Acute liver failure (ALF) is an uncommon but devastating

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1 J Clin Gastroenterol 2001;33(3): Lippincott Williams & Wilkins, Inc. Clinical Reviews Liver Diseases Acute Liver Failure Riaz Q. Gill, M.D., and Richard K. Sterling, M.D., F.A.C.P., F.A.C.G. Abstract Acute liver failure (ALF) is defined as hepatic encephalopathy complicating acute liver injury. The most common etiologies are acute viral hepatitis A and B, medication overdose (e.g., acetaminophen), idiosyncratic drug reactions, ingestion of other toxins (e.g., amanita mushroom poisoning), and metabolic disorders (e.g., Reye s syndrome). Despite advances in intensive care management, mortality continues to be high (40 80%) and is partly related to ALF s complications, such as cerebral edema, sepsis, hypoglycemia, gastrointestinal bleeding, and acute renal failure. Several prognostic models have been developed to determine which patients will spontaneously recover. Treatment is directed at early recognition of the complications and general supportive measures. The only proven therapy for those who are unlikely to recover is liver transplantation. Therefore, recognition of ALF is paramount, and urgent referral to a transplant center is critical to assess transplantation status. Key Words: Acute liver failure Fulminant hepatic failure Therapy. Acute liver failure (ALF) is an uncommon but devastating sequelae of acute liver injury. Despite improvements in intensive care management, mortality continues to be between 40% to 80%. Emergent liver transplantation is currently the only effective treatment for those patients who are unlikely to spontaneously recover. Unfortunately, patients often die before a suitable organ is identified. This article will review the definitions, etiologies, prognostic factors, and issues in the management of patients with ALF. DEFINITIONS Acute hepatitis with jaundice and coagulopathy without hepatic encephalopathy is referred to as severe acute hepatitis. The prognosis is generally excellent. However, there are some who may progress to liver failure or develop chronic hepatitis; therefore, all patients with acute hepatitis From the Division of Gastroenterology, Section of Hepatology and Liver Transplantation, Medical College of Virginia, Commonwealth University, Richmond, Virginia, U.S.A. Address correspondence and reprint requests to Dr. Richard Sterling, Division of Gastroenterology, Section of Hepatology and Liver Transplantation, Medical College of Virginia Commonwealth University, Box , 1200 East Broad Street, West Hospital, Room 1492, Richmond, VA , U.S.A. rksterli@hsc.vcu.edu must be observed closely. The original definition of fulminant hepatic failure (FHF), proposed in 1970 by Trey and Davidson, 1 is a syndrome of severe acute hepatitis complicated by the rapid development of hepatic encephalopathy within 8 weeks of the onset of jaundice in a patient without previous history of liver disease. More recently, an alternative definition has been advocated by Bernuau et al., 2 who defined FHF as the development of encephalopathy within 2 weeks of the onset of jaundice. Patients with a more insidious onset in which encephalopathy is delayed for up to 8 to 12 weeks is classified as subfulminant hepatic failure (SFHF). Although both FHF and SFHF have similar etiologies and clinical manifestations, they have a different prognoses and, therefore, their differentiation is important (Table 1). Fulminant Hepatic Failure In FHF, hepatic encephalopathy develops within 2 weeks of the onset of jaundice. The most common etiologies are viral hepatitis (A, B, D, and E), acetaminophen overdose, and other drugs or toxins. Although many patients with FHF die, recovery is possible without transplantation. Patients who survive FHF usually have no long-term sequelae with normal hepatic architecture and no chronic liver disease. However, some patients with viral hepatitis B or B with D coinfection develop chronic viral hepatitis. Subfulminant Hepatic Failure In SFHF, the onset of encephalopathy is delayed beyond 2 weeks and could develop several months from the initial insult. Subfulminant hepatic failure is most frequently caused by viral infections and idiosyncratic drug reactions. Prognosis is poor without transplantation and those who survive often have some stigmata of chronic liver disease. ETIOLOGIES Acute liver failure is the final common pathway for a variety of liver insults. The underlying precipitating factors differ around the world, with viral hepatitis and druginduced liver damage predominating in North America and Europe (Table 2). 3 Children have unique etiologies, with indeterminate causes accounting for more then 50% of pediatric cases. 4 Data from a prospective study, sponsored by the National Institutes of Health Acute Liver Failure Study 191

2 192 J Clin Gastroenterol, Vol 33, No. 3, 2001 TABLE 1. Clinical features of severe acute hepatitis, FHF, and SFHF Clinical features Severe acute hepatitis FHF SFHF HE Never Always Always Onset of HE NA <2 wk >2 wk Survival without LTx Excellent 40% <20% Renal failure Uncommon Less common Common Chronic liver dx Rare Rare Frequent Cerebral edema Never Infection Rare Common Common Hypoglycemia Possible CVS collapse No Multiorgan dysfunction No HE indicates hepatic encephalopathy; LTx, liver transplant; dx, disease; CVS, cardiovascular system; NA, not applicable. Group, of 206 patients (73% female with a mean age of 39 years; range, years) from 16 centers in the United States were recently reported. 5 The authors found that acetaminophen was the most common (38%) cause of ALF and that idiosyncratic drug reactions were responsible for 14% and acute viral infections accounted for 12% of cases (4% hepatitis A virus and 8% hepatitis B virus [HBV]). Eighteen percent of cases were deemed indeterminate (Fig. 1). Pregnancy-related liver disease accounted for four cases, and other rare causes included cancer, lymphoma, Wilson s disease, acute ischemic liver injury, autoimmune hepatitis, and Budd Chiari syndrome (total, 19%). Of special note, no case of FHF was associated with acute hepatitis C virus infection. DRUG-INDUCED HEPATIC DAMAGE Drug-induced liver damage is a significant cause of death in patients with ALF in western countries, and the number of cases of acute acetaminophen toxicity in the United States is fast approaching the number of cases seen FIG. 1. Causes of ALF seen by the Acute Liver Failure Study Group. 5 in the United Kingdom. Risk factors for drug-induced hepatotoxicity include very young and very old age, abnormal renal function, obesity, preexisting liver disease, and concurrent use of other hepatotoxic agents. Because most drugs are metabolized by the liver, almost any drug can cause acute hepatitis; however, it is rare for such reactions to progress to ALF. Drug toxicities can occur in an intrinsic, dose-dependent, predictable manner (as with acetaminophen), but they more commonly occur as idiosyncratic reactions. Idiosyncratic drug toxicity is the result of immunologically mediated liver injury triggered by the drug itself or (more commonly) by the drug s metabolite. Most idiosyncratic drug reactions occur within 4 to 6 weeks of initiation of treatment, although rare cases have occurred after months or years of drug intake. Idiosyncratic drug reactions can culminate in SFHF and carry a poor prognosis without liver transplant. Acetaminophen Acetaminophen is generally safe when used within recommended doses in otherwise healthy individuals. However, it does have a narrow therapeutic range and is a dose-dependent hepatotoxic agent. As such, it is the most common cause of drug-induced liver injury in the United States and other developed countries. TABLE 2. Etiologies of ALF Viral HAV, HBV, HBV with coinfection/superinfection with HDV, spontaneous seroconversion of HBeAg to anti-hbe, HEV, non-a, non-b, non-c, CMV, VZV, adenovirus, SEN-V, yellow fever, Q-fever Drugs Dose-dependent Acetaminophen, haloalkanes Idiosyncratic INH, methyl-dopa, dilantin, Na valproate, antihyperglycemics such as troglitazone, antibiotics (PCN, tetracyclines, sulfonamides, quinolones), allopurinol, PTU, amiodarone, ketoconazole, NSAIDs Synergistic drug reactions Alcohol and acetaminophen, INH + rifampicin, trimethaprim + sulfamethoxazole, barbiturates + acetaminophen, amoxacillin + clavulanate acid Toxins CCI 4, yellow phosphorus, amanita phalloides, chlorobenzenes, industrial solvents, herbal medicines Metabolic Acute fatty liver of pregnancy, Wilson s disease, Reye s syndrome, hereditary galactosemia, hereditary tyrosinemia Systemic Autoimmune hepatitis, malignancy infiltration (i.e., lymphoma), acute shock liver, hyperthermia, sepsis Miscellaneous Indeterminate causes, Budd Chiari, portal vein thrombosis, acute right-sided failure, cardiac tamponade HAV indicates hepatitis A virus; HBV, hepatitis B virus; HDV, hepatitis D virus; Ag, antigen; HEV, hepatitis E virus; CMV, cytomegalovirus; VZV, varacella zoster virus; INH, isoniazid; PCN, penicillin; PTU, propothiouricil; NSAIDs, nonsteroidal antiinflammatory drugs.

3 R.Q. Gill and R.K. Sterling ACUTE LIVER FAILURE 193 Acetaminophen undergoes phase 1 metabolism by hepatic cytochrome P-450 E2 enzymes to a toxic intermediate compound (N-acetyl-para benzoquine imide), which is rapidly detoxified by hepatic glutathione into a nontoxic metabolite. Under normal conditions, little N-acetyl-para benzoquine imide accumulates. However, in an overdose, the liver cannot detoxify the large amounts of toxic metabolite that are produced, which results in hepatocyte necrosis. 6 The amount of liver injury is directly related to the amount of ingested acetaminophen and the amount of N-acetyl-para benzoquine imide that is produced. Chronic alcohol consumption induces synthesis of cytochrome P-450 enzymes and, to a lesser extent, depletes glutathione stores. Consequently, even therapeutic doses of acetaminophen can result in an accumulation of N-acetyl-para benzoquine imide and can precipitate ALF in the alcoholic patient (a so-called therapeutic misadventure). Other medications that induce the action of P-450 E2 enzymes, such as antileptics, can also cause ALF in patients who chronically abuse alcohol. TOXINS Acute toxic-mediated injury is responsible for 2% to 5% of ALF cases. Amanita phalloides mushroom poisoning is common in the Pacific Northwest and the Appalachian Mountain areas of the United States, as well as in parts of Europe. Cases of poisoning peak in the autumn when mushrooms are plentiful. The toxin, -amanitin, is heat-stable and is not destroyed by cooking. As little as 50 g (three medium-sized mushrooms) can cause significant liver injury. Other hepatotoxins include yellow phosphorus, carbon tetrachloride, aflatoxins, and some herbal medicines. METABOLIC DISEASES Acute fatty liver caused by pregnancy, shock liver, autoimmune hepatitis, Wilson s disease, and Budd Chiari syndrome are encountered in clinical practice and can lead to FHF. Wilson s disease should be suspected in a young patient who presents with Coombs-negative hemolytic anemia, low serum alkaline phosphatase, and hypouricemia associated with ALF. This diagnosis is important because, without urgent transplantation, the disease is uniformly fatal. HEPATOTROPIC VIRUSES Most cases of acute viral hepatitis are cause by hepatitis A virus and HBV, with FHF developing in 0.2% to 0.4% of cases and in 1.0% to 1.2% of cases, respectively. 3 Hepatitis B virus can result in ALF through several mechanisms: acute primary HBV infection, reactivation of hepatitis B in patients with chronic HBV, superinfection with hepatitis D virus, and spontaneous seroconversion of individual from HBV e antigen to HBV e antibody. Acute liver failure is seen in 2.5% to 6% of hepatitis D virus cases. Hepatitis E virus can result in FHF, especially in the third trimester of pregnancy. Other viruses implicated in the pathogenesis of FHF that may be responsible for some of the indeterminate cases include cytomegalovirus, Epstein Barr virus, herpes virus, Varicella zoster virus, adenovirus, paramyxoma virus, and, most recently, SEN-V. 7 PATHOGENESIS AND LIVER HISTOPATHOLOGY Acute liver failure develops from both cytotoxic and cytopathic injury, either alone or in combination. Cytotoxic injury results from direct injury to hepatocytes by hepatotoxic viruses (hepatitis A virus), drugs or their toxic metabolites, and other toxins. Cytopathic injury is caused by an immune-mediated response to hepatocytes that express abnormal cell surface antigens, as observed in HBV and idiosyncratic drug reactions. The most common histologic pattern seen in ALF is hepatocellular necrosis with or without preservation of hepatic architecture. Other patterns of injury associated with necrosis include lobular collapse, islands of regenerative hepatocytes, infiltration with polymorphonuclear cells, lymphocytes, plasmocytes or eosinophils, and proliferation of duct-like structures around approximated portal areas. The other histologic pattern observed is microvesicular fatty infiltration, which occurs in cases of acute fatty liver caused by pregnancy, Reye s syndrome, and sodium valproate or tetracycline toxicity. This pattern of injury is associated with abnormalities in mitochondrial fatty acid and ammonia metabolism leading to hepatocyte lipid accumulation and hyperammonemia. CLINICAL FEATURES The most common clinical features of ALF are abnormal liver chemistries, jaundice, and, by definition, hepatic encephalopathy. Patients usually present with icterus and marked elevations in liver aminotransferase levels. Exceptions include those patients with microvesicular steatosis. This group often presents with mental status changes and marked elevations of serum ammonia, with only minor elevations in serum aminotransferase, bilirubin, and prothrombin levels. The magnitude of aminotransferase levels and their rate of decline do not affect prognosis. In patients who spontaneously recover, serum bilirubin and prothrombin time normalize, whereas patients whose disease progresses have continued rise in bilirubin levels and prolongation of prothrombin time despite declining aminotransferases. The high mortality rates associated with ALF are caused by the complications of ALF, which include the development of cerebral edema, renal failure, sepsis, and cardiopulmonary collapse that results in multisystem organ failure. Hepatic Encephalopathy The presence of hepatic encephalopathy is the essential clinical feature that differentiates FHF from acute severe

4 194 J Clin Gastroenterol, Vol 33, No. 3, 2001 hepatitis, and the time to onset after the appearance of jaundice distinguishes FHF from SFHF. Hepatic encephalopathy is graded on a scale of 1 to 4 (Table 3). Although usually progressive late in the course of FHF, the severity of encephalopathy may fluctuate in the early phase of disease, as well as throughout the course of SFHF. In cases acetaminophen overdose, encephalopathy usually occurs on the 3rd or 4th day after ingestion and can rapidly progress to stage 4 within 24 to 48 hours. Alterations in mental status can increase the risk of other complications, such as aspiration pneumonia, hypoxia, and adult respiratory distress syndrome, which further compound the overall poor prognosis. The pathophysiologic basis of hepatic encephalopathy is poorly understood and multifactorial. Ammonia and other putative markers have been identified and include endogenous substances, false neurotransmitters, short chain fatty acids, benzodiazepines, and gamma amino butyric acid. 8 Electroencephalogram findings typically show diffuse slowing of cortical activity and a high amplitude wave form of five to seven cycles per second. In a recent article from King s College, the importance of electroencephalogram monitoring of patients with ALF has been stressed by the identification of subclinical seizure activity in patients with grades 3 and 4 encephalopathy. 9 They found that prophylaxis with phenytoin in patients with severe encephalopathy not only reduced subclinical seizure activity but also reduced cerebral edema. Seizure activity in FHF has been linked to excessive central nervous system glutamate, the main excitatory neurotransmitter in the brain. CEREBRAL EDEMA Cerebral edema is a unique feature of FHF that is uncommon in patients with SFHF and chronic liver disease. It is not the direct result of hepatic encephalopathy, and its exact mechanism is poorly understood. Disruption of the blood brain barrier with accumulation of low molecularweight substances and loss of autoregulation of cerebral blood flow are some of the features of cerebral edema Cerebral edema develops in 70% to 80% of patients with grade 4 encephalopathy, irrespective of the cause of FHF, and is a major cause of death. Computed tomographic scanning and physical exam are not helpful, and a great deal of clinical suspicion is required for diagnosis. Perhaps the best way to diagnosis and manage this complication is through the use of intracranial epidural pressure monitors. 13,14 Cerebral perfusion pressure (CPP) can be calculated from mean arterial pressure (MAP) and intracranial pressure (ICP) with the equation CPP MAP ICP. Late clinical features of cerebral edema include systemic hypertension, decerebrate posturing, hyperventilation, pupillary abnormalities, seizures, and paralysis of brain stem reflexes with uncal herniation and death. Therefore, the identification and prompt treatment of cerebral edema is paramount. COAGULOPATHY Acute liver failure results in an abrupt and profound decrease in the synthesis of coagulation proteins, which is manifested by the prolongation of prothrombin time. Several coagulation factors can be easily measured and have clinical significance. Vitamin K dependent factor 7 has the shortest half-life (4 6 hours), and serial measurement has prognostic implications. Failure to increase factor 7 by 25% after intravenous vitamin K suggests that there is little hepatic reserve. Recent studies emphasize the prognostic value of vitamin K independent factor 5, which is the preferred prognostic method in some European centers. 15 Only factor 8, synthesized in vascular endothelium and not the liver, is markedly elevated in ALF cases. As such, a factor 8/5 ratio of more then 30 is associated with poor prognosis. 16 Like coagulation factors, a number of anticoagulation factors, such as protein C and protein S, are synthesized in the liver, and many of the activated clotting factors are removed from circulation by the liver. Subsequently, the procoagulant and anticoagulation balance is disturbed in liver failure. This may cause the coagulation profile to resemble a disseminated intravascular coagulopathy-like picture, and distinction between the two can be difficult. 17 METABOLIC DERANGEMENTS There are numerous metabolic abnormalities seen in ALF cases (Table 4). Hypoglycemia, seen in up to 45% of patients with ALF and caused by depletion of glycogen TABLE 3. Grading scale and associated findings in hepatic encephalopathy Grade Clinical features Asterixis EEG Pupillary changes 1 Subtle changes, slowness of mentation, disturbed Usually mild Usually normal None sleep Patient alert and lucid 2 Increasing drowsiness and inappropriate behavior Present Abnormal generalized None to hyperactive Arousable and conversant slowing 3 Marked confusion and disorientation, agitated behavior, can follow simple commands Present Abnormal Hyperactive to hippus to slow reactive 4 May or may not respond to painful stimuli Usually lacking Abnormal Slow reactive to fixed and dilated as coma worsens

5 R.Q. Gill and R.K. Sterling ACUTE LIVER FAILURE 195 stores and impaired gluconeogenesis, is common and could be refractory to intravenous dextrose. Metabolic acidosis is particularly a problem in acetaminophen overdose, and a ph value of less than 7.3 carries a poor prognosis. Other metabolic abnormalities include hyponatremia, alkalosis, hypokalemia, hypophosphatemia (more frequent in acetaminophen toxicity), and lactic acidosis, which occurs late in the course because of tissue hypoxia. 18 Acute renal failure is seen in 30% to 70% of patients with ALF and can result from a combination of factors, such as intravascular volume depletion, sepsis, disseminated intravascular coagulopathy, or from direct nephrotoxicity from drugs such as acetaminophen or nonsteroidal antiinflammatory drugs. 19 Other common complications include pancreatitis and gastrointestinal hemorrhage, which can significantly increase the risks of mortality. CARDIOVASCULAR, HEMODYNAMIC, AND RESPIRATORY COMPLICATIONS Circulatory failure that mimics sepsis (with high cardiac output) and low systemic vascular resistance (with decreased blood pressure) can be observed in ALF and is thought to be caused by high levels of circulating endotoxin and tumor necrosis factor. With deepening encephalopathy, rising ICP coupled with decreasing MAP can result in a decrease in CPP (see the Cerebral Edema section above). Relative hypovolemia with reduced systemic vascular resistance results in difficulties in determining optimal fluid balance and is best assisted with Swan Ganz catheters. Cardiac arrhythmias can result from metabolic abnormalities and require constant monitoring. Hyperventilation, hypercapnia, and respiratory alkalosis may occur in the course of ALF, and worsening encephalopathy, respiratory depression, and apnea may ensue. Arterial hypoxemia is multifactorial and is caused by aspiration, ventilation/perfusion mismatch caused by intrapulmonary shunting, sepsis, adult respiratory distress syndrome, and noncardiogenic pulmonary edema. opsonization. Covert infection is difficult to assess and a high degree of clinical suspicion must be kept so treatment can be started early. Staphylococcus, Streptococcus and coliforms are the usual organism. Between 10% to 80% of patients experience bacterial infection with attributed mortality of 10% to 37%. Recently, the systemic inflammatory response syndrome has been described in FHF. 20 Systemic inflammatory response syndrome is believed to be the end product of multiple inflammatory pathways mediated through the chemokine-cytokines response seen in ALF and associated with a poor prognosis. It has as been linked to adult respiratory distress syndrome, sepsis syndrome and multiorgan function syndrome or MODS Prolong hospitalization also predisposes to fungal infection. This is especially true in patients with advance liver failure. PROGNOSTIC SCORING SYSTEMS Survival in patients with ALF is 40% to 80% and depends on many factors, including etiology, patient age, severity of liver dysfunction, degree of liver necrosis, number and nature of complications, and duration of illness. Patients with grade 2 encephalopathy have a mortality of 30%; those who progress to grade 4 have a mortality rate of greater than 80% (Fig. 2). In general, the survival rate tends to be better in cases of acute hepatitis A virus and acetaminophen overdose (40%). In contrast, patients with ALF caused by idiosyncratic drug reactions, toxins, HBV hepatitis D virus coinfection, and idiopathic etiologies have mortality rates approaching 80% to 90%. Several prognostic systems have been developed for FHF to help determine the likelihood of spontaneous recovery (Table 5). Ideally, the prognostic system should be accurate, be readily available, use both static and dynamic variables, be able to predict the outcome of ALF cases, and identify patients who need liver transplantation early in the clinical course. 3 The King s College criteria have been the most widely used worldwide and are different for acetaminophen- and nonacetaminophen-induced ALF. 18 The criteria have re- SEPSIS AND MULTIORGAN FAILURE SYNDROME Patients with FHF are at substantial risk of sepsis caused by impaired reticuloendothelial dysfunction and decrease TABLE 4. Metabolic abnormalities in ALF Hyponatremia Hypokalemia Hypophosphatemia Metabolic acidosis with acetaminophen Alkalosis (metabolic and respiratory) Lactic acidosis Hypoglycemia Acute pancreatitis Renal failure FIG. 2. Correlation of hepatic encephalopathy and mortality.

6 196 J Clin Gastroenterol, Vol 33, No. 3, 2001 cently been evaluated by the University of Pittsburgh in 177 patients seen over a 13-year period 24 and were found to be relatively effective in predicting death and the need for transplantation. However, failure to fulfill the King s College criteria did not predict survival. The APACHE II system, a measure of illness severity used in many intensive care unit settings, has also been applied to FHF and has been found to be to be comparable to the King s College criteria in predicting death in acetaminophen-induced FHF. 25,26 The Cliché criteria use a factor 5 assay of less than 20% in patients younger than 30 years of age or a factor 5 of less than 30% with grades 3 to 4 hepatic encephalopathy in patients of any age to identify those who are unlikely to spontaneously recover without transplantation. 27 Other prognostic variables used in clinical practice include a factor 8/5 ratio of more than 30, 16 serial AFP levels, 28 and plasma Gc globulin levels. 29,30 ROLE OF LIVER BIOPSY Liver biopsy may confirm the suspected etiology of ALF and may determine the degree of hepatocyte necrosis. 31 A biopsy with more than 70% necrosis is associated with a mortality rate approaching 90% without transplantation. 32 The presence of coagulopathy makes the percutaneous route of biopsy impractical and, consequently, the transjugular biopsy approach is often preferred. Therefore, although a liver biopsy is not mandatory, it can be valuable in prognosis and the decision for early transplantation. SPECIFIC THERAPIES AND MANAGEMENT OF THE COMPLICATIONS OF ACUTE LIVER FAILURE The liver has the unique ability to regenerate after acute, self-limited injury. Because there is no specific medical therapy for ALF, treatment is limited to general supportive measures that anticipate complications and treat the patient accordingly to allow the liver time to regenerate. 33 N- acetylcysteine should be prescribed in all cases of acetaminophen overdose to help replenish hepatic glutathione stores; it is most beneficial if given within 12 hours of acetaminophen ingestion. However, studies also demonstrated benefit even when N-acetylcysteine was administered up to 36 hours after overdose, 34,35 and most authors recommend that it be given to all patients with acetaminophen overdose, regardless of the time from ingestion. Recent data also suggest that N-acetylcysteine may also be effective therapy for nonacetaminophen-induced ALF 36,37 and is currently under study in a large multicenter National Institutes of Health sponsored trial. All patients with ALF should be cared for in an intensive care unit. If transplantation is a potential option and is not available at the current facility, prompt referral to a transplant center is strongly recommended. HEPATIC ENCEPHALOPATHY The treatment of encephalopathy associated with ALF is directed at limiting the production of ammonia and avoiding precipitating factors, such as benzodiazepines. Most ammonia is derived from intestinal bacteria, and lactulose may be useful in the treatment of patients with grades 1 or 2 encephalopathy. However, it has not been shown to improve survival in patients with more advanced encephalopathy grades. 33 Oral antibiotics directed against gut flora, such as flagyl and neomycin, can also be administered. Although neomycin is labeled as nonabsorbable, it has the potential for ototoxicity and nephrotoxicity in patients with severe liver disease and is best avoided. Various experimental therapies, such as exchange transfusion, charcoal hemoperfusion, and plasmapheresis, have been used to lower ammonia levels. However, none of these have shown any benefit with regard to survival. There is upregulation of gamma amino butyric acid receptors on the neuronal membrane adjacent to benzodiazepine receptors in patients with ALF, and endogenous benzodiazepine-like substances have been identified in the cerebrospinal fluid of patients with hepatic encephalopathy. 38 Therefore, because of the potential confounding effects on encephalopathy, benzodiazepines should be avoided in the management of agitation in patients with ALF. An intravenous benzodiazepine receptor blocker, flumazenil, has been used with some success in patients with liver failure to provide short-term improvements in hepatic encephalopathy. 39 TABLE 5. Prognostic criteria used in ALF King s College criteria In acetaminophen overdose Arterial ph < 7.3 or all three of the following: PT > 100 s, serum creatinine > 3.4 mg/dl, grade 3 4 HE In other causes of ALF PT > 100 s, INR > 6.7, or any three of the following: unfavorable causes (non-a, non-b, drug reaction), jaundice > 7dbeforeHE, age < 10or > 40y, bilirubin > 17.4 mg/dl Cliché criteria Factor V < 20% in person < 30 y or both of the following: factor V < 30% and grade 3 4 HE Serum Gc level Scavenger protein bound to actin, released into the circulation by dying hepatocytes (not widely available) Serum AFP level Serial increase from day 1 to day 3 has shown correlation with survival Liver biopsy 70% necrosis is only discriminant PT indicates prothrombin time; HE, hepatic encephalopathy; INR, international normalized ratio; AFP, alpha-fetoprotein.

7 R.Q. Gill and R.K. Sterling ACUTE LIVER FAILURE 197 CEREBRAL EDEMA Cerebral edema is a common cause of death in patients with FHF and is present when the ICP exceeds 30 mm Hg. Intracranial pressure monitoring has been recommended for all patients with grades 3 and 4 encephalopathy, especially those who are candidates for transplantation. 14,40 The optimal management of cerebral edema requires a delicate balance between MAP, ICP, and cerebral oxygen consumption that, in turn, is dependent on effective CPP. Ideally, the CPP should be maintained at more than 50 mm Hg. An ICP more than 30 mm Hg and a CPP less than 40 Hg for more than 2 hours have been associated with irreversible brain injury. 14,33 Mannitol is the primary therapy to lower ICP, but caution must be exercised in patients who have or who are developing renal failure. The role of high-dose steroids has not been confirmed and is not effective in the treatment of cerebral edema associated with ALF. General measures to prevent cerebral edema include elevation of the head of the bed to 30 to 40 degrees and a minimization of tactile stimulation. Attempts should also be made to avoid prolonged coughing or tracheal stimulation during suctioning. 14 Hyperventilation may be required to keep a pco 2 of 30 mm Hg. As alluded to before, the routine use of phenytoin for subclinical seizure activity may reduce cerebral edema. 9 However, until more data is available, its routine use can not be recommended at this time. Intravenous thiopental and phenobarbital have been used to slow cerebral activity and limit irreversible brain injury in the treatment of selected patients with cerebral edema who do not respond to the above measures. 41 COAGULOPATHY Although most patients with ALF have a significant coagulopathy, spontaneous hemorrhage is uncommon. Patients should be given a trial of parental vitamin K, 10 mg daily, for 3 consecutive days. As mention previously, serial measurement of factors 5 and 7 can be used to help assess prognosis for spontaneous recovery. Routine use of fresh frozen plasma is not recommended unless spontaneous bleeding occurs or an invasive procedure is being contemplated. If correction of coagulopathy is deemed necessary, then exchange transfusion with either fresh frozen plasma or cryoprecipitate is used. 42,43 GENERAL SUPPORTIVE MEASURES Optimal fluid balance is of paramount importance as both under- and overhydration can have dire consequences. Infections should be suspected early and treated aggressively, as they adversely affect survival. Many patients with ALF will not develop an elevated white blood count or fever. Therefore, serial blood cultures every 48 hours are recommended. All nephrotoxic medications, including aminoglycoside antibiotics and nonsteroidal antiinflammatory drugs, should be avoided. Because patients are at risk for gastrointestinal bleeding, acid suppression is recommended to prevent stress-induced bleeding. The risk of aspiration is significant in patients with grades 3 and 4 encephalopathy, and elective intubation to protect the airway should be planned in these patients before aspiration occurs. Because renal failure is common, patients often need renal support. If required, those modalities that cause less rapid fluid shifts, such as continuous venovenous hemofiltration, are preferred over hemodialysis, which can affect MAP dramatically and, therefore, can worsen cerebral perfusion. Most patients with ALF are not malnourished before the onset of ALF, and nutritional support is generally not needed in the 1st week of illness. However, nutritional support should be considered in patients with SFHF, as they may be ill for weeks to months before development of hepatic encephalopathy and may have profound malnutrition. These patients should be provided with either parental or enteral nutritional support. Most patients can handle lipid infusion and dextrose to provide energy and prevent hypercatabolism, which can cause an increase in nitrogenous waste in the blood. Although not proven to reduce encephalopathy or improve survival, branch chain amino acid formulations may be preferable to standard amino acid regimens in the nutritional support of patients with liver failure. Lastly, serum glucose levels should be frequently monitored, as patients with liver failure are prone to the development of hypoglycemia. 33 Other therapies that have been tried in ALF include insulin and glucagon, 44 prostaglandin E1, 45 corticosteroids, 46 charcoal hemoperfusion, 47 exchange transfusion, 48 and plasmapheresis. 49 Unfortunately, controlled trials of these modalities have not been shown to improve survival. LIVER-ASSISTING DEVICES AND HEPATIC TRANSPLANTATION Over the past 10 years, replacement of hepatocytes in various forms as liver-assisting devices have been promoted for the treatment of ALF with the goal of providing functional liver mass until the native liver regenerates. These techniques use porcine or human liver cells maintained in a cartridge through which patient plasma or blood flows in a manner similar to hemodialysis. 50,51 Although experience with these devices is limited, a multicenter trial is underway to assess the effectiveness of a bioartificial liver. 52,53 Transplantation of human hepatocytes directly into the splenic bed has also been performed with some success. 54,55 Xenotransplantation, using a transgenic pig modified to prevent hyperacute rejection, is also under investigation for the treatment of ALF. 56 With advancements in technology, these modalities may provide a bridge until spontaneous recovery or a suitable organ for transplantation is available. The only proven therapy for ALF is liver transplantation. 3,5,33,57,58 With improvements in technique, survival af-

8 198 J Clin Gastroenterol, Vol 33, No. 3, 2001 ter transplantation is 50% to 90% and depends on pretransplant morbidity, with the best outcomes occurring in patients who are transplanted before significant complications develop. The major limitation of transplantation is a shortage of available organs. As a result, once a patient with ALF is identified, urgent referral to a transplant center is critical so that their transplant status can be quickly evaluated and a search for an organ can be initiated. Recently, living related liver transplantations, including adult-to-adult right lobes, have been used and could be an option in select patients with ALF REFERENCES 1. Trey C, Davidson CS. The management of fulminant hepatic failure. In: Popper H, Schaffner F, eds. Progress in liver diseases, vol 111. New York: Grun & Stratton, 1970: Bernuau J, Rueff B, Benhamou JP. Fulminant and subfulminant hepatic failure: definition and causes. 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