If a strong clinical suspicion exists, obtain hepatitis C viral load testing.

If the HBsAg assay is positive, consider testing for hepatitis D virus (HDV) IgM. This test is particularly advisable if the patient is a known intravenous (IV) drug abuser.

Other viral studies may be helpful in the posttransplantation setting or when patients are otherwise heavily immunosuppressed. Such studies include cytomegalovirus viremia and cytomegalovirus antigenemia. Also consider herpes simplex virus (HSV).

Hepatic enzymes

The levels of the transaminases (aspartate aminotransferase [AST]/serum glutamic-oxaloacetic transaminase [SGOT], and alanine aminotransferase [ALT]/serum glutamic-pyruvic transaminase [SGPT]) are often elevated dramatically as a result of severe hepatocellular necrosis.

In instances of acetaminophen toxicity (especially alcohol-enhanced), the AST and ALT levels may be well over 10,000 U/L. The alkaline phosphatase (ALP) level may be normal or mildly elevated.

Serum bilirubin

By definition, the serum bilirubin level should be elevated in fulminant hepatic failure. It climbs as hepatic dysfunction worsens. A serum bilirubin level that is elevated to greater than 4 mg/dL suggests a poor prognosis in the setting of acetaminophen poisoning.

Serum ammonia

The serum ammonia level may be elevated dramatically in patients with fulminant hepatic failure. The arterial serum ammonia level is the most accurate measurement, but venous ammonia levels are generally acceptable. An elevated serum ammonia level does not exclude the possibility of another cause for mental status changes (notably, increased intracranial pressure and seizures).

Serum glucose

Serum glucose levels may be dangerously low. This decrease results from impairments in glycogen production and gluconeogenesis.

Serum lactate

Arterial blood lactate levels, either at 4 hours (>3.5 mmol/L) or at 12 hours (>3.0 mmol/L), are early predictors of outcome in acetaminophen-induced acute liver failure. Blood lactate levels are often elevated as a result of both impaired tissue perfusion, which increases production, and decreased clearance by the liver.

Patients with elevated lactate levels may have an associated metabolic acidosis due to an increased anion gap. Alternatively, this condition may be accompanied by a respiratory alkalosis as a result of hyperventilation.

Arterial blood gases

Like pulse oximetry, arterial blood gas evaluation is valuable for identifying acid-base imbalances. However, because of significant disturbances in the acid-base balance, which are usually progressive, arterial blood gas evaluation is required, rather than only monitoring pulse oximetry. Placement of an arterial line is recommended.

Additionally, arterial blood gases may reveal hypoxemia, which is a significant concern as a result of adult respiratory distress syndrome (ARDS) or other causes (eg, pneumonia).

Serum creatinine

Serum creatinine levels may be elevated, signifying the development of hepatorenal syndrome or some other cause of acute renal failure.

Serum free copper

Patients with Wilson disease have low ceruloplasmin and total serum copper levels. However, ceruloplasmin acts as an acute-phase reactant as well as a copper transporter, and levels may be increased (eg, from active inflammation, pregnancy, or estrogen treatment) or depressed in a nonspecific fashion as a result of hepatic failure. Thus, determination of serum free copper (ie, non-ceruloplasmin–bound copper) is important when Wilson disease must be excluded or confirmed. Fulminant hepatic failure from Wilson disease appears to be uniformly fatal without transplantation.

The free copper level is determined by subtracting 3 times the ceruloplasmin level (mg/dL) from the total serum copper level (µg/dL). Normal free copper levels range from 1.3 to 1.9 µmol/L (8-12 µg/dl); in Wilson disease, levels exceed 3.9 µmol/L (>25 µg/dL).

Serum phosphate

Levels of serum phosphate may be low. It has been hypothesized that hypophosphatemia develops in people whose livers regenerate rapidly. Elevated phosphate levels suggest impaired regeneration.

Autoimmune markers

Antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA), and immunoglobulin levels are important markers for the diagnosis of autoimmune hepatitis.

Acetaminophen studies

In patients with liver failure from acetaminophen toxicity, the acetaminophen level may have decreased by the time a patient presents with fulminant hepatic failure. Nevertheless, this assay may be helpful for documentation purposes.

Acetaminophen-protein adducts are specific biomarkers of acetaminophen-related toxicity. These can be measured in blood. Measurement of acetaminophen-protein adducts is particularly useful for diagnosis in cases lacking historical data or other clinical information ⁹. Serum acetaminophen-protein adducts decrease in parallel to aminotransferases and can be detected up to 7 days.

Drug screen

Consider a drug screen in a patient who is an intravenous drug abuser.

Blood cultures

Most patients with acute liver failure develop infection during or before hospitalization. Patients are at risk of catheter sepsis and complications from all other invasive procedures. Fungal infections are common, most likely as a result of decreased host resistance and antibiotic treatment ¹⁰.

Infection may be associated with bacteremia. Early identification and treatment of bacteremia is important because the mortality from fulminant hepatic failure increases significantly with the development of this serious complication.

Imaging studies

Liver ultrasonography

A Doppler ultrasonography scan of the liver establishes the presence of ascites and may determine the patency and flow in the hepatic veins (allowing exclusion of Budd-Chiari syndrome), hepatic artery, and the portal vein.

Liver ultrasonography may not be necessary if an obvious explanation exists for the hepatic failure. However, it may assist the clinician in excluding the presence of a hepatocellular carcinoma or intrahepatic metastases.

Computed Tomography Scanning

Computed tomography (CT) scanning (or magnetic resonance imaging [MRI]) of the abdomen may be required for further definition of hepatic anatomy and to help the clinician exclude other intra-abdominal processes, particularly if the patient has developed massive ascites, if the patient is obese, or if transplantation is being planned.

Intravenous contrast media may compromise renal function. Consider performing a contrast-free study.

CT scanning of the head may help identify cerebral edema, although CT scans do not reliably demonstrate evidence of edema, especially at early stages. Head imaging with CT scanning is also used to exclude other causes of decline in the mental status, such as intracranial mass lesions (especially hematomas) that may mimic edema from fulminant hepatic failure. It can also exclude subdural hematomas.

Liver biopsy

A percutaneous liver biopsy is contraindicated in the setting of coagulopathy. However, a transjugular biopsy is helpful for diagnosis if autoimmune hepatitis, metastatic liver disease, lymphoma, or herpes simplex hepatitis is suspected. Liver biopsy findings may be nonspecific, but in general, the findings depend on the underlying etiology of the acute liver failure.

Liver biopsy specimens in patients with idiosyncratic medication-induced hepatitis leading to fulminant hepatic failure generally shows panlobular necrosis. In patients with acetaminophen-induced fulminant hepatic failure, centrilobular necrosis is typical but panlobular injury may also be observed.

Viral hepatitis typically produces a panlobular injury and may be difficult to distinguish from medication-induced hepatitis. The presence of microvesicular steatosis suggests certain medications (eg, valproic acid, salicylates in Reye syndrome) as a cause for fulminant hepatic failure, but this finding is also observed in acute fatty liver of pregnancy.

Intracranial pressure monitoring

When establishing a diagnosis of intracranial hypertension or cerebral edema, intracranial pressure monitoring is frequently necessary. Monitoring also has value in guiding management.

Typically, extradural catheters are safer than intradural catheters. However, intradural catheters are somewhat more accurate and, in the hands of a neurosurgeon experienced with their use, may be equally safe.

Fulminant hepatic failure treatment

The management of patients with fulminant hepatic failure requires a thorough understanding on how to deal with the complications that may be present, including renal failure, circulatory dysfunction, coagulopathy, gastrointestinal bleeding, encephalopathy, cerebral edema and metabolic disturbances like metabolic acidosis and hypoglycemia. In the course of these complexities, patients with fulminant hepatic failure should be managed in an intensive care unit and should be transferred as soon as possible to centers with a liver transplant program ¹¹. Liver transplantation remains the main promising option of treatment of fulminant hepatic failure. However, depending on the cause, specific therapies may be used. For example, N-acetylcysteine can significantly improve prognosis of patients with acetaminophen intoxication ¹². Other interventions may be helpful in other specific settings as: forced diuresis, silibilin and activated charcoal in patients with amanita phalloides poisoning. Due to the development of new antiviral medication Hepatitis B virus infection can be treated even in the acute phase ¹³. Acyclovir may improve prognosis in patients with herpes virus infection and fulminant hepatic failure. Transjugular intrahepatic portosystemic stent shunt is the treatment of choice in patients presenting with fulminant hepatic failure due to acute Budd-Chiari syndrome. Liver support systems that substitute in part the functions including detoxification and homeostasis of metabolism have been developed and tested. The efficacy has been demonstrated in only a small number of patients ¹⁴.

Management of complications

Every attempt should be made to avoid the development of multi-organ dysfunction.

• 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.
• 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 fulminant hepatic failure.
• 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 fulminant hepatic failure 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.
• Cerebral edema: The most common cause of death in fulminant hepatic failure 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 cerebral perfusion pressure 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.
• Encephalopathy: Encephalopathy is a key feature of fulminant hepatic failure. CT of the head should be done in patients with grade 3 encephalopathy and above to assess for intracranial bleeding and cerebral edema.
• Coagulopathy: Like encephalopathy, coagulopathy is also a defining feature of fulminant hepatic failure. 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.

Indication for liver transplantation

In patients with fulminant hepatic failure, the decision to transplant depends on the probability of spontaneous hepatic recovery, which is variable and cannot be predicted reliably. The most important factors for predicting survival in fulminant hepatic failure are the degree of encephalopathy, the patient’s age, and the cause of fulminant hepatic failure. As an example, spontaneous recovery is more likely with lower grades of encephalopathy ¹⁵, which is between 65 to 70 percent in patients with encephalopathy grade I-II and is less than 20 percent in patients with encephalopathy grade IV ¹⁵. Patients older than 40 or less than 10 years are less likely to show spontaneous recovery compared to patients between these ages. Patients with fulminant hepatic failure due to acetaminophen intoxication, hepatitis A, hepatitis B have a better prognosis than those with idiosyncratic drug reactions or Wilson’s disease ¹⁶. Several other variables have been used to predict the probability of recovery but their predictive value have not been established so far: the prothrombin time in addition with serum bilirubin concentration and arterial pH ¹⁷, low serum phosphate levels ¹⁸, high arterial ammonia levels ¹⁹. Liver histology has not been shown to be reliable for predicting recovery, and is not recommended routinely in patients with fulminant hepatic failure ²⁰.

Statistical models have been developed for predicting the outcome in patients with fulminant hepatic failure ²¹. The most commonly used scoring system are the King’s College Hospital criteria (KCC) [ 20 ]. The model was developed in a series of 588 patients with acute liver failure who were managed without transplantation between 1973 and 1985 ¹⁵. These criteria discriminate between acetaminophen induced liver failure and other etiologies (see below ). In acetaminophen-induced fulminant hepatic failure, there are two important criteria for indication to liver transplantation: an arterial pH of less than 7.3, irrespective of grade of encephalopathy; or a prothrombin time (PT) greater than 100 seconds and a serum creatinine concentration greater than 3.4 mg/dL (301 µmol/L) in patients who have grade III or IV encephalopathy. In other causes of fulminant hepatic failure, liver transplantation is indicated in patients who have either a PT greater than 100 seconds, irrespective of the grade of encephalopathy, or any three of following variables: age less than 10 or greater than 40, non-A, non-B hepatitis, idiosyncratic drug reactions, duration of jaundice before development of encephalopathy greater than seven days, PT greater than 50 seconds, or serum bilirubin greater than 18 mg/dL. The accuracy of the King’s College Criteria has been evaluated in separate cohorts. Although, relatively low negative predictive values have been shown for these criteria no other scores have been shown to be superior ²².

King’s College Hospital criteria for liver transplantation in fulminant hepatic failure ¹⁵:

• Acetaminophen-induced disease
  • Arterial pH <7.3 (independent of the grade of encephalopathy)
• OR
  • Grade III or IV encephalopathy and
  • Prothrombin time >100 s and
  • Serum creatinine >3.4 mg/dL (301 μmol/l)
• All other causes of fulminant hepatic failure
  • Prothrombin time >100 s (independent of the grade of encephalopathy)
• OR
• • Any three of the following variables (independent of the grade of encephalopathy)
    • 1. Age <10 years or >40 years
    • 2. Etiology: non-A, non-B hepatitis, halothane hepatitis, idiosyncratic drug reactions
    • 3. Duration of jaundice before onset of encephalopathy >7 days
    • 4. Prothrombin time >50 s
    • 5. Serum bilirubin >18 mg/dl (308 μmol/l)

Fulminant hepatic failure prognosis

Before the introduction of orthotopic liver transplantation for fulminant hepatic failure, mortality was generally greater than 80%. Approximately 6% of orthotopic liver transplantations performed in the United States are for fulminant hepatic failure. However, with improved intensive care, the prognosis is much better now than in the past, with some series reporting a survival rate of approximately 60%. 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 etiologic factor and the development of complications are the main determinants of outcome in fulminant hepatic failure. Patients with fulminant hepatic failure caused by acetaminophen have a better prognosis than those with an indeterminate form of the disorder. Patients with stage 3 or 4 encephalopathy have a poor prognosis. The risk of mortality increases with the development of any complications, which include cerebral edema, renal failure, adult respiratory distress syndrome (ARDS), coagulopathy, and infection.

Preoperative prognostic factors for liver transplantation survival in patients with fulminant hepatic failure appear to include the recipient’s pretransplantation lowest pH and body mass index ²³. According to Hoyer et al ²³, the recipient’s lowest preoperative pH is also independently associated with inpatient mortality, in which the calculated cutoff is a pH of 7.26.

Viral hepatitis

In patients with fulminant hepatic failure due to hepatitis A virus (HAV), survival rates are greater than 50-60%. These patients account for a substantial proportion (10-20%) of the pediatric liver transplants in some countries despite the relatively mild infection that is observed in many children infected with hepatitis A virus . The outcome for patients with fulminant hepatic failure due to other causes of viral hepatitis is much less favorable.

Acetaminophen toxicity

Fulminant hepatic failure due to acetaminophen toxicity generally has a relatively favorable outcome, and the prognostic variables permit reasonable accuracy in determining the need for orthotopic liver transplantation. Patients in deep coma (hepatic encephalopathy grades 3-4) on admission have a higher mortality than patients with milder encephalopathy. An arterial pH of lower than 7.3 and either a prothrombin time (PT) greater than 100 seconds or serum creatinine level greater than 300 mcg/mL (3.4 mg/dL) are independent predictors of poor prognosis.
Non-acetaminophen-induced fulminant hepatic failure

In non-acetaminophen-induced fulminant hepatic failure, a PT of greater than 100 seconds and any three of the following five criteria are independent predictors of a poor prognosis ²⁴:

• Age younger than 10 years or older than 40 years
• Fulminant hepatic failure due to non-A, non-B, non-C hepatitis; halothane hepatitis; or idiosyncratic drug reactions
• Jaundice present longer than 1 week before the onset of encephalopathy
• PT longer than 50 seconds
• Serum bilirubin level greater than 300 mmol/L (17.5 mg/dL)

In patients who meet three or more of these criteria, preparations for orthotopic liver transplantation should be arranged.

The above criteria were developed at King’s College Hospital in London ²⁴ and have been validated in other centers. However, significant variability occurs in terms of the patient populations encountered at any center, and this heterogeneity may preclude widespread applicability.

Many other prognosticating tests have been proposed. The combination of reduced levels of group-specific component (Gc)-globulin (a molecule that binds actin) is reported in fulminant hepatic failure ²⁵ and a persistently increasing PT portends death. These and other parameters have not been widely validated yet.

Wilson disease

Wilson disease that presents as fulminant hepatic failure is almost uniformly fatal unless the patient undergoes orthotopic liver transplantation.

Onset of encephalopathy

Paradoxically, rapid progression from the onset of jaundice (usually the first unequivocal sign of liver disease recognized by the patient or family) to encephalopathy is associated with improved survival. When this interval is less than 2 weeks, patients have hyperfulminant hepatic failure. Although the grade of encephalopathy is a prognostic factor in cases of acetaminophen overdose, it does not correlate with outcome in other settings.

References

1. Daniel Gotthardt, Carina Riediger, Karl Heinz Weiss, Jens Encke, Peter Schemmer, Jan Schmidt, Peter Sauer, Fulminant hepatic failure: etiology and indications for liver transplantation, Nephrology Dialysis Transplantation, Volume 22, Issue suppl_8, 1 September 2007, Pages viii5–viii8, https://doi.org/10.1093/ndt/gfm650
2. Hirode G, Vittinghoff E, Wong RJ. Increasing Burden of Hepatic Encephalopathy Among Hospitalized Adults: An Analysis of the 2010-2014 National Inpatient Sample. Dig. Dis. Sci. 2019 Jun;64(6):1448-1457.
3. Chauhan A, Webb G, Ferguson J. Clinical presentations of Hepatitis E: A clinical review with representative case histories. Clin Res Hepatol Gastroenterol. 2019 Nov;43(6):649-657.
4. Shah NJ, Royer A, John S. Acute Liver Failure. [Updated 2020 Jun 24]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2020 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482374
5. Axley P, Ahmed Z, Arora S, Haas A, Kuo YF, Kamath PS, Singal AK. NASH Is the Most Rapidly Growing Etiology for Acute-on-Chronic Liver Failure-Related Hospitalization and Disease Burden in the United States: A Population-Based Study. Liver Transpl. 2019 May;25(5):695-705.
6. Colaci CS, Mendizabal M, Bessone F. Idiosyncratic Drug-Induced Acute Liver Failure: A Challenging and Distressing Scenario. Curr Drug Saf. 2019;14(2):94-101.
7. [Guideline] European Association for the Study of the Liver. Electronic address: [email protected]. EASL clinical practical guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017 May. 66(5):1047-81.
8. [Guideline] Chalasani NP, Hayashi PH, Bonkovsky HL, et al, for the Practice Parameters Committee of the American College of Gastroenterology. ACG clinical guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. Am J Gastroenterol. 2014 Jul. 109(7):950-66; quiz 967.
9. Davern TJ 2nd, James LP, Hinson JA, et al, for the Acute Liver Failure Study Group. Measurement of serum acetaminophen-protein adducts in patients with acute liver failure. Gastroenterology. 2006 Mar. 130(3):687-94.
10. Rolando N, Harvey F, Brahm J, et al. Fungal infection: a common, unrecognised complication of acute liver failure. J Hepatol. 1991 Jan. 12(1):1-9.
11. Mas A, Rodes J. Fulminant hepatic failure, Lancet, 1997, vol. 349 pg. 1081-1085
12. Zimmerman HJ, Maddrey WC. Acetaminophen (paracetamol) hepatotoxicity with regular intake of alcohol: analysis of instances of therapeutic misadventure, Hepatology, 1995, vol. 22 pg. 767-773
13. Eisenbach C, Sauer P, Mehrabi A, Stremmel W, Encke J. Prevention of hepatitis B virus recurrence after liver transplantation, Clin Transplant, 2006, vol. 20 Suppl 17 pg. 111-116
14. Kjaergard LL, Liu J, Als-Nielsen B, Gluud C. Artificial and bioartificial support systems for acute and acute-on-chronic liver failure: a systematic review, Jama, 2003, vol. 289 pg. 217-222
15. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure, Gastroenterology, 1989, vol. 97 pg. 439-445
16. White H. Rippe J. Evaluation and management of liver failure, Intensive Care Medicine, 1996 Boston Little Brown
17. Hoofnagle JH, Carithers RLJr., Shapiro C, Ascher N. Fulminant hepatic failure: summary of a workshop, Hepatology, 1995, vol. 21 pg. 240-252
18. Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity, Hepatology, 2002, vol. 36 pg. 659-665
19. Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration, Hepatology, 1999, vol. 29 pg. 648-653
20. Hanau C, Munoz SJ, Rubin R. Histopathological heterogeneity in fulminant hepatic failure, Hepatology, 1995, vol. 21 pg. 345-351
21. Dhiman RK, Seth AK, Jain S, Chawla YK, Dilawari JB. Prognostic evaluation of early indicators in fulminant hepatic failure by multivariate analysis, Dig Dis Sci, 1998, vol. 43 pg. 1311-1316
22. Shakil AO, Kramer D, Mazariegos GV, Fung JJ, Rakela J. Acute liver failure: clinical features, outcome analysis, and applicability of prognostic criteria, Liver Transpl, 2000, vol. 6 pg. 163-169
23. Hoyer DP, Munteanu M, Canbay A, et al. Liver transplantation for acute liver failure: are there thresholds not to be crossed?. Transpl Int. 2014 Jun. 27(6):625-33.
24. O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology. 1989 Aug. 97(2):439-45.
25. Schiodt FV, Rossaro L, Stravitz RT, et al, for the Acute Liver Failure Study Group. Gc-globulin and prognosis in acute liver failure. Liver Transpl. 2005 Oct. 11(10):1223-7.