Acute liver failure overview

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief:  Husnain Shaukat, M.D [2]

## Overview

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Acute liver failure is a sudden and severe loss of liver function with evidence of encephalopathy and coagulopathy with elevated prothrombin time (PT) and (INR) in a person without a preexisting liver disease. The effects of acute liver failure are due to the loss of its metabolic, secretory and regulatory effects. This results in the accumulation of toxic substances which causes deleterious effects. The major pathophysiological mechanisms of morbidity and mortality in patients with acute liver failure are cerebral edema, hypoperfusion to the liver, idiosyncratic drug reactions, depletion of glutathione and viral hepatitis. Acute liver failure may be classified on the basis of the time interval between the onset of symptoms and the development of encephalopathy as hyperacute, acute, subacute, fulminant, subfulminant and late-onset. Acetaminophen toxicity is the most common cause of acute liver failure in the developed world and viral hepatitis (most commonly hepatitis A, hepatitis B and hepatitis E) is most common in the developing world. Acute liver failure must be differentiated from other diseases that cause signs and symptoms of jaundice, coagulopathy, and encephalopathy. The further evaluation should include liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, gamma-glutamyl transpeptidase [GGT], total and direct bilirubin, albumin) and prothrombin time/INR. The diagnosis of acute liver failure is made in the presence of coagulopathy (international normalized ratio [INR], >1.5), hepatic encephalopathy and illness duration of fewer than 24 weeks. The commonly used prognostic indicators to predict mortality in patients with acute liver failure and to identify patients who are likely to benefit from liver transplantation include kings college criteria (use for liver transplantation) and model for end-stage liver disease (MELD) score (to predict mortality in patients with chronic and acute liver disease). Common symptoms of acute liver failure include anorexia, malaise, pruritis, bleeding tendencies, confusion, disorientation, and stupor. In the initial stages of acute liver failure, the patient may have mild mental status changes such as altered sleep pattern but may become confused or develop coma in the later stages as the disease progresses. Physical examination of acute liver failure is remarkable for hepatomegaly, right upper quadrant abdominal tenderness, ascites and [[encephalopathy. The management of acute liver failure involves resuscitation of the patient with adequate nutrition and optimization of fluid balance, monitoring and treating the complications and providing nutritional support. The patient should be treated in an appropriate setting preferably a center with liver transplantation facility. Infections and sepsis are common occurrences of fulminant liver failure. The high standards of infection control should be practiced to minimize the nosocomial sepsis. In stage 3 and 4 encephalopathy, intubation and mechanical ventilation are indicated. Acetylcysteine is used for acetaminophen poisoning for up to 72 hours after ingestion. Every effort should be made to seek out the specific cause of acute liver failure since specific treatments are available for some causes of acute liver failure. However, inappropriately prolonged investigations may make surgery impossible because of progression of sepsis and multiorgan failure. The candidates for liver transplantation should be identified as quickly as possible because the progression to multiorgan failure results in deterioration in many patients who are awaiting liver transplantation. While many people who develop acute liver failure recover with supportive treatment, liver transplantation is often required in people who continue to deteriorate or have poor prognostic factors. Effective measures for the primary prevention of acute liver failure include vaccination, proper personal hygiene, maintaining proper body weight, taking precautions while handling needles, blood, body piercing, tattooing and sexual practices. Effective measures for secondary prevention of acute liver failure include management of chronic liver disease and its complications.

## Historical Perspective

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The hepatic and mental disturbance association dates back to Hippocrates. In the sixteenth century, Ballonius was the first to describe hepatic coma. In 1860, Frerichs described the terminal mental changes in patients with cirrhosis and yellow atrophy of the liver. In 1970, Trey and Davidson introduced the term fulminant hepatic failure. Later it was suggested that the term fulminant should be confined to patients who develop jaundice to encephalopathy within 2 weeks. Terms subfulminant hepatic failure and late-onset hepatic failure were coined for onset between 2 weeks to 3 months and for 8 weeks to 24 weeks respectively. The term of acute liver failure was proposed by King's college group.

## Classification

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Acute liver failure may be classified on the basis of the time interval between the onset of symptoms and the development of encephalopathy as hyperacute, acute, subacute, fulminant, subfulminant and late-onset. The different classification systems used are O’Grady system, Bernuau system, and Japanese system. This classification based on time duration provides helpful clues about etiology, complications, and prognosis such as in hyperacute cases, the cause is usually viral infections or acetaminophen toxicity. The subacute cases can be due to idiosyncratic drug reactions and can also be confused with chronic liver disease. The hyperacute liver failure has a better prognosis than subacute liver failure.

## Pathophysiology

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Acute liver failure is a sudden and severe loss of liver function with evidence of encephalopathy and coagulopathy with elevated prothrombin time (PT) and (INR) in a person without a preexisting liver disease. The effects of acute liver failure are due to the loss of its metabolic, secretory and regulatory effects. This results in the accumulation of toxic substances and causes deleterious effects. The major pathophysiological mechanisms of morbidity and mortality in patients with acute liver failure are cerebral edema, hypoperfusion to the liver, idiosyncratic drug reactions, depletion of glutathione and viral hepatitis. Cerebral edema in acute liver failure can be due to vasogenic and cytotoxic effects. In cytotoxic type, there is intracellular swelling and blood-brain barrier is intact. In vasogenic type, the blood-brain barrier breaks down and plasma and water accumulate in the extracellular space. The increased ammonia concentration in liver failure in combination with the glutamine produced by the astrocytes causes excess levels of glutamine with the help of enzyme glutamine synthetase. The excess glutamine is cytotoxic and can disturb the osmotic gradient which can result in brain swelling. In acute liver failure, the increased levels of nitric oxide in the circulation can also disrupt the cerebral autoregulation. Acetaminophen is the leading cause of acute liver failure in the United States. Acetaminophen causes dose-related toxicity. Toxicity is rarely seen at normal therapeutic doses (up to 4 g/day) without underlying liver disease. Viral hepatitis is the leading cause of acute liver failure in the developing world. Hepatitis A, B, D (associated with B), and E (in endemic countries) are commonly associated with acute liver failure.

## Causes

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The causes of acute liver failure can be categorized into viral, drugs and toxins, vascular and metabolic. Common causes of acute liver failure include acetaminophen toxicity, viral hepatitis (most commonly hepatitis A, hepatitis B and hepatitis E), alcoholic hepatitis, autoimmune, sepsis, right heart failure and idiopathic. Acetaminophen toxicity is the most common cause of acute liver failure in the developed world and viral hepatitis (most commonly hepatitis A, hepatitis B and hepatitis E) is most common in the developing world.

## Differentiating Acute liver failure from other Diseases

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Acute liver failure must be differentiated from other diseases that cause signs and symptoms of jaundice, coagulopathy, and encephalopathy. The differentials include acute hepatitis, cholestatic jaundice, and hemolytic jaundice. The common causes of acute hepatitis causing acute liver failure include acetaminophen toxicity, viral hepatitis, alcoholic hepatitis, autoimmune hepatitis, acute fatty liver of pregnancy, Wilson's disease, ischemic hepatitis and hepatic congestion due to right heart failure and Budd–chiari syndrome.

## Epidemiology and Demographics

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The incidence of acute liver failure in the United States is 2000-2300 cases annually. In the year 2009, the diagnosis of acute hepatic necrosis was 420 cases per 100,000 cases of all adult liver transplants in the United States. In the year 1998 to 2008, according to the United States acute liver failure (ALF) registry statistics, the most common cause of acute liver failure was acetaminophen with 46000 cases per 100,000 individuals and 12000 cases per 100,000 individuals for other drugs. Acute hepatitis B is the cause of acute liver failure in 1000 individuals per 100,000 individuals but it increases to 20,000 individuals per 100,000 individuals with hepatitis D virus co-infection. Acute liver failure is more common in women than men, and women with acute liver failure were older than men. Women are more commonly affected with autoimmune hepatitis and hepatitis E viral infection than men. The acute liver failure is seen more in the white population with 74,000 individuals per 100,000 individuals, 10,000 individuals per 100,000 individuals in the Hispanics, 3000 individuals per 100,000 individuals in the Black population and 5000 individuals per 100,000 individuals in the Asian population. The most common cause of acute liver failure in the developing countries is viral infection mainly hepatitis A and hepatitis B. The most common cause of acute liver failure in the developed world is acetaminophen toxicity. The acute liver failure secondary to hepatitis B is also on the rise in the developed world due to immigration.

## Risk Factors

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The risk factors in the development of acute liver failure can be categorized into viral, drugs and toxins, vascular, metabolic and systemic illnesses. Common risk factors of acute liver failure include acetaminophen toxicity, viral hepatitis (most commonly hepatitis A, hepatitis B and hepatitis E), alcoholic hepatitis, autoimmune hepatitis, sepsis, heart failure, renal failure, immunocompromised state, older age and malnourishment. Acetaminophen toxicity is the most common risk factor of acute liver failure in the developed world and viral hepatitis (most commonly hepatitis A, hepatitis B and hepatitis E) is most common in the developing world.

## Screening

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There is insufficient evidence to recommend routine screening for an acute liver failure.

## Natural History, Complications and Prognosis

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Acute liver failure is a sudden and severe loss of liver function with evidence of encephalopathy and coagulopathy with elevated prothrombin time (PT) and (INR) in a person without the preexisting liver disease. The commonly used time duration for an acute liver disease is < 26 weeks. Acute liver failure can be hyperacute, acute or subacute depending upon how long the patient has signs and symptoms of liver failure. If left untreated, patients with acute liver failure can eventually progress to develop confusion, comatose state, and death. Common complications of acute liver failure are hepatic encephalopathy, cerebral edema, coagulopathy, a systemic inflammatory response syndrome, acute renal failure and acute pulmonary failure. The important factors in determining the prognosis of acute liver failure include patients' age, the severity of encephalopathy and the underlying cause of acute liver failure. The commonly used prognostic indicators to predict mortality in patients with acute liver failure and to identify patients who are likely to benefit from liver transplantation include kings college criteria ( use for liver transplantation ) and model for end-stage liver disease (MELD) score (to predict mortality in patients with chronic and acute liver disease).

## Diagnosis

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Acute liver failure is a sudden loss of hepatic function in a patient without any evidence of underlying liver disease. Acute liver failure should be suspected in a patient with mental status changes, jaundice, and right upper quadrant pain or nonspecific symptoms such as malaise, nausea and fatigue of fewer than 26 weeks. The further evaluation should include liver function tests (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline phosphatase, gamma-glutamyl transpeptidase [GGT], total and direct bilirubin, albumin) and prothrombin time/INR. The diagnosis of acute liver failure is made in the presence of coagulopathy (international normalized ratio [INR], >1.5), hepatic encephalopathy and illness duration of fewer than 24 weeks.

### Diagnostic Criteria

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Acute liver failure is a sudden loss of hepatic function in a patient without any evidence of underlying liver disease. The diagnosis of acute liver failure is made in the presence of coagulopathy (international normalized ratio [INR], >1.5), hepatic encephalopathy and illness duration of fewer than 24 weeks.

### History and Symptoms

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Obtaining the focused history is an important aspect of making a diagnosis of an acute liver failure. It provides insight into the cause, precipitating factors, prognosis and the correct therapy. Specific areas of focus when obtaining a history from the patient include timing of the onset of jaundice, alcohol intake, medications, family history, risk factors of viral hepatitis and past medical history. Common symptoms of acute liver failure include anorexia, malaise, pruritis, bleeding tendencies, confusion, disorientation, and stupor.

### Physical Examination

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Patients with acute liver failure may appear lethargic, anorexic and fatigue. In the initial stages of acute liver failure, the patient may have mild mental status changes such as altered sleep pattern but may become confused or develop coma in the later stages as the disease progresses. Physical examination of acute liver failure is remarkable for hepatomegaly, right upper quadrant abdominal tenderness, ascites and encephalopathy.

### Laboratory Findings

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Acute liver failure can present with nonspecific symptoms and it occurs in healthy individuals without a previous history of liver disease. So, the initial labs in the acute liver failure are planned to evaluate both the etiology and the severity of the disease. All patients with clinical or laboratory evidence of moderate to severe acute hepatitis should have an immediate measurement of prothrombin time and careful evaluation of mental status. If the prothrombin time is prolonged (INR ≥1.5) and there is any evidence of altered sensorium, the diagnosis of acute liver failure should be strongly suspected and hospital admission is mandatory.

### Imaging Findings

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There are no chest x-ray findings associated with acute liver failure. Computed tomography (CT) scanning can also be done in the workup of acute liver failure especially when the ultrasound is not very sensitive as in case of obese patients and massive ascites. CT scan of the head can be done to exclude other causes of altered mental status such as brain abscess or intracranial mass lesions as well as cerebral edema which is a complication of acute liver failure. Acute liver failure can be accompanied by renal failure. Intravenous contrast used with CT scan can further aggravate renal failure. An ultrasound of the liver can be done in the workup of acute liver failure to evaluate ascites and other causes of hepatic failure. It can also assist in the evaluation of intrahepatic mass, abscess, cirrhosis, and malignancy. A doppler ultrasonography can also evaluate the flow and patency of hepatic vessels (hepatic vein and hepatic artery) to rule out Budd-Chiari syndrome, hepatic congestion, and portal hypertension. In a patient with acute liver failure secondary to hepatic ischemia (elevated transaminases), an echocardiogram can be used to identify the etiology if history, labs and other imaging studies do not identify the cause of hepatic ischemia.

### Other Diagnostic Studies

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Liver biopsy can be used to identify the definite etiology of acute liver failure. A percutaneous liver biopsy is often contraindicated due to the risk of coagulopathy and overt bleeding. The transjugular liver biopsy is helpful in the workup of acute liver failure if there is a risk of bleeding and findings of biopsy depends on the etiology of the acute liver failure. Liver biopsy can identify the definite cause of acute liver failure such as Wilson disease, autoimmune hepatitis, malignant infiltration or acute fatty liver of pregnancy.

## Treatment

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### Medical Therapy

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The management of acute liver failure involves resuscitation of the patient with adequate nutrition and optimization of fluid balance, monitoring and treating the complications and providing nutritional support. The patient should be treated in an appropriate setting preferably a center with liver transplantation facility. Infections and sepsis are common occurrences of fulminant liver failure. The high standards of infection control should be practiced to minimize the nosocomial sepsis. The diagnosis of hepatic injury in hyperacute cases can be a challenge as jaundice can be minimal during that period and confusion or agitation may be the dominant findings. In acute liver failure, the sedative medications should be used with caution as they may mask the worsening encephalopathy and the hepatic clearance may be decreased which can aggravate the sedative effect. However, the short-acting benzodiazepines in low dose can be used during agitation. In acute liver failure patients, opioids are avoided as they decrease the seizure threshold. H2 receptor blockers and proton pump inhibitors are indicated to prevent and treat stress gastropathy. In stage 3 and 4 encephalopathy, intubation and mechanical ventilation are indicated. Acetylcysteine is used for acetaminophen poisoning for up to 72 hours after ingestion. It can dramatically improve the outcome if administered within eight hours of acetaminophen ingestion. The patients with acute liver failure may not have a clear history of acetaminophen intake. Therefore, the threshold for administering acetylcysteine should be low and can also be administered in an acute liver failure of unknown etiology. Every effort should be made to seek out the specific cause of acute liver failure since specific treatments are available for some causes of acute liver failure. However, inappropriately prolonged investigations may make surgery impossible because of progression of sepsis and multiorgan failure.

### Surgery

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The candidates for liver transplantation should be identified as quickly as possible because the progression to multiorgan failure results in deterioration in many patients who are awaiting liver transplantation. While many people who develop acute liver failure recover with supportive treatment, liver transplantation is often required in people who continue to deteriorate or have poor prognostic factors. The patient's candidacy for liver transplantation should be assessed based on the patient's clinical scenario, as well as upon social and financial factors. Patient evaluation for liver transplantation should be done as soon as possible and before encephalopathy occurs. The key common feature among various prognostic evaluation systems is the presence of encephalopathy. Other common features are patient's age and severity of the liver injury which is assessed by coagulopathy or jaundice. To address the limitations, a wide variety of prognostic systems have been proposed but none has universal acceptance. King's college criteria is the most well-characterized evaluation system. Common absolute contraindications for liver transplantation include untreated sepsis, uncontrolled extrahepatobillary infection, alcohol abuse, uncontrolled cardiopulmonary disease, cholangiocarcinoma, metastatic malignancy to the liver and life-threatening systemic illness. Common postoperative complications for liver transplantation include infections, graft failure, vascular compromise, biliary stricture or stenosis, anastomosis leakage, thrombosis of hepatic artery and portal vein and depression.

### Primary Prevention

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Effective measures for the primary prevention of acute liver failure include vaccination, proper personal hygiene, maintaining proper body weight, taking precautions while handling needles, blood, body piercing, tattooing and sexual practices.

### Secondary Prevention

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Effective measures for secondary prevention of acute liver failure include management of chronic liver disease and its complications. In patients with resolved hepatitis B infection, antiviral prophylaxis can be considered in the patients who have a risk of reactivation such as during increasing levels of immunosuppression.

## References

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