Acute Hepatic Failure


Fulminant hepatic failure, Acute liver failure

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Related Conditions

Acute liver injury

Drug overdose

Liver transplantation

1. Description of the problem

Acute hepatic failure is characterized by acute onset of acute liver injury, hepatocellular dysfunction, hepatic encephalopathy (any grade) and coagulopathy (INR>1.5), all occurring within 26 weeks’ duration, in a patient with previously normal liver function.

Regardless of the cause, typical clinical features include nonspecific symptoms such as malaise, fatigue, nausea, vomiting developing in a previously healthy person, which is then followed by jaundice, rapid onset of altered mental status, and eventually coma.

In general, patients with fulminant hepatic failure can deteriorate very rapidly; therefore, admission to the ICU is advised at the time of diagnosis, preferably in a transplant center, especially when patient has an advanced grade of encephalopathy.

2. Emergency Management

Cause of death in patients with fulminant hepatic failure is cerebral edema and brain herniation.

The following measures should be done or considered:

  • General measures such as elevating the head of the bed to a 30-degree angle, and maintaining the patient’s neck in a neutral position

  • Endotracheal intubation for grade III and IV encephalopathy

  • Minimize stimulation, including airway suctioning.

  • Avoid hypovolemia and hypervolemia.

  • Avoid hypercapnia and hypoxia.

  • Maintain intracranial pressure <15mmHg if an ICP monitor is available.

  • Maintain cerebral perfusion pressure >50mmHg.

  • If ICP monitoring is unavailable, then use other surrogate measures such as maintaining SVJO2 between 55% and 85% or A-V O2 difference between 4 and 6, or serial transcranial Doppler.

  • Adequate use of sedatives and analgesics

In cases of proven intracranial hypertension/cerebral edema, the following should be done or considered:

  • Mannitol boluses 0.5-1g/Kg body weight as long as serum osmolarity is <320mosm/L

  • Induction of moderate hypothermia to 32-33 degrees C

  • Maintain serum sodium level of 145-155mEql/L using intravenous hypertonic saline solution.

  • Induce, with propofol or pentobarbital titrated to burst suppression of 5-10 cycles per second

  • May consider indomethacin 25mg intravenous bolus

  • Plasmapheresis

  • Total hepatectomy as bridge to transplantation

3. Diagnosis

Diagnosis of acute hepatic failure consists of fulfilling clinical features in addition to supportive laboratory and imaging testing. As mentioned above, history should include acute onset (<26 weeks) of liver injury associated with coagulopathy and encephalopathy. Also ask about history of acetaminophen poisoning, viral hepatitis, pregnancy, drug reaction, toxin ingestion such as mushrooms (
Amanita phalloides) or herbal product.

Supportive diagnostic laboratory data include INR>1.5, elevated bilirubin, AST, and ALT of any degree, acidosis, and hypoglycemia.

When acute hepatic failure is suspected, common screening tests should be performed, and these may include the following.

  • Hepatic function panel (bilirubin, AST, ALT, ALP, albumin)

  • PT, INR, PTT

  • CBC

  • Electrolytes, Cr

  • Arterial blood gas/lactate

  • Acetaminophen level, toxicology screen

  • Acute viral serology including EBV, CMV, HSV, hepatitis A and B

  • Autoimmune screen (ANA, ASMA, AMA)

  • AFP

  • Ceruloplasmin, alpha-1-antitrypsin

Liver biopsy, although controversial, may be helpful in certain cases to determine the degree of liver necrosis and elucidate the cause. Greater than 70% necrosis in liver biopsy specimen is associated with almost 90% mortality without liver transplantation. If liver biopsy is performed, transjugular route is preferred, due to coagulopathy.

In encephalopathic patients, CT head can be done to rule out other causes of intracranial pathology. It is not a sensitive test for cerebral edema but it is a specific one. (Figure 1)

Figure 1.

Non contrast CT head showing cerebral edema.

Ultrasound of abdomen with Doppler can aid in the diagnosis of vascular thrombosis such as hepatic vein thrombosis (Budd-Chiari syndrome).

Chest x-ray and ECG should be checked as a baseline.

CT scan of the abdomen and pelvis can aid in the diagnosis of infiltrative diseases involving the liver such as lymphoma, metastatic tumor, and liver necrosis.

MRI of the brain with diffusion is helpful in the evaluation of the degree of cerebral edema; however, patients are usually not stable to go for testing.

Other possible diagnoses

It is important to differentiate acute hepatic failure (FHF) from similar conditions such as acute severe hepatitis, in which case there is no encephalopathy. Also acute-on-chronic liver disease may present in similar fashion, but it occurs in patients with pre-existing liver disease.

4. Specific Treatment

Optimal management of acute hepatic failure should be in the ICU, preferably in a transplant center. Because liver can regenerate, treatment can be limited to general supportive measures. However, liver transplantation may be required for patients who rapidly deteriorate.

It is important to treat specific conditions that led to acute hepatic failure.

  • All patients with acute hepatic failure should be started on N-acetylcysteine (NAC), whether it is related to acetaminophen or not. NAC is a specific antidote for acetaminophen, and if given within first 8-10 hours after acute overdose, it replenishes glutathione stores and prevent development of hepatotoxicity. Duration of NAC is not well established. Some suggest using this until INR normalizes. However, prolonged NAC use has been shown to impair liver regeneration in animal studies.

  • In acute hepatic failure secondary to herpes simplex virus, intravenous acyclovir or ganciclovir should be used. Usually this is started until HSV serology returns negative.

  • In mushroom poisoning, benefits have been reported with use of penicillin G or silibinin, especially when used early after mushroom ingestion.

  • In acute hepatic failure from Wilson’s disease, plasma exchange with fresh frozen plasma is an effective way of removing copper. However, these patients eventually require liver transplantation. Chelating agents such as penicillamine, hemofiltration, or albumin dialysis can also be used.

  • In acute hepatic failure from autoimmune hepatitis, methylprednisone or an immunosuppressant agent can be considered, although its role has not been well established.

  • Delivery is the treatment of choice for patients with acute fatty liver of pregnancy or HELLP syndrome.

  • Urgent chemotherapy is indicated for acute hepatic failure caused by infiltration of lymphoma.

Management of cerebral edema was mentioned earlier in the Emergency Treatment section.

It is essential to aggressively treat encephalopathy, targeting elevated ammonia levels, as there has been a good correlation between an elevated ammonia level of >150 and development of cerebral edema.

  • Lactulose by oral route or enema is commonly used as a first-line therapy despite the lack of its effect on survival.

  • Antibiotics such as metronidazole, neomycin, or rifaximin are used and are directed against ammonia-producing gut flora.

  • Probiotic, acarbose, ornatine aspartate, and sodium benzoate may be considered in treating hepatic encephalopathy.

  • Finally, enteral nutrition without protein restriction should be started.

  • Flumazenil has been used to provide short-term improvement in encephalopathy.

Management of coagulopathy with fresh frozen plasma or vitamin K or Novo VII is not indicated unless an invasive procedure such as ICP monitor placement is planned.

INR is a good indicator for the function of the hepatocyte, and improvement of INR without external correction usually indicates liver regeneration and spontaneous recovery.

Patients with acute hepatic failure commonly have other organ systems affected, such as:

1. Respiratory system: Patients with acute hepatic failure can progressively develop acute lung injury and ARDS. Mechanism include direct lung insult via aspiration in encephalopathic patients or related to the severe inflammatory response syndrome that can cause secondary lung injury. Lung-protective strategy with low tidal volume and high PEEP cannot be recommended because of the associated hypercapnia that will have an adverse outcome on the ICP. In these patients, avoiding hypercapnia is a must and interventions such as ECMO may be considered. However, interventions such as prone ventilation have been used successfully in our institution as long as the head is maintained at midline and a reverse Trendelenberg at 30 degrees is used.

2. Cardiovascular system: Patients with acute hepatic failure typically behave like septic shock patients with severe vasodilation, high cardiac output, and a low systemic vascular resistance. Vasodilation is thought to be due to inflammatory mediators and cytokines.

3. Renal system: Acute renal failure can complicate the course in up to 50-70% of patients with acute hepatic failure.

The etiology of renal failure is multifactorial and includes ATN, hepatorenal syndrome, and direct toxic effect of etiologic agents responsible for liver failure. Early introduction of renal replacement therapy, preferably via CVVH, is recommended. CVVH provides a smoother hemodynamic and fluid management and its use can avoid rapid fluid shift and abrupt changes in ICP that can be associated with intermittent dialysis.

4. Endocrine system: Glycemic control is vital is patients with advanced encephalopathy. The goal is to maintain euglycemia, and nutrition should be started as soon as possible.

5. Sepsis: Patients with acute hepatic failure have impaired host resistance and are at higher risk for bacterial and fungal infection. This is likely due to diminished hepatic reticuloendothelial function and opsonic activity, defective polymorphonuclear leukocyte function, and impaired cell-mediated and humoral immunity. We generally place patients on broad-spectrum antibiotics and antifungal medication during their acute illness.

Drugs and dosages

NAC 150mg/Kg over 15 minutes, followed by 50mg/Kg given over 4 hours, followed by 100mg/Kg over 16 hours

Penicillin G 250mg/Kg/day

Silibinin 20-50mg/Kg/hr for a total of 1400mg per day for 3-4 days

Acyclovir 5-10mg/Kg every 8 hours intravenously

Ganciclovir 5mg/Kg twice a day intravenously

Lactulose 30gm every 2 hours enterally or 300gm every 4-6 hours rectally

Metronidazole 500mg per day orally

Neomyicin 4-12gm per day orally

Rifaximin 1100mg per day orally

The use of artificial and bioartificial liver support devices has been shown to improve biochemical and physiological indices of the liver without any improvement in transplant-free or overall survival. The MARS and Prometheus are examples of artificial systems used.

Bioartificial systems can use either porcine hepatocyte or human blastoma cells, and they are currently under evaluation to establish their role in acute hepatic failure.

5. Disease monitoring, follow-up and disposition

It is essential to monitor patients in specialized ICUs. Frequent monitoring of arterial blood gases, arterial lactate, INR, LFTs, electrolytes, and osmolarity are helpful in guiding therapy.

Patients with advanced encephalopathy (grade III or IV) usually require intubation and intracranial pressure monitoring, whether is done directly via ICP monitors or monitoring using surrogate methods for measurement of cerebral blood flow.

There has been an extensive debate regarding ICP monitor placement and if so which kind (intraparenchymal versus epidural). The fact that ICP monitoring has never proven to improve outcome in patients with FHF has made neurosurgeons reluctant to place them in this high-risk patient population who have significant coagulopathy.

It is our practice to place a pulmonary artery catheter to monitor cardiac output/stroke volume and pulmonary artery pressures.

Recently, less-invasive monitors that measure the pulse pressure variation for volume responsiveness have been used. Hemodynamic monitoring devices will assist us in choosing agents to increase mean arterial pressure. For example, if the cardiac output is low in a patient with hypotension, the choice of agent will be a B1 agonist instead of a pure alpha agent.

Also, we frequently place a jugular bulb catheter to obtain SVJO2 that will assist in evaluating cerebral blood flow and indicate the state of hyperemia or ischemia. This method assumes that cerebral metabolism of oxygen remains constant.

Transcranial Doppler (TCD) is used as a surrogate measure for intracranial pressure, assuming that the diameter of the middle cerebral artery is constant.


The liver is responsible for many vital functions. An abrupt insult to the liver will lead to deterioration of liver function, and this is manifested by encephalopathy, coagulopathy, hypoglycemia, acidosis, brain edema, and eventually multiple organ failure.

A wide variety of substances, including ammonia, glutamine, free fatty acid, bile acids, and benzodiazepine-like substances, can lead to hepatic encephalopathy, by the following mechanisms:

– Direct cellular effect

– Metabolic derangement

– Conversion to false neurotransmitters

Death occurs from cerebral edema, which is thought to be due to ammonia, which causes both cytotoxic and vasogenic cerebral edema due to the cerebral energy failure, excessive intracellular accumulation of osmolyte glutamine, and alteration in aquaporin-4 integral membrane protein. A high level of ammonia is associated with an increased risk of brain edema and herniation in patients with acute hepatic failure.

Each different etiology for acute hepatic failure has its own mechanism leading to acute liver injury:

1) Acetaminophen toxicity

It is the leading cause of acute hepatic failure in the United States and it accounts for almost 50% of cases. Hepatotoxicity usually develops 1-2 days after overdose and ALT and INR usually reach their peak around day 3. Continued increase of ALT beyond day 3 is associated with a 90% mortality rate. Acetaminophen undergoes phase 1 metabolism by hepatic cytochrome P450 (2E1) (CYP2E1) enzymes to the toxic intermediate compound NAPQI, which is rapidly detoxified by hepatic glutathione. In an overdose situation, unconjugated NAPQI accumulates and causes hepatocellular necrosis.

Genetic variability within the population affecting expression of cytokines tumor necrosis factor alpha also has been implicated in determining the severity of drug reaction related to acetaminophen.

2) Idiosyncratic drug reaction

Drug-induced liver damage is a significant cause of death in acute hepatic failure in the Western countries. Hepatocellular injury is common in younger patients, whereas a cholestatic picture is more common in elderly. Most drug reactions are due to single agents. Women generally predominate among patients with idiosyncratic drug injury, in addition to patients with extremes of age, abnormal renal function, obesity, pre-existing liver disease, and concurrent use of other hepatotoxic drugs. Most reactions occur within 4-6 weeks after initiation of treatment and are immunologically mediated either by drug itself or its metabolites. There are several mechanisms, including disruption of intracellular calcium homeostasis, injury to canalicular transport pumps, T-cell-mediated immunological injury, and inhibition of mitochondrial beta oxidation. Common drugs implicated include isoniazid, pyrazinamide, antibiotics (amoxicillin-clavulate, tetracyline, and macrolide), anticonvulsant, antidepressant, NSAIDs, and halothane. Finally, herbal medicines and certain dietary supplements are also implicated.

3) Viral hepatitis

This remains the most common identifiable cause of acute hepatic failure worldwide, with considerable geographic variations. Hepatitis B virus is common in the Far East, and hepatitis E virus is common in the Indian subcontinent. In the United States, ~12% of cases referred for liver transplantation are due to hepatitis A and B, although only 0.2-0.4% of patients with hepatitis A have acute hepatic failure, and 1-4% have hepatitis B.

Hepatitis A infection in patients with pre-existing liver disease can result in acute hepatic failure; therefore it is important to offer hepatitis A vaccinations to this group of patients.

Hepatitis B infection could be due to acute primary HBV infection, reactivation of hepatitis B in chronic hepatitis B, or superinfection with hepatitis D virus. Acute hepatitis B infection is diagnosed by positive IgM antibodies against HBcAg.

Coinfection with HBV and HDV or superinfection by HDV in patients with chronic hepatitis B can also cause acute hepatic failure. The incidence of coinfection is higher when intravenous drug abuse is present.

Infection by HEV occurs in travelers to endemic areas. Pregnant women infected with HEV are more likely to develop acute hepatic failure.

Other viruses implicated in acute hepatic failure include cytomegalovirus (CMV), human herpesvirus-6 (HHV-6), Epstein-Barr virus (EBV), herpes simplex virus (HSV), varicella-zoster virus (VZV), parvovirus B19 in children, adenovirus, paramyxovirus, etc.

4) Miscellaneous

Other less common causes include acute liver ischemia, Budd-Chiari syndrome, veno-occlusive disease, or malignancy associated with poor hepatic blood flow. Rarely Wilson’s disease presents with acute hepatic failure, in patients without a prior history of chronic liver disease. Acute fatty liver of pregnancy occurs in the third trimester, and the treatment of choice is delivery of the fetus.


In North America and Europe, acetaminophen toxicity is the number-one cause for acute hepatic failure, followed by idiosyncratic drug reaction, particularly due to INH, pyrazinamide, valproic acid, and antibiotics. Other causes of acute hepatic failure include acute hepatitis B viral infection (7%), other viral infections (3%), autoimmune hepatitis (5%), ischemic hepatitis (4%), and various other causes such as Wilson’s disease, or pregnancy-related liver abnormalities (5%). Up to 15% of acute hepatic failure cases remain of undetermined etiology.

In the developing world, including the Indian subcontinent, viral hepatitis remains the most common cause for acute hepatic failure.

Both prognosis and management are determined in part by the underlying etiology of acute hepatic failure.


Patients with acute hepatic failure can develop several complications, such as cerebral edema, renal failure, hypoglycemia, and multiple organ failure. The only therapy that is proven to improve outcome is liver transplantation. It is clear that the decision to perform liver transplantation depends on the probability of spontaneous hepatic recovery, which can be difficult to predict.

There are several prognostic criteria that we currently use to guide our decision to transplant or not.

Survival in patients with acute hepatic failure depends on etiology, age, degree of liver necrosis, nature of complications, and the duration of illness, but most importantly the degree of encephalopathy; those with grade IV encephalopathy have a <20% chance of spontaneous recovery.

Various prognostic scoring systems exist. However, none of them are perfect.

King’s College criteria are the most widely used. This system provides a reasonable prediction of the likelihood of death, and need for liver transplantation.

It addresses the liver failure due to acetaminophen and non-acetaminophen toxicity.

Acetaminophen toxicity:

  • Arterial pH <7.3 irrespective of grade of encephalopathy or

  • PT >100 sec (INR >6.5)

  • Serum creatinine >3.4mg/dL

  • Patients with grade III or IV encephalopathy

Non-acetaminophen toxicity:

  • PT >100 sec (INR >6.5) (irrespective of grade of encephalopathy) or any three of the following variables:

    Age <10 or >40 years

    Non-A, non-B hepatitis, halothane hepatitis, idiosyncratic drug reactions

    Jaundice >7 days before onset of encephalopathy

    Serum bilirubin 17.4mg/dL

    PT >50 sec

APACHE II has been found to be of equal accuracy in predicting mortality in acetaminophen-induced liver failure.

A liver biopsy with 70% hepatic necrosis is discriminant of 90% mortality.

Other markers include phosphate >1.2 mmol/L on day 2 or 3, blood lactate >3 mmol/L after adequate resuscitation or Model for End-stage Liver Disease (MELD) score >32.

Special considerations for nursing and allied health professionals.


What's the evidence?

Cho, SM, Murugan, R, Al-Khafaji, A, Fink, MP, Abraham, E, Vincent, JL, Kochanek, P. “Fulminant hepatic failure”. Textbook of Critical Care. 2011. Latest up-to-date comprehensive review on FHF.

Polson, J, Lee, WM. “AASLD position paper: the management of acute liver failure”. Hepatology. vol. 41. 2005. pp. 1179-97. A comprehensive review with many references related to management of acute liver failure.

Tunon, MJ, Alvarez, M, Culebras, JM, Gonzalez-Gallego, J. “An overview of animal models for investigating the pathogenesis and therapeutic strategies in acute hepatic failure”. World J Gastroenterol. vol. 15. 2009. pp. 3086-98. A comprehensive review of the treatment strategies currently available in animal models of acute liver failure.

O’ Grady, JG, Alexander, GJ, Hayllar, KM, Williams, R. “Early indicators of prognosis in fulminant hepatic failure”. Gastroenterology. vol. 97. 1989. pp. 439-45. Classic paper that established the most widely used Kings College Criteria criteria for predicting liver transplant-free mortality in a large cohort of patients with either acetaminophen- or non–acetaminophen-induced FHF.

Heard, KJ. “Acetylcysteine for acetaminophen poisoning”. N Engl J Med. vol. 359. 2008. pp. 285-92. Review of the role of acetaminophen in the management of acute liver failure.

Bjerring, PN, Eefsen, M, Hansen, BA, Larsen, FS. “The brain in acute liver failure. A tortuous path from hyperammonemia to cerebral edema”. Metab Brain Dis. vol. 24. 2009. pp. 5-14. Great review of the pathogenesis of cerebral edema in the setting of ALF.

Dmello, D, Cruz-Flores, S, Matuschak, GM. “Moderate hypothermia with intracranial pressure monitoring as a therapeutic paradigm for the management of acute liver failure: a systematic review”. Intensive Care Med. vol. 36. 2010. pp. 210-3. A comprehensive review of hypothermia’s role in treatment of acute liver failure–induced cerebral edema.