Acute liver failure implies is a life-threatening illness where a previously normal liver [without preexisting cirrhosis ] fails within days to weeks [less than 26 weeks]. The condition leads to a sudden loss of synthetic and detoxification function of the liver which results in coagulopathy and alteration in the mental status [encephalopathy], jaundice, and multiorgan failure.
Read more about Jaundice and its Causes
American association of study of liver disease defines acute liver failure as
A clinical syndrome characterized by evidence of coagulopathy (international normalized ratio [INR] >5) and any degree of altered mental status in a patient without preexisting liver disease and duration of illness <26 weeks.
Acute liver failure can be
- Fulminant hepatic failure- encephalopathy within 8 weeks of the onset of symptoms
- Subfulminant hepatic failure – liver disease for up to 26 weeks before the development of hepatic encephalopathy.
Fulminant liver failure in children differs in presentation and is discussed separately.
Patients with Wilson’s disease, vertically-acquired hepatitis B [from mother to infant] or autoimmune hepatitis may be included in spite of the possibility of cirrhosis if their disease has been manifest for less than 26 weeks.
Read more about Cirrhosis of Liver-Causes, Presentation, and Treatment
The most important step in the assessment of patients with acute liver failure is to identify the cause, and the most important aspect of treatment is to provide good intensive care support.
The incidence of acute hepatic failure is less in the developed world and more in the developing world.
Drug toxicity of liver is the most common factor in the developed nation [acetaminophen overdose is the most common cause] whereas in less developed nations viral hepatitis is the most common cause.
Approximately 1-6 persons per million people are affected in a year in developed nations. Incidence may be higher in the developing world, but data is lacking.
Hepatitis E virus as a cause of acute liver failure typically affects pregnant women and affects women living in or traveling through the endemic areas which include Mexico and Central America, India and the subcontinent, and the Middle East.
Causes of Acute Liver Failure
- Hepatotoxicity due to overdose
- Acetaminophen overdose [most common]
- Chronic alcoholism increases susceptibility
- Fluoroquinolones particularly, moxifloxacin
- Acetaminophen overdose [most common]
- Hepatotoxicity due to idiosyncratic drug reactions
- Can happen with any drug
- Most common drugs listed
- Antibiotics – ampicillin-clavulanate, ciprofloxacin, doxycycline, erythromycin, isoniazid, nitrofurantoin, tetracycline
- Antidepressants – amitriptyline, nortriptyline
- Anesthetic agents – halothane
- Antiepileptics- phenytoin, valproate
- Drugs for lowering lipid levels – atorvastatin, lovastatin, simvastatin
- Immunosuppressive agents -cyclophosphamide, methotrexate
- Salicylates [aspirin] and other NSAIDs
- Other drugs – disulfiram, flutamide, gold, propylthiouracil
- Illicit drugs – ecstasy, cocaine herbal or alternative medicines
- Other drugs – ginseng, pennyroyal oil, teucrium polium, chaparral or germander tea, kawakawa
- Weight loss drugs – OxyELITE
- Toxin Causing hepatotoxicity
- Amanita phalloides mushroom toxin
- Bacillus cereus toxin
- Cyanobacteria toxin
- Organic solvents (eg, carbon tetrachloride)
- Yellow phosphorus
- Viral hepatitis
- Hepatitis A and B most common
- Hepatitis E in pregnancy
- Hepatitis D, as a coinfection or superinfection with hepatitis B virus
- Atypical causes
- Hemorrhagic fever viruses
- Herpes simplex virus
- Epstein-Barr virus
- Dengue virus
- Vascular Causes
- Ischemic hepatitis (consider especially in the setting of severe hypotension or recent hepatic tumor chemoembolization)
- Hepatic vein thrombosis (Budd-Chiari syndrome)
- Hepatic veno-occlusive disease
- Portal vein thrombosis
- Hepatic arterial thrombosis (consider posttransplant)
- Miscellaneous Causes
- Autoimmune hepatitis
- Malignant infiltration of the liver
- Metabolic causes
- Wilson disease
- Alpha1-antitrypsin deficiency
- Fructose intolerance
- Lecithin-cholesterol acyltransferase deficiency
- Reye syndrome
Pathophysiology of Acute Liver Failure
Acute failure of the liver results in disruption of liver functions, both secretory and excretory.
In addition, there occurs multiple organ systems malfunction. The reasons and mechanisms for most of these effects are not known.
Following systems get affected
Hyperbilirubinemia or increased levels of bilirubin are almost always present at the presentation. In fact, the degree of hyperbilirubinemia is an indicator of the severity of liver failure.
There is hepatocellular necrosis which is indicated by increased aminotransferase levels.
The liver is responsible for the synthesis of coagulation factors. Impairment of this function leads to coagulopathy. Coagulopathy due to the impaired hepatic synthesis of coagulation factors is common.
However, overt bleeding is rare.
There is a hyperdynamic circulation with increased heart rate and cardiac output but there is low mean arterial pressure and low systemic vascular resistance It is caused by high blood levels of nitric oxide and cGMP.
Volume depletion [poor oral intake, extravasation of fluid into the third space] leads to worsening of the situation.
Blood loss, if any may also deplete the volume further.
Encephalopathy occurs, most likely due to increased ammonia production by nitrogenous substances in the gut. Cerebral edema occurs in patients with severe encephalopathy [25-35% of patients with grade III encephalopathy and in approximately 75% of those with grade IV encephalopathy] and could lead to intracranial hypertension.
Brain herniation is possible and usually fatal.
The edema occurs because of cell injury [ammonia ] and alteration of cerebral flow.
Acute kidney injury is seen in almost half of the patients. The reason is not known though suggested causes are drug-induced nephrotoxicity; acute tubular necrosis; and abdominal compartment. Due to low levels of blood urea nitrogen [ hepatic synthetic function], the creatinine level better indicates kidney injury.
The defects in the immune system may occur and make the patient prone to infections by bacteria, virus, and fungi.
Common infections that can occur are bacterial pneumonia, urinary tract infection, intravenous catheter-induced sepsis, and spontaneous bacterial peritonitis. Fungal infections occur in 30% of patients with acute liver failure
Following metabolic derangements occur :
- Recurrent hypoglycemia [decrease in blood sugar levels]
- Glycogen depletion occurs in liver
- Defective glycogenolysis [breakdown of glycogen]
- Defective gluconeogenesis [synthesis of glucose]
- Impairment of insulin degradation
- Hyperlactatemia [Increase in lactate levels]
- Poor systemic microcirculation
- Failure of liver to clear lactate.
- Increased lactate levels can aggravate hemodynamic instability
- Decreased serum phosphorus, potassium, and magnesium levels
- Acid-base imbalance
- Metabolic and respiratory alkalosis may occur in early stage
- In case of shock, metabolic acidosis develops
- Glycogen depletion occurs in liver
Noncardiogenic pulmonary edema may develop. Rarely ARDS may occur
Clinical Presentation of Acute Liver Failure
The initial symptoms of acute liver failure are nonspecific. These generally include
- Loss of appetite
- Pain in the abdomen
With advancing disease, the following symptoms are seen
- Altered mental status
- Hemodynamic instability
Complications also may result. These are
- Acute renal failure
- Lung injury
- Metabolic derangements
Hematemesis [blood per mouth] or melena [blackened stools due to the presence of blood] indicate upper gastrointestinal bleeding.
On examination, jaundice is often seen but not always. The liver may not be palpable because of shortening due to necrosis.
An enlarged liver may be seen with heart failure, viral hepatitis, or Budd-Chiari syndrome.
Presence of papilledema, hypertension, and bradycardia indicate increased intracranial pressure.
Rapidly developing ascites and abdominal pain is seen in hepatic vein thrombosis (Budd-Chiari syndrome).
The patient might have reduced vascular resistance leading to a shock-like state.
The patient should be enquired for alcohol use, any prescription drug, family history of liver disease, and any exposure to viral hepatitis risk.
- Acute Decompensation of Cirrhosis
- Eclampsia or preeclampsia [in pregnancy]
- Multiple Organ Dysfunction
- PT/International normalized ratio
- To check for the presence and severity of coagulopathy
- Sensitive marker of hepatic failure
- Prolongation of more than 1.5 warrants aggressive monitoring
- Thrombocytopenia may be seen
- Liver Function Tests
- Elevated bilirubin levels
- Elevated transaminases [aspartate aminotransferase or AST and alanine aminotransferase or ALT].
- Show a drastic rise in acetaminophen toxicity [greater than 10,000 U/L]
- The alkaline phosphatase (ALP) level is usually normal or mildly elevated.
- Serum ammonia
- Important as ammonia levels affect encephalopathy.
- Serum glucose
- Could be low
- Arterial blood lactate levels
- Often elevated
- Impaired tissue perfusion
- Decreased clearance by the liver
- Could be associated with metabolic acidosis or respiratory alkalosis
- Predictor of outcome in acetaminophen toxicity
- Often elevated
- Arterial blood gases
- For acid-base imbalance
- May reveal hypoxemia
- Serum creatinine
- To check renal function
- Serum free copper
- For confirmation or exclusion of Wilson disease
- Serum phosphate
- Elevated phosphate may indicate impaired liver regeneration.
- Autoimmune markers
- Antinuclear antibody
- Anti-smooth muscle antibody
- Immunoglobulin levels
- Important for diagnosis of autoimmune hepatitis.
- Acetaminophen studies
- Acetaminophen levels
- Acetaminophen-protein adducts
- Specific biomarkers of acetaminophen-related toxicity
- Drug screen
- In intravenous drug abusers.
- Blood Cultures
- For infection
- Viral Serologies
- For knowing the type of hepatitis virus infecting the liver.
- Ultrasound of Liver
- May not be required
- Can establish the presence of ascites
- Determine the patency and flow in the hepatic and portal vessels
- Can exclude Budd-Chiari syndrome
- For detailed hepatic anatomy
- Can exclude intra-abdominal pathologies
- CT head for cerebral edema
- Liver Biopsy
- For establishing of tissue diagnosis
- Contraindicated in presence of coagulopathy
- Can identify autoimmune hepatitis, metastatic liver disease, lymphoma, or herpes simplex hepatitis
- Findings vary with the cause
- May show necrosis only without revealing causation
Treatment of liver failure involves providing support to the patient and addressing the specific issues.
Bed rest is recommended. When patients progress to stage III coma, intubation should be performed. Patients with acute liver failure are given nil by mouth and may require large amounts of intravenous (IV) glucose to avoid hypoglycemia.
The patient is frequently evaluated. Grade I encephalopathy patient can be managed in the ward but for higher grades, ICU is needed.
The patient is intensively monitored for encephalopathy and coagulation profile. Fluid management is done for proper hemodynamics.
Unconscious patients require intubation and airway protection when coma becomes severe. A nasogastric tube is inserted for stomach decompression.
When enteral feeding is not feasible, total parental nutrition is started.
Cause-specific treatment, wherever feasible, should be instituted. For example, acetaminophen (paracetamol) overdose is treated with N-acetylcysteine and Amanita phalloides mushroom intoxication is treated with intravenous penicillin G.
Oral silibinin [a water-soluble derivative of silymarin] and oral charcoal may be helpful by binding the mushroom toxin.
For metabolic derangements, replacements should be made by supplementation. The patient should be put on early nasogastric feeding. Parenteral nutrition should be considered where enteral nutrition cannot be given.
Propofol may be used for sedation and fentanyl for pain. The patient should not be given sedatives except short-acting benzodiazepines for short period for agitation that can not be managed.
The head end of the bed should be elevated at 30 degrees.
Lactulose might help prevent or treat cerebral edema by reducing ammonia levels. The patient should be monitored for raised intracranial pressure (ICP) and treated for when present. Frequent neurologic evaluation for signs of elevated ICP should be conducted.
Intravenous mannitol administration helps to reduce intracranial pressure.
Hyperventilation reduces the partial pressure of carbon dioxide in the blood can quickly lower ICP via vasoconstriction, causing decreased cerebral blood flow, but this effect is short-lived.
Barbiturate agents (thiopental or pentobarbital) may also be considered when severe intracranial hypertension (ICH) does not respond to other measures.
Moderate hypothermia may prevent or control ICH. It can be achieved by using external cooling blanket.
Seizures should be treated with phenytoin or short-acting benzodiazepines.
The aim of therapy in acute liver failure is to maintain intracerebral pressure less than 20 mm of Hg and cerebral perfusion pressure greater than 60 mm of Hg. Monitoring may be indicated in a subset of patients.
An arterial line should be placed for continuous blood pressure monitoring.
If systolic blood pressure is less than 80 mm Hg, fluid resuscitation is required.
Non-responsive patients should be given norepinephrine. The goal is to achieve a mean arterial pressure of 75 mm of Hg.
Vasopressin or its analog terlipressin may be used as an adjuvant.
Adrenal insufficiency should be looked for when patients do not respond to fluid resuscitation and vasopressors.
In the absence of bleeding, the patient is just monitored.
Fresh frozen plasma, recombinant factor VIIa and platelet transfusions are used for treatment coagulopathy when bleeding occurs or a major procedure is planned.
The goal is to maintain INR less than 1.5 when an invasive procedure is planned.
Recombinant factor VIIa should be considered when fresh frozen plasma fails to correct INR adequately.
Cryoprecipitate is recommended in patients who have low fibrinogen levels (<1 g/L).
Thrombocytopenia should be corrected if the platelet count is <10,000 cells/mm3, in the presence of active bleeding or when an invasive procedure is planned.
Liver transplantation is the only definitive therapy for patients with irreversible liver injury. The overall survival of acute liver failure has improved to 60% after liver transplantation.
When the allograft is immediately available, some patients may be supported with support with a bioartificial liver or artificial liver support system. This is a short-term measure only to buy time.
Patients with early grades of encephalopathy at presentation have a better prognosis than those presenting with an advanced coma. Early identification of patients that require liver transplantation is evaluated using King’s College criteria. A discussion on transplant warrants another article and is discussed separately.
Hepatocyte transplantation is under trial.
Liver transplantation has reduced overall mortality of acute liver failure from 80 percent to 60 percent.
The etiology [cause] and presence of complications are the main determinants of outcome in acute liver failure.
For example, acetaminophen toxicity, hepatitis A have a better prognosis.
Patients with severe encephalopathy have a poor prognosis. The risk of mortality increases with the development of any complications.
Following are predictors of poor outcome
- An arterial pH of lower than 7.3
- Prothrombin time (PT) greater than 100 seconds
- Serum creatinine level greater than 3.4 mg/dL
When acute liver failure is due to causes other than acetaminophen, and any three of the following are independent predictors of poor prognosis:
- Patient age less than 10 years or older than 40 years
- Fulminant hepatic failure due to
- Non-A, non-B, non-C hepatitis
- Idiosyncratic drug reactions
- Jaundice is present for more than one week before the onset of encephalopathy
- PT longer than 50 seconds
- Serum bilirubin level greater than 300 mmol/L (17.5 mg/dL)
If prothrombin time is greater than 100 seconds, it singly predicts poor prognosis.
Wilson’s disease that presents as fulminant hepatic failure is almost uniformly fatal unless the patient undergoes transplant.
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