Acute Liver Failure

Introduction

Arvind R Murali, MD
KV Narayanan Menon, MD

Acute liver failure (ALF) is a rare but a life-threatening condition. ALF causes severe injury and massive necrosis of hepatocytes resulting in severe liver dysfunction that can lead to multi-organ failure and death. It can occur in patients without preexisting liver disease and cause rapid deterioration of liver function within days. Patients with ALF are almost always managed in an intensive care unit and in some cases need a liver transplantation to prevent death. Therefore, all physicians need to recognize the early signs of ALF and employ appropriate lifesaving interventions.

Incidence

Acute liver failure is a rare clinical syndrome with an annual incidence of less than 10 cases per million population in the developed world. In the United States, approximately 2,000 cases of ALF are diagnosed each year. Acute liver failure often affects younger people and has a high morbidity and mortality. Geographically, ALF is more common in developing countries due to the higher incidence of infectious hepatitis in these regions.

Classification

O'Grady and colleagues classify ALF into 3 categories based on the interval between the development of jaundice and the onset of encephalopathy.

1. Hyperacute liver failure: the onset of encephalopathy less than 7 days after the development of jaundice.
2. Acute liver failure: the onset of encephalopathy 8 to 28 days after the development of jaundice.
3. Sub-acute liver failure: the onset of encephalopathy more than 5 weeks but less than 12 weeks after the development of jaundice.

This classification may help to inform the etiology of the liver failure. For example, hyperacute liver failure is usually from acetaminophen toxicity or viral infections, while subacute liver failure is usually caused by an idiosyncratic drug-induced liver injury, autoimmune hepatitis or Wilson’s disease. However, the classification does not have a prognostic significance that is distinct from the etiology of the illness itself.

Etiology

Acute liver failure has many etiologies (Table 1). The most common cause of ALF in the U.S. and Western Europe is drug-induced liver injury. In developing countries, viral hepatitis is the predominant cause of ALF. Emphasis on vaccination and improved public sanitation measures have reduced the incidence of infectious hepatitis in the developed counties.

Table 1: Etiologies of ALF

NSAID = nonsteroidal anti-inflammatory drug, CMV = cytomegalovirus, EBV = Epstein-Barr virus, HELLP = hemolysis, elevated liver enzymes, low platelet count.

Identifying the etiology of ALF is important for defining the treatment approach and prognosis. For example, the timely use of antidotes for several forms of acute liver injury depends on identifying the inciting agent.

Drug-induced acute liver injury

Drug-induced liver injury accounts for about 50% of ALF cases in the U.S. Many over-the-counter medications, dietary supplements, weight loss medications, and prescription medications can lead to acute liver injury (Table 1). Liver injury from drugs may be dose-dependent and predictable (acetaminophen toxicity) or idiosyncratic and unpredictable (carbamazepine, valproate). Idiosyncratic drug-related hepatotoxicity can occur within 6 months of drug administration. Obtaining a detailed medication history is important and should include the dosage, therapy start, duration of treatment, and last dose. History regarding recent mushroom ingestion and use of herbal products should also be elicited. Despite a good history, determination of a particular drug as the cause of hepatotoxicity is usually a diagnosis of exclusion, thus alternative causes for ALF should be excluded in all cases of suspected drug-induced liver injury.

Acetaminophen hepatotoxicity

Acetaminophen hepatotoxicity is the most common cause of ALF in the U.S. and Western Europe. It results from excessive ingestion of acetaminophen either from suicidal ideations or inadvertent use of supratherapeutic doses for pain control. Hepatic toxicity from acetaminophen is due to increased production of the toxic metabolite N-acetyl-p-benzoquinoneimine. Acetaminophen toxicity is dose related with typically at least 10 gram/day required to cause ALF; however, patients with history of chronic alcohol abuse and who are on concomitant cytochrome P450 enzyme inducing drugs are at increased risk of developing acetaminophen toxicity at substantially lower acetaminophen doses. More recently, patients with cirrhosis have been reported to develop acetaminophen toxicity at lower doses, especially when ingested over many days.

Viral hepatitis

Viral hepatitis is the most common cause of ALF worldwide and is the predominant cause of ALF in developing countries. Hepatitis A, B, and E infections have been implicated, as well as other rare viral causes including herpes simplex virus, Epstein-Barr virus, cytomegalovirus, and parvoviruses.

Hepatitis A and E viruses are transmitted through the fecal-oral route mainly through consumption of contaminated food or water and are associated with poor hygiene and sanitation. Hepatitis A viral infection occurs in about 1.5 million people a year worldwide; however, less than 1% of patients affected by hepatitis A virus develop ALF. Hepatitis A infection follows a more severe course in adults compared with children and usually results in a hyperacute or acute pattern of liver failure. In elderly patients, a subacute pattern of liver failure may develop and it is usually associated with poorer outcomes. In developed countries, improved sanitary conditions as well as effective use of hepatitis A vaccination has led to a lower incidence of acute hepatitis A.

Hepatitis E infection also has mortality rate of less than 1%. Elderly patients and patients with preexisting liver disease have poor outcomes. Hepatitis E virus infection is an important cause of viral hepatitis in pregnant women and is thought to be associated with high rates of mortality, though recent studies have not confirmed this. However in neonates, hepatitis E results in ALF in more than half of patients infected through vertical transmission.

Hepatitis B is the most common cause of ALF in Asia and parts of Europe. It is transmitted through exposure to blood or other bodily fluids of infected persons. Vertical transmission is also an important factor in East Asian countries. Less than 1% of patients infected with hepatitis B will develop ALF; however the mortality from hepatitis B-induced ALF is higher than in those with hepatitis A or E infection. A particularly important clinical scenario is patients with previously stable, subclinical hepatitis B virus infection with without established chronic liver disease. Reactivation of hepatitis B infection in these patients may lead to ALF. Reactivation can occur spontaneously but it is most commonly seen when the patient is immunocompromised. For example, chemotherapy-induced immunosuppression can cause a reactivation of previously subclinical hepatitis B infection causing ALF. The prognosis is particularly poor in this group of patients and prompt identification of subclinical hepatitis B infection in these high-risk patients and appropriate antiviral prophylaxis prior to chemotherapy may help reduce mortality.

Hepatitis C virus is not believed to cause ALF in the absence of a coexisting etiology. However, rare cases of ALF from hepatitis C have been reported.

Mushroom poisoning

Mushroom poisoning, though rarely seen, is an important cause of ALF. Amanita phalloides is the most common mushroom to cause hepatotoxicity. The diagnosis should be suspected in patients with a history of recent mushroom ingestion and in those who present with severe gastrointestinal (GI) symptoms such as nausea, vomiting, abdominal cramping, and diarrhea. Symptoms usually start within 6 to 12 hours of mushroom ingestion and AFL occurs in a subset of patients. The diagnosis of mushroom poisoning is made clinically because no blood test is available to confirm mushroom ingestion.

Reversible causes of ALF

Autoimmune hepatitis can present as ALF. Prompt identification and early institution of immunosuppressive therapy may decrease the need for liver transplantation in patients who respond to medical treatment. Patients with hematological malignancies such as lymphoma rarely present with ALF. Severe liver involvement may be seen in some systemic infections such as leptospirosis, rickettsial infections, hepatic amoebiasis, dengue, malaria, and typhoid. In these situations, early administration of targeted antimicrobial medication may reverse ALF and restore normal functioning.

Miscellaneous

Wilson’s disease can rarely present as ALF (see Wilson’s disease).

Malignancy may also lead to ALF, either due to the presence of multiple hepatic metastases, or as a result of diffuse infiltration of the liver by malignant cells, usually in hematologic malignancies. Primary hepatic malignancies such as fibrolamellar carcinoma and multifocal hepatocellular carcinoma are rarely reported causes of ALF.

Any condition that results in acute ischemic injury to the liver can lead to ALF. Budd Chiari syndrome, prolonged systemic hypotension and sepsis are some of the clinical conditions that can cause hepatic ischemia, hepatocyte injury and necrosis, and subsequent ALF.

Pregnancy specific liver diseases can result in ALF and may be associated with significant morbidity and mortality. Preeclampsia-associated liver diseases, acute fatty liver of pregnancy, and hemolysis, elevated liver enzymes and low platelet count (HELLP) syndrome can all lead to ALF. It is important to recognize these conditions early and provide appropriate treatment to decrease maternal and fetal morbidity and mortality. For more information, see Liver Disease in Pregnancy.

Clinical Features

The manifestation and timing of the clinical features of ALF vary based on the etiology of ALF. The initial manifestation of ALF may range from simple constitutional symptoms such as malaise, fatigue, nausea, vomiting, and abdominal pain to severe hypotension, sepsis, and hepatic encephalopathy. In patients in the former group, the diagnosis of ALF may be missed or delayed due to further testing and the opportunity to provide definitive therapy is lost. Therefore it is important to have a high index of suspicion to make an early diagnosis of ALF.

The clinical course of ALF typically follows that of multiple organ failure. The pathophysiology includes loss of hepatocyte function and the release of toxins and cytokines due to liver necrosis causing severe systemic inflammation and secondary bacterial infections from decreased immunity in ALF.

Hemodynamic alterations

Acute liver failure results in circulatory dysfunction. The mechanism is multifactorial and is initially associated with hypovolemia due to a combination of poor oral intake and increased fluid loss. As ALF progresses, the release of circulatory cytokines and inflammatory mediators cause systemic vasodilation and worsens hypotension. The end result is the combination of low systemic vascular resistance, systemic hypotension, and increased cardiac output resembling septic shock. These hemodynamic derangements lead to decreased peripheral tissue oxygenation and eventually multiorgan failure.

Central nervous system manifestations of ALF

Encephalopathy

Encephalopathy is a key neurological manifestation of ALF and is necessary to make a diagnosis of ALF. Encephalopathy encompasses a number of clinical manifestations of varying severity, ranging from drowsiness, slowed mentation, cognitive impairment, confusion, and euphoria to deep coma. Hepatic encephalopathy is usually classified based on severity from grade 1 to grade 4. Grade 1 is defined as altered behavior with euphoria, anxiety, and decreased attention span; grade 2 is marked by disorientation, lethargy or asterixis; grade 3 is associated with marked disorientation, incoherent speech, and somnolence; and grade 4 being comatose or unresponsive to verbal or pain stimuli. Prognosis is directly related to the grade of encephalopathy with higher grades of encephalopathy portending a worse prognosis.

Pathogenesis of hepatic encephalopathy. The pathogenesis of hepatic encephalopathy is not fully understood. It has been linked to the presence of inflammatory mediators and circulatory neurotoxins such as ammonia. Acute liver failure leads to both systemic inflammation and local inflammation in the brain, resulting in the release of cytokines and neurotoxins. These products alter the cerebral blood flow and the blood-brain permeability barrier causing astrocyte swelling, cerebral edema, and encephalopathy. In addition, hemodynamic alterations and systemic hypotension associated with ALF further contribute to the development of encephalopathy.

Ammonia and hepatic encephalopathy. Ammonia is a byproduct of the catabolism of nitrogen compounds and is toxic at high concentrations. The human body excretes ammonia through the urea cycle, which takes place mainly in the liver. Through the urea cycle, toxic ammonia is converted to metabolically inert urea. In addition to ammonia, other nitrogenous wastes are also metabolized to nontoxic substances by the liver. Ammonia is also metabolized to a minor extent by the brain and the muscle. Astrocytes are the brain cells that metabolize ammonia. In these cells ammonia is detoxified by utilizing glutamate, which is converted to glutamine. In ALF, increased levels of ammonia and other nitrogenous wastes in the circulating blood result increased exposure to ammonia by the brain. This leads to increased production of glutamine in the astrocytes and because glutamine is an osmolyte, water moves into the astrocytes causing them to swell. This results in cerebral edema and encephalopathy. It has also been shown that the risk of development of hepatic encephalopathy increases with the increasing concentration of ammonia in the blood.

Cerebral edema and intracranial hypertension

Cerebral edema is seen in 75% to 80% of patients with ALF and grade 4 hepatic encephalopathy. Intracranial pressure above 20 mm Hg is usually associated with cerebral edema. Cerebral edema progresses to intracranial hypertension (ICH), which accounts for 20% to 25% of deaths in ALF. Initial signs suggestive of intracranial hypertension include systolic hypertension and bradycardia. This may progress to increased muscle tone, opisthotonus, decerebrate posturing, loss of pupillary reflex and eventually apnea or respiratory failure. A high index of suspicion for the development of ICP is necessary as it can develop before other clinical signs of ALF and may result in cerebellar herniation and brain death prior to any intervention.

Seizures

Seizures are occasionally seen in patients with ALF. Persistent seizure activity causes cerebral hypoxia which leads to cerebral edema and ICH. Hence they should be treated promptly.

Coagulopathy

All clotting factors except von Willebrand factor and factor VIII are synthesized in the liver. Many of these proteins have half-lives measured in hours. Accordingly, coagulation abnormalities are typical of ALF. Similar to encephalopathy, an elevated international normalized ratio (INR) is required to diagnose ALF. The main mechanism for the elevated prothrombin and partial thromboplastin times in ALF are the decreased production of clotting factors II, V, VII, IX, and X by the injured liver. Intravascular coagulation and fibrinolysis leading to consumption of platelets and coagulation factors, also contributes to coagulopathy. In addition, vitamin K deficiency has been seen in patients with ALF, which contributes to the decreased production of clotting factors. Thrombocytopenia is commonly seen in patients with ALF. It has been reported that more than 60% of patients with ALF have a platelet count of less than 150,000 cells per cubic millimeter during their clinical course. In addition to the quantitative deficits, there is also qualitative impairment in the platelet function, thus further increasing the risk of bleeding.

Despite the presence of coagulopathy in ALF, clinically significant spontaneous bleeding is uncommon. Routine administration of fresh frozen plasma is discouraged in ALF not only because of lack of need, but also because it results in improvement in coagulation metrics (eg, prothrombin time, INR), one of the most important metrics related to patient improvement. Selective use prior to placement of intracranial pressure (ICP) measurement devices, other invasive procedures, or in response to clinically significant bleeding is advocated. Gastrointestinal or genitourinary bleeding are the usual sites for spontaneous bleeding in ALF. Variceal bleed almost never occurs in ALF and intracranial hemorrhage is seen in less than 1% of patients. However, there is an increased risk of bleeding with invasive procedures in patients with ALF.

Infection and sepsis

Patients with ALF are prone to develop multiple infections due to a decrease in immunity. Bacterial and fungal infections predominate. The presence of a fungal infection is a poor prognostic sign in patients with ALF. The mechanism for decreased immunity in ALF is multifactorial. There is impaired functioning of the polymorphonuclear leukocytes, decreasing their ability of phagocytosis and opsonization. Both cell-mediated and humoral immunity have been noted to be suboptimal. In addition, patients with ALF usually have multiple central and peripheral lines and indwelling catheters, which increase the risk of nosocomial infections. Furthermore, these patients may be on medications such as glucocorticoids or proton-pump inhibitors which further increase risk of infections.

Renal manifestations

Acute renal failure is an important and a frequent complication of ALF and is mainly a result of the hemodynamic alterations in ALF. The mechanism for renal failure is multifactorial. Initially it can be prerenal in etiology due to hypovolemia, but prolonged ischemia of renal tubules can cause progression to acute tubular necrosis. Functional renal failure similar to the hepatorenal syndrome in patients with cirrhosis may be seen in patients with ALF. Certain etiologies for ALF such as that of acetaminophen toxicity, amanita poisoning, or an idiosyncratic reaction to trimethoprim-sulfamethoxazole, also cause direct renal toxicity and hence renal failure is more frequently seen in these patients.

Metabolic disorders

Hypoglycemia is an important complication of ALF. It contributes to altered mental status, and thus the true extent of hepatic encephalopathy may be unclear in the presence of hypoglycemia. There are 2 main mechanisms that contribute to hypoglycemia in ALF: impaired gluconeogenesis in the injured liver in ALF; and decreased uptake of insulin by the hepatocytes. This increases the insulin level in the peripheral blood resulting in hypoglycemia. Electrolyte abnormalities such as hyponatremia, hypokalemia, hypophosphatemia, and acid-base imbalances such as respiratory acidosis are commonly seen in ALF. Hyponatremia, when present, is usually due to hypervolemia. Central nervous system induced hyperventilation in ALF leads to respiratory alkalosis. This in turn causes the kidneys to absorb hydrogen ions in exchange for potassium, thus resulting in hypokalemia. These electrolyte abnormalities may rarely result in cardiac arrhythmias contributing to mortality.

Management

There is no proven therapy for ALF and hence understanding the progression of ALF, from loss of hepatocyte function to the development of multiorgan failure, helps in disease management. Diagnosis of ALF may be delayed in certain situations such as in patients presenting with altered mental status with minimal jaundice and absence of other features of ALF. A high index of suspicion is necessary in these cases as early intervention is imperative to decrease morbidity and mortality.

Broadly, the management of ALF should involve

1. Identification of the etiology of ALF whenever possible and initiation of specific treatment
2. Supportive and symptomatic management of ALF, with timely transfer to the critical care unit
3. Early discussion with liver transplant specialists and safe transfer of patients to a liver transplant center when required.

Identification and Treatment of underlying etiology

Acetaminophen-induced hepatotoxicity

A history of ingestion of acetaminophen and elevated serum acetaminophen levels indicate acetaminophen hepatotoxicity. The AASLD recommends obtaining acetaminophen levels in all patients with ALF, irrespective of the history of acetaminophen ingestion. This is mainly due to the fact that acetaminophen hepatotoxicity is the most prevalent cause of ALF in the U.S., and there is an effective antidote available for the treatment of acetaminophen toxicity. Acetaminophen levels in the blood vary with the time from consumption, and thus a low acetaminophen level does not exclude acetaminophen-induced hepatotoxicity. Additionally, as the time of ingestion may be remote or unknown or occurring over several days, measuring acetaminophen levels in patients with liver tests suggesting liver failure may not yield meaningful information. However it is still recommended to check levels in all patients with ALF.

Hepatotoxicity is not typically seen soon after acetaminophen ingestion and the treatment of patients with acetaminophen toxicity differs from the treatment of patients with ALF. The Rumack-Mathew nomogram helps predict the development of hepatotoxicity in patients with acetaminophen toxicity. The administration of activated charcoal is useful early (1 to 4 hours) after ingestion. Activated charcoal at a dose of 1gram/ kilogram body weight orally is most effective when given within 1 hour of ingestion and acts by decontamination of the GI tract. More important than GI decontamination is the early administration of N-acetylcysteine (NAC), the antidote for acetaminophen toxicity. It should be given as soon as the diagnosis of acetaminophen toxicity is suspected. In confirmed cases of acetaminophen toxicity, acetaminophen levels should be plotted on the nomogram to determine the risk of development of hepatotoxicity. If the risk is high, then NAC should be promptly started. NAC is most efficacious when given within 8 hours of ingestion. It may still be efficacious when given beyond 48 hours of ingestion. NAC has very few side effects and they are usually benign (predominately nausea and vomiting; rash, urticarial, and bronchospasm rarely occur). Hence NAC should be administered in all patients with suspected or confirmed acetaminophen toxicity even if they present beyond 8 hours of presentation.

Administration of activated charcoal prior to NAC does not decrease the efficacy of NAC. Hence it is recommended to give activated charcoal prior to NAC if acetaminophen ingestion is within 4 hours of presentation. NAC can be administered either orally or intravenously. The intravenous dosing regimen as recommended by AASLD is NAC at a loading dose of 150 mg/kg in 5% dextrose solution over 15 minutes, followed by a maintenance dose of 50 mg/kg given over 4 hours, followed by 100 mg/kg administered over 16 hours. The oral dosing regimen of NAC is 140 mg/kg by mouth or as a 5% diluted solution through nasogastric tube, followed by 70 mg/kg every 4 hours for a total of 17 doses. Studies have shown that the oral NAC is as effective as intravenous NAC. In addition, the cost of oral NAC is substantially lower than the cost of intravenous NAC. However, intravenous NAC is more commonly used in clinical settings as a majority of patients with acetaminophen-induced hepatotoxicity have significant nausea, vomiting or altered mental status which makes use of oral NAC impractical. In patients with acetaminophen toxicity who have ALF, in addition to NAC, the general principles of supportive and symptomatic treatment of ALF in a critical care setting remains the mainstay of treatment. These are described later in the chapter.

Drug-induced hepatotoxicity

Drug-induced hepatotoxicity is a diagnosis of exclusion. As noted earlier, a detailed medication history must be obtained. Any drug identified as the likely etiology of ALF has to be stopped immediately. In addition, all medications except for those that are absolutely essential should be discontinued. The efficacy of NAC has not clearly defined in drug-induced ALF as compared with acetaminophen-induced liver injury. One prospective double-blind controlled trial showed that intravenous NAC improved transplant-free survival in patients with early stage nonacetaminophen-related ALF. However in this study, patients with advanced coma grades did not show a benefit from NAC and required emergency liver transplantation. However NAC is recommended in all cases of drug-induced ALF. Further controlled studies are needed to clearly determine the efficacy of NAC in drug-induced liver injury.

Mushroom poisoning

The diagnosis of mushroom poisoning induced ALF is made clinically and there is no available blood test to confirm the diagnosis. Activated charcoal and gastric lavage via nasogastric tube may be useful during initial hours after ingestion of mushroom. Supportive care and medical treatment should be instituted promptly in an attempt to decrease the need for liver transplantation. Three drugs have been proposed to be efficacious and have been used in mushroom poisoning: penicillin G, silibinin (silymarin or milk thistle), and NAC. Intravenous penicillin G in doses of 300,000 units to 1 million units/kg/day is used for mushroom induced ALF in the U.S. In Europe, silibinin at doses of 30 to 40 mg/kg/day either intravenously or orally for a period of 3 to 4 days has been used. Silibinin is not routinely available in the U.S. NAC at the same dosage as for acetaminophen-induced hepatotoxicity may be administered in mushroom poisoning. However despite the presence of medical therapy, mushroom poisoning induced ALF has a high mortality rate without liver transplantation so these patients should be listed for transplantation at the earliest.

Viral hepatitis

All patients presenting with ALF should have acute hepatitis serology testing performed, even if another etiological agent has been identified. Hepatitis A- and hepatitis E-induced ALF have no specific treatment and should receive supportive care. Acute hepatitis B-induced ALF patients may benefit from antiviral agents and their use is recommended by the AASLD. If patients with acute hepatitis B-induced ALF undergo liver transplant, treatment with antiviral agent should be continued post-transplant to prevent recurrence. Patients, who are carriers of hepatitis B or have chronic hepatitis B infection and are to receive immunosuppression or chemotherapy, should receive prophylaxis with antiviral agents. Antiviral therapy should be continued for 6 months after completion of immunosuppressive therapy to prevent hepatitis B reactivation-induced ALF. Patients with ALF, who have documented or suspected herpes virus or varicella zoster virus infection, should be considered for treatment with intravenous acyclovir at a dose of 5 to 10 mg/kg every 8 hours for at least 7 days. These patients may also be listed for liver transplantation.

Supportive and symptomatic management of ALF

Management of neurological dysfunction—hepatic encephalopathy

Treatment of hepatic encephalopathy depends on the grade of hepatic encephalopathy. Grade 1 hepatic encephalopathy can be managed in the medical floor with skilled nursing; however, beyond grade 1, all patients should be managed in an intensive care unit. As patients progress to grade 3 and 4 hepatic encephalopathy, intubation and mechanical ventilation, with elevation of the head of the bed, are necessary.

The general steps involved in the management of hepatic encephalopathy include

1. providing a peaceful environment to avoid agitation
2. performing frequent neurological checks
3. avoiding sedatives or using only short-acting benzodiazepines to control severe agitation
4. consideration for liver transplantation and transfer to a transplant facility.

The goals in the treatment of hepatic encephalopathy are to prevent the onset of encephalopathy if possible, decrease the progression to severe grades of encephalopathy, and to minimize the development of cerebral edema and ICH, which can lead to cerebral herniation and death. A computed tomography scan of the head is performed in most cases to rule out other causes of agitation or neurological decline.

Role of lactulose. As discussed earlier, serum hyperammonemia plays an important role in the pathogenesis of hepatic encephalopathy and cerebral edema. Lactulose, when administered orally, decreases the enteral absorption of ammonia and has been used to treat and prevent hepatic encephalopathy in patients with cirrhosis. In patients with ALF, lactulose has not been shown to improve mortality. Though it may be useful in decreasing blood ammonia levels and may have a beneficial effect on cerebral edema, one should watch for the development of gaseous distention of the bowel during its use and modify the dosage accordingly. Similarly, use of antibiotics such as neomycin and rifaximin, have no clear benefit to treat hepatic encephalopathy in ALF and are not routinely recommended.

Prevention and treatment of cerebral edema and intracranial hypertension

The development of cerebral edema and ICH depends on the severity of hepatic encephalopathy. Cerebral edema is rarely seen in grade 1 and grade 2 hepatic encephalopathy, but has been reported to be seen in 25% to 35% in grade 3 and 65% to 75% in grade 4 hepatic encephalopathy. In addition to high grade encephalopathy, other important high risk factors for the development of cerebral edema and ICH include high serum ammonia levels, acute renal failure, and those needing vasopressor support.

Intracranial hypertension needs aggressive management. Cerebral perfusion pressure (CPP) is defined as the difference between the mean arterial pressure (MAP) and ICP. The goal in the management of ICH is to lower the ICP to less than 20 to 25 mm Hg and maintain the cerebral perfusion pressure above 50 to 60 mm Hg. This is mainly performed by both increasing the MAP and decreasing the ICP by methods mentioned below.

Achieving hemodynamic stability. Maintaining cerebral perfusion is a key component in the treatment of hepatic encephalopathy as it lowers the development of ICH. Fluid resuscitation, intravascular volume repletion, and occasionally vasopressors may be needed to maintain MAP, which in turn helps to maintain cerebral perfusion. However, large volume infusions of hypotonic fluids should however be avoided as they result in hyponatremia and cerebral edema. In addition, electrolyte abnormalities and acid base imbalances should be promptly identified and corrected as that may contribute to altered mental status.

ICP monitoring. Clinical features of elevated ICP such as bradycardia, systemic hypertension, abnormal breathing pattern, and papillary changes may not be seen in all patients with raised ICP, especially in the early stages. Hence ICP monitors are inserted for the assessment of CPP, early identification of elevated ICP, and prompt treatment. However placement of ICP monitors has its own risks and complications. Though infrequent, they may lead to severe intracranial hemorrhage and death. In addition there is a risk of introducing infections with the procedure. Hence the use of ICP monitors has varied from institution to institution. The AASLD recommends ICP monitoring in patient with ALF with high grade hepatic encephalopathy, who are awaiting or undergoing liver transplantation, and in centers with expertise in ICP monitoring.

Mannitol. Osmotic agents such as mannitol are the first-line therapy of ICH in patients with ALF. Mannitol given intravenously at a dose of 0.5 to 1.0 g/kg is effective in decreasing cerebral edema and may also decrease mortality. However their ability to decrease cerebral edema is transient. The dose may be repeated, provided the serum osmolality is below 320 mOsm/L. The adverse effects of mannitol include volume overload, hypernatremia, and hyperosmolality. Currently, there is no role for the prophylactic administration of mannitol in patients with ALF.

Hyperventilation. Patients with ALF hyperventilate spontaneously. Hyperventilation decreases the partial pressure of carbon dioxide of arterial blood, which results in cerebral vasoconstriction and decreased ICP. Thus, spontaneous hyperventilation in ALF should not be inhibited. This effect of hyperventilation on restoring cerebral autoregulation is however transient and studies have not shown survival benefit for hyperventilation in ALF. Hyperventilation is only recommended in life threatening ICH and when all other therapies have failed. There is no known benefit of hyperventilation prophylactically in ALF.

Seizure control. Phenytoin is effective in controlling seizures. Patients refractory to phenytoin can be treated with short-acting benzodiazepines. Currently there is no role of prophylactic anti-seizure medication in ALF as it has not shown to improve survival.

Role of hypothermia. Hypothermia has been proposed in ALF to prevent and manage refractory ICH. Hypothermia, by slowing the total body metabolism, may decrease the production of ammonia, and its cerebral uptake. Observational studies have shown that hypothermia to 32º to 34º C may decrease cerebral edema and be used in patients with ICH as a bridge to liver transplantation.

Role of hypertonic saline. Studies have shown that prophylactic use of hypertonic saline to induce hypernatremia to 145 to 155 mEq/L in patients with ALF with high grade encephalopathy has delayed the development of ICH. Hence hypertonic saline is recommended prophylactically to prevent ICH in patients at high risk of hepatic encephalopathy. Hypertonic saline may be used to treat ICH in cases where mannitol has failed, though its benefit in established cases of ICH is not clear.

Miscellaneous treatment. Short acting barbiturates decrease ICP and are used in patients with refractory ICH who have not responded to mannitol or other osmotic agents. Intravenous indomethacin has also been proposed for use in refractory ICH. However, corticosteroids have not shown a benefit in patients with ALF and should not be used.

Management of coagulopathy

Routine correction of thrombocytopenia or elevated INR by plasma infusion, in the absence of bleeding, is not indicated in ALF. The reasoning behind this recommendation is the low incidence of bleeding manifestations in ALF and the risk of volume expansion with plasma replacement. In addition, INR being an important prognostic indicator in ALF, correction of coagulopathy would alter the INR and interfere in the assessment of prognosis.

Patients with ALF have been known to have vitamin K deficiency and hence the AASLD recommends routine administration of vitamin K (5 to10 mg subcutaneously) in ALF. The indications for plasma or clotting factor replacement therapy in ALF include clinically significant bleeding or the need for a procedure with a high bleeding risk such as ICP monitor insertion. Plasma infusion is the first step in correcting INR. If the INR is markedly high, plasma infusion alone may not correct the INR or high volumes of plasma infusion may be needed, which increases the risk of volume overload. Hence in these cases, recombinant activated factor VII may be used to correct coagulopathy. It is important to note that in addition to its high cost, recombinant activated factor VII is associated with increased risk of thromboembolic complications such as myocardial infarction and portal venous thrombosis. Plasmapheresis may be considered as an alternative to correct coagulopathy.

Patients with thrombocytopenia with platelet count less than 50,000 cells/mm and who have clinically significant bleeding should receive platelet transfusions. In the absence of bleeding there is no need to initiate platelet transfusion. Though the consensus seems to be to initiate transfusion with a platelet count less than 10,000 to 20,000 cells/mm, more studies are needed in patients with ALF to ascertain this aspect. In patients with ALF who require invasive procedures, the need for platelet transfusion depends on the degree of thrombocytopenia and the bleeding risk of the invasive procedure. Platelet transfusion may be initiated at platelet counts below 30,000 cells/mm for low-risk invasive procedures. For high- risk invasive procedures it is reasonable to restore the platelet count to above 50,000 cells/mm to minimize bleeding.

Treatment of Infections

Infections complicate the course of ALF and can worsen the severity of hepatic encephalopathy and can preclude liver transplantation. Fever may also worsen ICH. Though studies have not shown a survival benefit of prophylactic antibiotics in all patients with ALF, patients with severe grades of encephalopathy may benefit from prophylactic antibiotics. In patients with low grade encephalopathy, routine surveillance cultures for bacterial and fungal infections with a low threshold to start antibacterial or antifungal therapy at the earliest sign of infection are appropriate. In patients with severe hepatic encephalopathy, prophylactic antibiotics and anti-fungal agents may be started. Gram-positive cocci (staphylococci, streptococci) and enteric gram-negative bacteria are the most common organisms isolated in critically ill patients with ALF. Fungal infections, predominantly candidiasis, have also been frequently reported in patients with ALF. Hence broad spectrum antibiotics such as a third generation cephalosporin and vancomycin would be appropriate for prophylaxis in critically ill patient with ALF. It is also reasonable to start fluconazole for antifungal prophylaxis in a critically ill patient with ALF. If an organism has been isolated during surveillance cultures, antibiotic therapy can be tailored based on culture and sensitivity. Fever when present should be promptly controlled to prevent worsening of ICH.

Management of renal dysfunction

Acute renal failure (ARF) is a high risk feature of ALF and has a poor prognosis. Correction of ARF begins with identifying the etiology, though this may not be possible due to the multifactorial nature of renal failure in ALF. Prerenal failure is managed by correcting hypovolemia, maintaining hemodynamic stability, and use of vasopressors when needed. Avoiding the use of nephrotoxic agents, including antibiotics such as aminoglycosides and nonsteroidal anti-inflammatory agents should be considered. Acetaminophen, an analogue of phenacetin (a nephrotoxic analgesic) may cause renal injury when taken in high dose. Intravenous contrast agents should be avoided or used with caution as they may result in contrast-induced nephropathy and worsen renal function. Infections may result in acute tubular necrosis and should be promptly identified and treated. Acute renal failure from hepatorenal syndrome usually only improves with improvement in liver function or liver transplantation. Initiation of dialysis should be considered promptly when indicated. Continuous mode of dialysis is preferred over intermittent hemodialysis as studies have shown that continuous renal replacement therapy results in improved cardiovascular, hemodynamic, and intracranial parameters as compared with intermittent hemodialysis.

Prophylaxis for gastrointestinal bleeding

Randomized placebo-controlled trials have demonstrated marked reduction in upper GI bleeding in the setting of ALF in those given acid-suppressive medication. Patients with ALF should receive prophylaxis with proton-pump inhibitors or H2 blockers to prevent upper GI bleeding from stress ulcers. Sucralfate has also been used as a second-line agent as it has shown to be as effective as H2 blockers in preventing upper GI bleed and may be associated with a lower risk of nosocomial pneumonia. In addition, presence of thrombocytopenia may limit the use of proton-pump inhibitors and H2 blockers, and sucralfate may be used in these patients.

Correction of metabolic abnormalities and providing nutritional support

Frequent monitoring of blood glucose is essential as hepatic encephalopathy will mask the symptoms of hypoglycemia. Intravenous glucose should be provided for the prophylaxis and treatment of hypoglycemia. Electrolyte abnormalities should be promptly identified and corrected urgently.

Acute liver failure is associated with severe catabolism and high expenditure of energy. Enteral feeding is recommended and should be started at the earliest in patients who are unlikely to resume oral nutrition within 5 days. There is very little data to strongly support a particular nutritional recommendation. The European society for clinical nutrition in ALF recommends providing energy 1.3 times the resting energy expenditure. Severe protein restriction should be avoided. Amino acids at 0.8 to 1.2 gram/kg/day are recommended in critically ill patients with ALF. Serum ammonia levels should be monitored and if found to be rising the protein load be lowered accordingly. Parenteral feeding should be considered when enteral feeding cannot be instituted or is contraindicated, though parenteral feeding is associated with increased risk of infections. Both enteral and parenteral feeding has shown to reduce stress related gastric ulcers in ALF patients.

Liver Transplantation

An early decision should be made about whether or not the patient is a candidate for liver transplantation (LT). If the patient is a candidate, early transfer to a transplant center is recommended to initiate simultaneous LT evaluation and ALF management. Liver transplantation has improved survival in ALF. The 1- year post-LT survival in ALF in less than that of elective LT performed for chronic liver disease. This is primarily due to increased ICH and sepsis resulting in increased mortality in the first 3 months following LT in ALF. Beyond the first year, ALF patients have better long-term survival.

Both whole organ deceased donor and living donor LT have been performed in ALF with great success. Another type of LT is auxiliary transplantation in which the recipient liver is left in place and a partial left or right lobe from the donor is transplanted, thus providing hepatic function until the native liver regenerates. Good survival rates of 60% to 65% have been reported with this procedure and immunosuppression can be withdrawn in 65% to 85% of patients at the end of 1-year post-LT.

Emerging Therapies

Numerous liver supportive devices have been proposed to replace or support liver function in ALF. These can be used to support liver function and stabilize the patient while awaiting liver transplantation or until the native liver regenerates and recovers its function. Two types of support devices are being developed: artificial and bioartificial systems. Artificial support systems are extracorporeal devices that have either charcoal or other adherent particles in an extracorporeal circuit to help with detoxification. They do not have any cellular material and they do not perform synthetic liver functions. Unfortunately, randomized control trials have not shown conclusive benefits with these devices in patients with ALF and further study is needed. Bioartificial systems use cryopreserved cells and they are able to not only detoxify but also perform synthetic liver functions.

Hepatocyte transplantation is an interesting procedure that is being studied in ALF. It involves infusion of human or mammalian hepatocytes into the splenic or hepatic portal venous system or into the peritoneal cavity. These hepatocytes are thought to provide adjunctive hepatic function to the damaged liver. This procedure has been used in infants with inborn errors of metabolism, but is undergoing trials for its beneficial effect in ALF. One of the drawbacks for this procedure is the fact that these hepatocytes may not be able to provide sufficient liver function in patients with a severely damaged liver.

High-Volume Plasma Exchange

High-volume plasma exchange (HVPE), defined as plasma exchange of 8% to 15% of ideal body weight with fresh frozen plasma, is an established therapy for several immune disorders. In ALF, accumulation of various metabolites and toxins, and decreased synthesis of coagulation and complement factors by the injured liver, lead to local and systemic inflammation causing multiorgan dysfunction and death. By removing plasma cytokines and replacing plasma factors and immune modulation, HVPE may help in decreasing inflammation in ALF. Several retrospective studies have evaluated the effect of HVPE in patients with ALF. More recently, a randomized controlled trial studied the effect of HVPE in patients with ALF and found that patients who received HVPE in addition to supportive medical therapy had increased transplant-free survival as compared with patients who received supportive medical therapy alone. This survival benefit with HVPE was mainly seen in the group of patients with ALF who were ineligible for LT. No survival benefit was seen in patients who underwent LT with HVPE compared with supportive care alone. No significant increase in adverse effects was noted in patients who received HVPE compared with supportive medical care alone. In a randomized controlled trial at our institution, HVPE is done for all patients with ALF irrespective of the etiology. Three sessions of HVPE are done on 3 consecutive days. In addition to a survival benefit demonstrated in the study, plasma exchange by replacing clotting factors and correcting coagulopathy facilitated placement of intracranial pressure monitor when needed by minimizing the risk of bleeding.

Summary

• Acute liver failure (ALF) is associated with significant mortality and morbidity.
• Prompt identification and aggressive management of ALF and its complications are imperative. Liver transplantation is the only life-saving modality in many patients with ALF and identification of these patients at the earliest is important to decrease mortality.
• Plasma exchange may improve survival in patients with ALF who are ineligible for transplant.

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