Etiology and Management of Fulminant Hepatic Failure

Javier Vaquero, MD and Andres T. Blei, MD*

Classifications and Definitions
Since the initial definition of FHF by Trey and Davidson [3] 30 years ago, several classifications have been proposed. However, none of these systems has been accepted universally, and overlap in terms and time intervals among them is an obvious source of confusion (Table 1). Hepatic encephalopathy is the hallmark of FHF in all classifications and clearly marks the transition from a severe condition to a deadly disease. In the different classifications, the interval between the onset of symptoms or jaundice and the appearance of encephalopathy allows grouping of patients with similar etiologies, clinical characteristics, and prognosis.
Address *Department of Medicine, Northwestern Feinberg Medical School and VA Lakeside Medical Center, Searle 10-573, 303 East Chicago Avenue, Chicago, IL 60611, USA. E-mail: a-blei@northwestern.edu Current Gastroenterology Reports 2003, 5:3947 Current Science Inc. ISSN 1522-8037 Copyright 2003 by Current Science Inc.

Fulminant hepatic failure (FHF) remains a rare but devastating disease. Viruses and drug-induced hepatotoxicity are the most common causes of the syndrome, but the relevance of each differs depending on the geographic area. In a large proportion of patients no cause for FHF can be identified. Good intensive care is critical for patient survival. Orthotopic liver transplantation (OLT) remains a definitive therapeutic option. Prognostic indices have helped to optimize patient selection and timing for performance of OLT. However, the accuracy of these prognostic indices decreases when they are applied to different populations, probably because of regional differences in etiology and peculiar native host factors. More accurate prognostic criteria and new therapeutic alternatives to OLT are required.

Etiology
Viral hepatitis is the most common identifiable cause of FHF worldwide, but the contribution of each etiologic category to the total number of cases of FHF varies by geographic region (Table 2). Thus, hepatitis B virus (HBV) is a common cause of FHF in the Far East, and hepatitis E virus (HEV) is relevant in India [13]. Occurrence of FHF within the larger number of patients with viral hepatitis, however, is rare (0.2%0.4% for hepatitis A, 1%4% for hepatitis B) [1]. Hepatitis A virus (HAV) is associated with a higher risk of developing FHF if infection is acquired in older adulthood. Thus, vaccination is recommended for adults traveling from developed countries to endemic areas. The relevance of HAV as a cause of FHF in patients with preexisting chronic liver disease has been recognized recently, and vaccination has also been suggested [15]. Acute HBV infection is diagnosed by detection of IgM antibodies against hepatitis B core antigen (HbcAg) because a substantial number of patients have negative serum hepatitis B surface antigen (HBsAg) and serum HBV-DNA. Low or absent levels of HBsAg and HBV-DNA are associated with better prognosis and lower rate of recurrence after OLT [16]. The risk of developing FHF after infection by precore mutants remains controversial, with an increase reported by some authors [17] but not by others [18]. FHF following reactivation of chronic hepatitis B has been described mainly in male patients under diverse immunosuppressant conditions; it usually has a subfulminant course and poor prognosis.

Introduction
Fulminant hepatic failure (FHF) is a rare clinical syndrome with an estimated incidence of 2000 cases per year in the United States [1]. For practical purposes, it is defined as the appearance of hepatic encephalopathy in a patient with acute deterioration of liver function and no previous history of liver disease. Viruses, drugs, toxins, and miscellaneous conditions such as cardiovascular and metabolic disorders are the main causes of FHF. Orthotopic liver transplantation (OLT) is used increasingly to salvage patients with FHF. Although medical management of FHF has improved, early prediction of which patients need a liver transplant to survive is still the most important task for the clinician. Between 10% and 30% of patients on the waiting list for emergent OLT may recover spontaneously. In contrast, approximately 25% of patients in the United States die while awaiting an organ [2]. These facts have prompted the search for more accurate prognostic criteria and for alternatives to OLT, including bioartificial liver-assist devices, auxiliary liver transplantation, and hepatocyte transplantation.

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Table 1. Different classifications of fulminant hepatic failure* Trey and Davidson [3] Fulminant hepatic failure: development of HE within 8 weeks of onset of symptoms England [4] Acute liver failure (includes only patients with encephalopathy) Subclassification depending on the interval between jaundice and HE Hyperacute liver failure: 0 to 7 days Acute liver failure: 8 to 28 days Subacute liver failure: 29 to 72 days Late-onset acute liver failure: 56 to 182 days France [5] Acute hepatic failure: a rapidly developing impairment of liver function Severe acute hepatic failure: prothrombin time or factor V concentration below 50% of normal with or without HE Subclassification Fulminant hepatic failure: HE within 2 weeks of onset of jaundice Subfulminant hepatic failure: HE between 3 and 12 weeks of onset of jaundice International Association for the Study of the Liver [6] Acute liver failure (occurrence of HE within 4 weeks after onset of symptoms) Subclassification Acute liver failurehyperacute: within 10 days Acute liver failurefulminant: 10 to 30 days Acute liver failurenot otherwise specified Subacute liver failure (development of ascites and/or HE from 5 to 24 weeks after onset of symptoms) Subclassification by etiology Hepatitis AE Other viruses Other Not known
*A short interval between symptoms or jaundice and encephalopathy (most of acetaminophen-induced FHF and some of hepatitis A or B etiology) is associated with the high risk of brain edema and greater possibility of spontaneous recovery, whereas a long interval is associated with less frequency of brain edema, lower survival, and more common nonA-to-E cryptogenic etiology. FHFfulminant hepatic failure; HEhepatic encephalopathy.

Most studies indicate that hepatitis C virus (HCV) infection alone does not result in FHF. However, isolated cases of HCV-RNA in serum or tissue of patients with FHF and negative markers for other viruses have been noted in Western countries [11]. Involvement of HCV in FHF is slightly more common in the Far East [19]. An increased risk of FHF in patients with chronic hepatitis B and superinfection by HCV has been suggested. Coinfection with HBV and hepatitis D virus (HDV), or superinfection by HDV in patients with chronic hepatitis B, can also cause FHF. The incidence of such coinfection is higher in studies in which intravenous drug abuse is a relevant risk factor. Diagnosis of acute infection by HDV is made by the presence of HDV antigen, anti-HDV IgM antibody, or HDV-RNA. Infection by HEV is uncommon in Western countries and is mainly diagnosed in travelers to endemic areas [11]. Pregnant women infected by HEV seem to have a special propensity for developing FHF. Diagnosis is made by detection of anti-HEV IgM antibodies. Acetaminophen overdose accounts for more than 70% of FHF in the UK. It has also become the most common cause in the United States based on a recent series [9], and its frequency is increasing in other Western countries [11]. Even doses considered nontoxic (< 4 g/d

in adults, < 8 mg/kg in infants) may cause hepatotoxicity if other concurrent factors exist, such as alcohol ingestion, fasting, or malnutrition. Hepatotoxicity usually develops 1 to 2 days after the overdose, with alanine aminotransferase levels and prothrombin time reaching their peak around day 3. A continued increase of prothrombin time after day 3 is associated with a 90% mortality rate. Acetaminophen is also nephrotoxic, and renal failure may occur in the absence of liver necrosis. Other idiosyncratic drug reactions and toxins may cause FHF. Isoniazid, pyrazinamide, antidepressants, nonsteroidal anti-inflammatory drugs, and halothane and its derivatives are most frequently implicated. Two histologic patterns are usually distinguished, one characterized by confluent necrosis (isoniazid or halothane) and the other by hepatocyte microvesicular fatty change (valproic acid or tetracyclines). Reemergence of tuberculosis in the last decade has increased the frequency of FHF caused by isoniazid. Cotreatment with rifampin or pyrazinamide may increase the risk. Mushroom poisoning is relatively common in Europe. Florid muscarinic effects such as sweating or watery diarrhea occur early, with FHF usually occurring 4 to 8 days after mushroom ingestion. Other toxins (eg, carbon tetrachloride or yellow phosphorus) are rare causes of FHF.

Table 2. Etiology of fulminant hepatic failure worldwide Year 1994 1994 1994 1995 1999 1994 1996 1993 1996 2002 315 8 2 2 17 12 423 28 1.7 13 0 4.5 0 17 342 62 2.4 42 2.4 2 NR NR 73 0 2.6 8 11.4 6 295 1257 10 7.5 7 4.8 NR 0.4 20 60.9 12 6.1 NR 6.8 15 16 8.2 44 53 43 459 148 115 60 22.9 4.1 19 15 6.1 10.1 NR 8 1.5 NR 34 0 4.6 2 NR 18 10.6 8 14 15 NR 2 2 5 29.9 73.6 31 38 Patients, n HBV, % HAV, % Other virus, % Acetaminophen, % Drug or toxin, % Miscellaneous, % Indeterminate, %

Study

Country

Detre et al. [7] US Detre et al. [7] US (children) Dodson et al. [8] US Hoofnagle et al. US [1] Schiodt et al. [9] US Williams and UK Wendon [10] Williams [11] UK Castells et al. Spain [12] Acharya et al. India [13] Brandsaeter et Nordic al. [14] countries *

* Only includes patients listed for emergent liver transplantation.

Etiology and Management of Fulminant Hepatic Failure Vaquero and Blei

HAVhepatitis A virus; HBVhepatitis B virus; NRnot reported.

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Miscellaneous cardiovascular, metabolic, and other disorders account for 2% to 10% of cases of FHF. Acute liver ischemia secondary to hypotension, arrhythmia, or heart failure can result in hepatocyte necrosis, but the prognosis is good if the primary condition can be corrected. The prognosis is worse when other causes, such as Budd-Chiari syndrome, veno-occlusive disease, or malignancies, are responsible for the alteration of blood flow. Sporadically, the first manifestation of Wilsons disease is FHF, but underlying cirrhosis is always present. Death is the universal result without OLT. Acute fatty liver of pregnancy is rare, occurring in the third trimester of pregnancy, and responds well to fetal delivery. Other causes of FHF are autoimmune hepatitis or Reyes syndrome, the latter less commonly seen in the pediatric population once aspirin use was curtailed. In a large group of patients (20%50% in adults and up to 70% in children), FHF is classified as indeterminate despite intensive diagnostic efforts. Misdiagnosed hepatitis B may explain some cases, given that HBV-DNA has been found in serum and liver tissue of patients with FHF and negative serologic markers of HBV infection [20]. However, this is not a common situation in other series, probably reflecting geographic differences. Small case reports of FHF caused by Varicella or Herpes simplex virus in pregnant women, neonates, or immunosuppressed individuals, by parvovirus B19 in children, or by togavirus-like particles, explain another small proportion of cases. Although these causes are rare, they must be ruled out because some patients may benefit from specific therapies.

practitioners have administered the oral formulation intravenously after adequate filtering. In amanita intoxication, beneficial effects have been reported with the use of penicillin G, silymarin, and forced diuresis. Activated charcoal and cathartic agents may be useful if they are given early after mushroom ingestion. Hepatitis secondary to Herpesvirus may be misdiagnosed because of the lack of specificity of symptoms at presentation and the absence of typical mucocutaneous lesions. If herpesvirus is suspected, treatment with acyclovir or ganciclovir should be started. As noted previously, acute fatty liver of pregnancy usually responds to fetal delivery. Urgent chemotherapy is indicated for FHF caused by massive infiltration of the liver by lymphoma. Acute Budd-Chiari syndrome may be amenable to thrombolytic therapy or to transjugular intrahepatic portosystemic shunt placement.

Prevention and Management of Complications

Nutrition and metabolism Glycemia must be controlled frequently (every 12 hours) in patients with deep encephalopathy. Constant infusion of 10% to 20% glucose is preferable to bolus administration for maintainance of euglycemia. FHF is a catabolic state, and protein-caloric malnutrition develops quickly. Thus, nutrition should be started soon and adjusted individually to maintain an adequate caloric intake. Enteral nutrition through a nasogastric or nasojejunal tube is preferred to parenteral nutrition. Correction of hypomagnesemia, hypokalemia, or hypophosphatemia is accomplished by supplementation of these substances. H2-receptor antagonists, proton-pump inhibitors, or sucralfate are used to reduce the incidence of gastrointestinal ulceration. Coagulation When evaluation of mental state is not possible, evolution of coagulation parameters is the only way of assessing improvement or worsening of liver function. Administration of fresh-frozen plasma does not increase survival and may cause volume overload. Thus, correction of coagulopathy is not indicated unless bleeding occurs or invasive procedures are to be performed. In those instances, 2 to 4 units of fresh-frozen plasma should be administered every 6 to 12 hours according to severity of coagulopathy and transfusion of platelets, if the platelet count is below 50 109/L. Recombinant activated factor VII offers advantages of shorter half-life and avoidance of volume overload, compared with fresh-frozen plasma, but reports are only preliminary, and more studies are needed [21]. Infection A high index of suspicion should be maintained concerning infection in FHF. Fever and leukocytosis are absent in

Management of Fulminant Hepatic Failure

Early referral to a transplant center is important. Patients with slight alteration of mental state may deteriorate rapidly, leaving no time for alternatives. Patients should be managed in a critical care unit for close surveillance of mental state. Specific therapies Elucidation of the cause of hepatic failure allows some patients to benefit from specific treatments and may influence posttransplant management if a transplant is performed. N-acetylcysteine is used as specific antidote for acetaminophen overdose. If it is given in the first 8 to 10 hours after overdose, it replenishes glutathione stores and prevents the development of hepatotoxicity. The efficacy of N-acetylcysteine declines progressively thereafter, but it may be effective up to 72 hours after acetaminophen ingestion. It is used differently in Europe (intravenous, total dose of 300 mg/kg in 20 hours) than in the United States (oral, total dose of 1330 mg/kg in 72 hours). The poor oral bioavailability of N-acetylcysteine explains the high doses used in the United States. Because it is not well tolerated orally and the intravenous formulation is not approved by the US Food and Drug Administration (FDA), some US

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up to 30% of infected patients. Infection must be suspected in the presence of any sudden clinical or biochemical deterioration, and even more so if liver function has started to recover. Microbiologic cultures should be obtained from different sites, and empiric antibiotics covering both gramnegative and gram-positive bacteria should be started. There are no generally accepted guidelines regarding use of prophylactic antibiotics. Their use may be supported by recent studies in which infection and progression to deep encephalopathy were correlated [22]. In the two studies that have compared prophylactic antibiotics to placebo [23,24], the patients treated with antibiotics had a lower rate of infection, but there was no difference in survival. Both broadspectrum intravenous antibiotics and selective enteral bacterial-fungal decontamination seem to be efficient for decreasing the rate of infection. Selective enteral decontamination, however, does not add any benefit if the patient is already on intravenous antibiotics. Emergence of meticillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci has caused great concern in recent years. Cardiovascular system Arrhythmia occurs frequently if electrolyte abnormalities are not corrected promptly. A hyperdynamic circulation is characteristic of FHF, with systemic and splanchnic arterial vasodilation resulting in increased cardiac output and decreased arterial pressure. Correction of these abnormalities is difficult, especially in patients with intracranial hypertension. Reposition of volume is required to avoid or correct arterial hypotension, but normalization of blood pressure is rarely achieved. Monitoring of central venous pressure helps to guide the amount of fluid to be infused (target, 812 mmHg). In the presence of persistent hypotension or worsening renal function, sepsis needs to be ruled out. Placement of a pulmonary artery catheter can improve management in these patients, though invasive procedures entail risk. There is controversy over which volume expander is best, but blood, colloids or albumin are usually preferred over crystalloids. Isotonic or hypertonic, but not hypotonic, sodium-containing solutions should be used if acute volume expansion is needed in patients at risk of brain edema. Adrenaline or noradrenaline are the vasopressors of choice, but caution should be exercised because they may impair tissue oxygenation or produce an unwanted increase of cerebral blood flow. Lung Intubation and mechanical ventilation are usually required in patients with agitation or deep encephalopathy to avoid surges of intracranial pressure and pulmonary aspiration. Sedation must be maintained at the lowest possible level, but some patients require additional sedation during nursing manipulations.

Kidney Frequent control of serum creatinine level, urinary output, and urinary sodium concentrations is needed. Because of the risk of infection, a urinary catheter should be used only in patients with oliguria and should be removed in anuric patients. Adequate volume repletion is essential to prevent development of functional renal failure. Dopamine at diuretic doses (24 g/kg/h) has been used traditionally to improve renal perfusion, but it is not efficacious. Diuretics are not helpful and usually impair renal function. Potentially nephrotoxic drugs, such as aminoglycosides, should not be used in FHF. If dialysis is needed, continuous hemofiltration is preferred over intermittent hemodialysis to avoid rapid fluid shifts that may aggravate brain edema. Brain Hepatic encephalopathy Infection or any other precipitant factor must be identified and treated. The efficacy of lactulose in FHF has not been tested in clinical trials; it should be used with caution because of the risk of hypernatremia and functional ileus. Flumazenil (1 mg intravenously) may be useful if ingestion of benzodiazepines is suspected. Although monitoring of mental state is very important for assessing prognosis, sedation and intubation are usually required in advanced stages of encephalopathy. Cerebral edema Brain edema and intracranial hypertension may develop very quickly in patients with deep encephalopathy. An arterial ammonia level higher than 200 g/dL in stage III and IV encephalopathy is a strong predictor of brain herniation [25]. Monitoring of intracranial pressure should be limited to specialized units and to patients awaiting OLT because it has not been shown to increase survival. Intracranial pressure should be maintained below 15 mm Hg, and cerebral perfusion pressure over 50 mm Hg. Most centers prefer epidural to subdural or intraparenchymal transducers because of the lower rate of complications [26]. Monitoring of jugular bulb oxygen saturation with a reversed jugular venous catheter can also guide interventions to avoid intracranial hypertension. Decreased saturations (< 55%) indicate cerebral ischemia, and high saturations (< 85%) indicate either decreased metabolic demands of the brain or cerebral hyperemia, more commonly the latter. Current recommendations include maintaining the patients head at a 20 angle to improve jugular venous outflow. In episodes of intracranial hypertension, a bolus of 0.5 to 1 g/kg of mannitol can be administered intravenously and repeated until plasma osmolarity reaches 310 mOsm/L. Patients with oliguria and renal failure may require hemodialysis to avoid hyperosmolarity. Hyperventilation produces cerebral vasoconstriction and reduces cerebral blood flow, but the effect is usually transient. Finally, induction of barbiturate coma to decrease cerebral

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Table 3. Kings College Hospital and Clichy liver transplantation criteria for fulminant hepatic failure Kings College criteria [31] FHF secondary to acetaminophen overdose pH less than 7.30 (irrespective of encephalopathy grade), or Hepatic encephalopathy grade IIIIV, prothrombin time over 100 seconds (INR > 6.5), and serum creatinine over 300 mol/ L (3.4 mg/dL). FHF with other causes Prothrombin time over 100 seconds (INR > 6.5) (irrespective of encephalopathy grade), or any three of the following (irrespective of encephalopathy grade) Age under 10 or over 40 years Non-A, non-B hepatitis or drug-induced origin Duration of jaundice before encephalopathy over 7 days Serum bilirubin greater than 300 mol/L (17.6 mg/dL) Prothrombin time over 50 seconds (INR > 3.5) Clichy criteria [32] Presence of confusion or coma (stage IIIIV HE) associated with Factor V level lower than 20% of normal in patients aged less than 30 years Factor V level lower than 30% of normal in patients aged over 30 years
FHFfulminant hepatic failure; HEhepatic encephalopathy; INRinternational normalized ratio.

metabolic activity may be useful as a last resort, but such unwanted effects as myocardial depression or arterial hypotension limit its use. New therapies have been investigated. According to recent reports, mild hypothermia reduced intracranial pressure and cerebral blood flow and improved cerebral perfusion pressure both in patients with FHF [27] and in experimental models [28]. Indomethacin also reduced cerebral blood flow and prevented brain edema in experimental models, and it has been used in isolated cases in humans, with encouraging results [29]. In a recent controlled clinical trial, a prophylactic infusion of phenytoin decreased the incidence of subclinical seizure activity and appeared to prevent brain edema [30]. However, clinical experience with these agents remains scarce, and their efficacy and safety should be explored further.

suboptimal when applied to different countries [9,13]. Other prognostic parameters have been evaluated. Gcgammaglobulin levels are decreased in patients who do not spontaneously survive, although these values overlap considerably with those of survivors. Liver volume decreases with progression of the disease, and its measurement with CT scanning may help to assess prognosis. Other proposed prognostic tools include the proportion of necrosis in liver histology obtained by transjugular venous biopsy, the amount of fresh-frozen plasma to correct coagulopathy, or the determination of somatosensory evoked potentials. Recently, high-serum phosphate and blood lactate have been proposed as markers of poor prognosis in patients with acetaminophen-induced FHF [33,34]. Medical therapy N-acetylcysteine is used in Europe to treat established FHF of any cause, based on clinical reports from the Kings College group. Benefits of N-acetylcysteine on survival, brain edema, hemodynamics, oxygen delivery, and oxygen consumption were found in patients with established FHF [35]; however, these effects were not confirmed by other groups [36]. Moreover, N-acetylcysteine had deleterious effects in patients with critical illnesses other than FHF [37]. A randomized, controlled trial of N-acetylcysteine by the US Acute Liver Failure Study Group in patients with non-acetaminopheninduced FHF is currently underway and should clarify these issues. Preliminary reports of increased survival of patients treated with prostaglandin-E1 in uncontrolled studies were very encouraging, but no clear benefit supporting the use of this agent has been found in subsequent controlled trials [38].

Management of Liver Failure

Liver transplantation Liver transplantation is the only measure that can radically influence the course of FHF. However, it is an expensive and high-risk procedure with considerable morbidity and represents a commitment to indefinite immunosuppression. Moreover, patients transplanted for FHF have a worse outcome than those transplanted for other causes in most series, in part because of their poor clinical condition at the time of the procedure. Early identification of which patients would die if OLT were not performed is thus a very important objective. Both the Kings College and the Clichy criteria are used most often to identify such patients (Table 3). However, some reports suggest that these criteria may be

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Artificial liver-assist devices Several modalities of artificial liver support have shown a benefit in FHF. Charcoal hemoperfusion consists of the passage of plasma through columns of activated charcoal or resins with the goal of clearing lipophilic toxins. Clinical benefit was found in early reports, but randomized, controlled trials failed to confirm such results [39]. High-volume plasmapheresis has been used extensively in Copenhagen, and improvement of mental state, correction of hyperdynamic circulation, and lowering of ammonia were reported [40]. A few reports have also noted beneficial hemodynamic effects and lowering of ammonia levels with the Molecular Adsorbent Recirculating System (MARS) [41]. In this system, water-soluble and albumin-bound toxins are cleared by dialysis of blood against an albumin-containing dialysate. However, no randomized clinical trials of the last two techniques in FHF are available. Bioartificial liver-assist devices Several bioartificial liver-assist devices are currently undergoing clinical trials. Most of these devices use hollow-fiber cartridges housing hepatocytes in the extraluminal space. Blood or plasma is circulated through the hollow fibers, allowing exchange of substances by diffusion between plasma and hepatocytes. The cells used in these devices are primary porcine hepatocytes (Bioartificial Liver Device [BAL]) or human hepatoblastoma C3a line cells (Extra corporeal Liver Assist Device [ELAD]). The two systems with the most clinical experience are the BAL (Circe Biomedical HepatAssist, Lexington, MA) and the ELAD (Vitagen, San Diego, CA). In the ELAD, whole blood is perfused through the hollow fibers of the bioreactor. A controlled clinical trial of 24 patients showed improvement in galactose elimination time, encephalopathy, intracranial pressure, and hemodynamics in the group treated with the ELAD, compared with standard medical therapy, but no difference in survival was noted [42]. In the BAL system, plasma is separated from blood and is circulated through a charcoal column and then through the bioreactor. In several case reports, significant improvements in blood glucose, serum ammonia, and bilirubin levels; decrease of intracranial pressure; increase of cerebral perfusion pressure; and bridging to OLT were reported [43]. An interim analysis of the largest controlled clinical trial using a bioartificial liver-assist device was presented at the annual meeting of the American Association for the Study of Liver Diseases, November 910, 2001 in Dallas, TX [44]. One-hundred and forty-seven patients with FHF and 24 with primary graft nonfunction were randomly assigned to standard medical treatment alone or to standard medical treatment plus BAL. No significant differences were found in the endpoint (30-day survival) between standard medical treatment and BAL (59% vs 70%, not significant),

except in patients with disease caused by acetaminophen overdose (n=39; 37% vs 70%, P<0.05). The final results of this trial are anxiously awaited. Hepatocyte transplantation The rationale behind hepatocyte transplantation is to deliver a sufficient supply of hepatocytes to maintain liver function until regeneration of native liver occurs or a graft becomes available. Human hepatocytes from livers not used for transplantation can be cryopreserved, making them readily available if needed. Experimental studies in models of FHF showed engraftment and function of transplanted hepatocytes, with increased survival. Hepatocyte transplantation has also been performed on a few occasions in humans. Bilir et al. [45] reported engraftment of donor hepatocytes in five patients with stage III and IV encephalopathy and severe coagulopathy. In this and other reports from small studies, improvements in encephalopathy score and hemodynamics have been noted as well as decreased serum ammonia and bilirubin levels [45,46]. Pulmonary embolism of hepatocytes occurred in patients in whom the injection was intraportal but not in those with hepatocytes injected into the splenic artery [45]. Other concerns about this technique include transplantation and acquisition of an adequate number of hepatocytes (only 0.1580 g have been injected compared with 300 g [20% of normal liver mass required] to replace liver function), use of immunosuppression in FHF, and the need for a 48-hour period for engraftment and function. Methods that reversibly immortalize human hepatocytes are important to supply a sufficient amount of hepatocytes for transplantation or for bioreactors and to avoid the risks of tumorigenesis and xenotransplantation [47]. Auxiliary liver transplantation Auxiliary liver transplantation involves transplantation of a hepatic lobe from a living or cadaveric donor, leaving the whole liver or part of the liver of the recipient in situ. In auxiliary partial orthotopic liver transplantation (APOLT), one hepatic lobe of the recipient is resected, and the auxiliary graft is placed in its original position. In heterotopic auxiliary liver transplantation (HALT), the donor graft is placed below the unresected liver of the recipient. A minimum ratio of graft volume to recipient standard liver volume of 35% is necessary for the graft to support the metabolic activity in FHF. In this potentially reversible condition, auxiliary transplantation has the advantage of allowing regeneration of the native liver, after which the graft can be surgically removed or left to atrophy following withdrawal of immunosuppression. Thus, auxiliary transplantation may be especially valuable in young patients and in those with potentially reversible causes of FHF (ie, HAV, HBV, or drug-induced).

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In studies reported in the past 3 years, 1-year survival rates with auxiliary liver transplantation have been similar to those for OLT [48,49]. However, incidence of portal vein thrombosis and primary nonfunction are significantly higher with auxiliary transplantation (more with HALT than APOLT), reflecting the technical difficulties of these procedures. Sixty-five percent of patients surviving auxiliary liver transplantation for 1 year without retransplantation were free of immunosuppression, according to a recent report [48]. On an intention-to-treat basis, however, the efficacy of this procedure for full success (survival, liver regeneration, and withdrawal of immunosuppression or graft removal) is low, and reconsideration of the indications for this procedure may be needed in light of these technical complications [50].

Conclusions
FHF continues to be a major challenge for the clinician because of its high mortality rate and the requirement for a multidisciplinary approach. The geographic area in which the patient has acquired the disease is an important consideration, and efforts should be made to reach an etiologic diagnosis. Regional differences may influence the application of prognostic indices as well. New prognostic tools are needed to improve patient selection and timing for performance of OLT. Although medical management of liver failure has improved notably in the past decade and more therapies targeting specific complications of the disease have been developed, only OLT radically alters the course of the FHF. Promising experiences with artificial and bioartificial liver-assist devices are encouraging. A reevaluation of auxiliary partial liver transplantation is needed to optimize the results with this procedure.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: Of importance Of major importance
1. Hoofnagle JH, Carithers RL, Shapiro C, Ascher N: Fulminant hepatic failure: summary of a workshop. Hepatology 1995, 21:240252. McCashland TM, Shaw BW, Tape E: The American experience with transplantation for acute liver failure. Semin Liver Dis 1996, 16:427433. Trey C, Davidson CS: The management of fulminant hepatic failure. Prog Liver Dis 1970, 3:282298. O'Grady JG, Schalm SW, Williams R: Acute liver failure: redefining the syndromes. Lancet 1993, 342:2735. Bernuau J, Rueff B, Benhamou JP: Fulminant and subfulminant liver failure: definitions and causes. Semin Liver Dis 1986, 6:97106. Tandon BN, Bernauau J, O'Grady J, et al.: Recommendations of the International Association for the Study of the Liver Subcommittee on nomenclature of acute and subacute liver failure. J Gastroenterol Hepatol 1999, 14:403404.

2.

3. 4. 5.

6.

Detre K, Belle S, Beringer K, Daily OP: Liver transplantation for fulminant hepatic failure in the United States: October 1987 through December 1991. Clin Transplant 1994, 8:274280. 8. Dodson SF, Dehara K, Iwatsuki S: Liver transplantation for fulminant hepatic failure. ASAIO J 1994, 40:8688. 9. Schiodt FV, Atillasoy E, Shakil AO, et al.: Etiology and outcome for 295 patients with acute liver failure in the United States. Liver Transpl Surg 1999, 5:2934. 10. Williams R, Wendon J: Indications for orthotopic liver transplantation in fulminant liver failure. Hepatology 1994, 20:5S10S. 11. Williams R: Classification, etiology, and considerations of outcome in acute liver failure. Semin Liver Dis 1996, 16:343348. 12. Castells A, Salmeron JM, Navasa M, et al.: Liver transplantation for acute liver failure: analysis of applicability. Gastroenterology 1993, 105:532538. 13. Acharya SK, Dasarathy S, Kumer TL, et al.: Fulminant hepatitis in a tropical population: clinical course, cause, and early predictors of outcome. Hepatology 1996, 23:14481455. 14. Brandsaeter B, Hockerstedt K, Friman S, et al.: Fulminant hepatic failure: outcome after listing for highly urgent liver transplantation12 years experience in the Nordic countries. Liver Transpl 2002, 8:10551062. 15. Vento S, Garofano T, Renzini C, et al.: Fulminant hepatitis associated with hepatitis A virus superinfection in patients with chronic hepatitis C. N Engl J Med 1998, 338:286290. 16. Bernuau J, Goudeau A, Poynard T, et al.: Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology 1986, 6:648651. 17. Liang TJ, Hasegawa K, Rimon N, et al.: A hepatitis B virus mutant associated with an epidemic of fulminant hepatitis. N Engl J Med 1991, 324:17051709. 18. Feray C, Gigou M, Samuel D, et al.: Low prevalence of precore mutations in hepatitis B virus DNA in fulminant hepatitis type B in France. J Hepatol 1993, 18:119122. 19. Yoshiba M, Dehara K, Inoue K, et al.: Contribution of hepatitis C virus to non-A, non-B fulminant hepatitis in Japan. Hepatology 1994, 19:829835. 20. Wright TL, Mamish D, Combs C, et al.: Hepatitis B virus and apparent fulminant non-A, non-B hepatitis. Lancet 1992, 339:952955. 21. Kalicinski P, Kaminski A, Drewniak T, et al.: Quick correction of hemostasis in two patients with fulminant liver failure undergoing liver transplantation by recombinant activated factor VII. Transplant Proc 1999, 31:378379. 22. Rolando N, Wade J, Davalos M, et al.: The systemic inflammatory response syndrome in acute liver failure. Hepatology 2000, 32:734739. This study shows the association between the systemic inflammatory response and the severity of illness, progression of encephalopathy, and death in patients with FHF. 23. Rolando N, Gimson A, Wade J, et al.: Prospective controlled trial of selective parenteral and enteral antimicrobial regimen in fulminant liver failure. Hepatology 1993, 17:196201. 24. Salmeron JM, Tito L, Rimola A, et al.: Selective intestinal decontamination in the prevention of bacterial infection in patients with acute liver failure. J Hepatol 1992, 14:280285. 25. Clemmesen JO, Larsen FS, Kondrup J, et al.: Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 1999, 29:648653. This study demonstrates for the first time the correlation between ammonia levels and the development of brain edema and intracranial hypertension in humans with FHF. 26. Blei AT, Olafsson S, Webster S, Levy R: Complications of intracranial pressure monitoring in fulminant hepatic failure. Lancet 1993, 341:157158.

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27. Jalan R, Damink SW, Deutz NE, et al.: Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure. Lancet 1999, 354:11641168. This study shows the efficacy of hypothermia to reduce cerebral blood flow, restore cerebral blood flow autoregulation, and control intracranial hypertension in the clinical setting. It also confirms previous observations in experimental models of FHF. 28. Traber P, DalCanto M, Ganger D, Blei AT: Effect of body temperature on brain edema and encephalopathy in the rat after hepatic devascularization. Gastroenterology 1989, 96:885891. 29. Clemmesen JO, Hansen BA, Larsen FS: Indomethacin normalizes intracranial pressure in acute liver failure: a twentythree-year-old woman treated with indomethacin. Hepatology 1997, 26:14231425. 30. Ellis AJ, Wendon JA, Williams R: Subclinical seizure activity and prophylactic phenytoin infusion in acute liver failure: a controlled clinical trial. Hepatology 2000, 32:536541. 31. O'Grady JG, Alexander GJ, Hayllar KM, Williams R: Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989, 97:439445. 32. Bernuau J: Selection for emergency liver transplantation. J Hepatol 1993, 19:486487. 33. Schmidt LE, Dalhoff K: Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology 2002, 36:659665. 34. Bernal W, Donaldson N, Wyncoll D, Wendon J: Blood lactate as an early predictor of outcome in paracetamol-induced acute liver failure: a cohort study. Lancet 2002, 359:558563. 35. Harrison PM, Wendon JA, Gimson AE, et al.: Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med 1991, 324:18521857. 36. Walsh TS, Hopton P, Philips BJ, Mackenzie SJ, Lee A: The effect of N-acetylcysteine on oxygen transport and uptake in patients with fulminant hepatic failure. Hepatology 1998, 27:13321340. 37. Peake SL, Moran JL, Leppard PI: N-acetyl-L-cysteine depresses cardiac performance in patients with septic shock. Crit Care Med 1996, 24:13021310. 38. Sterling RK, Luketic VA, Sanyal AJ, Shiffman ML: Treatment of fulminant hepatic failure with intravenous prostaglandin E1. Liver Transpl Surg 1998, 4:424431. 39. O'Grady JG, Gimson AE, O'Brien CJ, et al.: Controlled trials of charcoal hemoperfusion and prognostic factors in fulminant hepatic failure. Gastroenterology 1988, 94:11861192. 40. Clemmesen JO, Kondrup J, Nielsen LB, et al.: Effects of highvolume plasmapheresis on ammonia, urea, and amino acids in patients with acute liver failure. Am J Gastroenterol 2001, 96:12171223.

Novelli G, Rossi M, Pretagostini R, et al.: Use of MARS in the treatment of acute liver failure: preliminar monocentric experience. Transplant Proc 2001, 33:19421944. 42. Ellis AJ, Hughes RD, Wendon JA, et al.: Pilot-controlled trial of the extracorporeal liver assist device in acute liver failure. Hepatology 1996, 24:14461451. 43. Chen SC, Hewitt WR, Watanabe FD, et al.: Clinical experience with a porcine hepatocyte-based liver support system. Int J Artif Organs 1996, 19:664669. 44. Stevens AC, Busuttil R, Han S, et al.: An interim analysis of a phase II/III prospective randomized, multicenter, controlled trial of the HepatAssist Bioartificial Liver Support System for the treatment of fulminant hepatic failure [abstract]. Hepatology 2001, 34:299A. The largest controlled randomized clinical trial of the use of a bioartificial liver-assist device in FHF. This study confirms the safety of the device, but only partial benefits in survival are shown. Publication of the final results of this trial are anxiously awaited. 45. Bilir BM, Guinette D, Karrer F, et al.: Hepatocyte transplantation in acute liver failure. Liver Transpl 2000, 6:3240. This study offers evidence of the engraftment of transplanted hepatocytes in the recipient in the clinical setting. It also illustrates some complications that may arise from this procedure, such as pulmonary embolism of hepatocytes. 46. Strom SC, Fisher RA, Thompson MT, et al.: Hepatocyte transplantation as a bridge to orthotopic liver transplantation in terminal liver failure. Transplantation 1997, 63:559569. 47. Kobayashi N, Fujiwara T, Westerman KA, et al.: Prevention of acute liver failure in rats with reversibly immortalized human hepatocytes. Science 2000, 287:12581262. This study shows a new way of obtaining adequate amounts of human hepatocytes to be used in hepatocyte transplantation or in bioartificial liver-assist devices, avoiding the currently limited source of hepatocytes. 48. van Hoek B, de Boer J, Boudjema K, et al.: Auxiliary versus orthotopic liver transplantation for acute liver failure. EURALT Study Group. European Auxiliary Liver Transplant Registry. J Hepatol 1999, 30:699705. 49. Miwa S, Hashikura Y, Mita A, et al.: Living-related liver transplantation for patients with fulminant and subfulminant hepatic failure. Hepatology 1999, 30:15211526. 50. Azoulay D, Samuel D, Ichai P, et al.: Auxiliary partial orthotopic versus standard orthotopic whole liver transplantation for acute liver failure: a reappraisal from a single center by a case-control study. Ann Surg 2001, 234:723731. This study reexamines the experience with auxiliary partial orthotopic liver transplantation in FHF and demonstrates the need to reconsider indications to optimize the results.

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