Etiology and Management of Fulminant Hepatic Failure Javier Vaquero, MD and Andres T

Etiology and Management of Fulminant Hepatic Failure Javier Vaquero, MD and Andres T. Blei, MD*

Address Classifications and Definitions *Department of Medicine, Northwestern Feinberg Medical School and Since the initial definition of FHF by Trey and Davidson VA Lakeside Medical Center, Searle 10-573, 303 East Chicago Avenue, [3] 30 years ago, several classifications have been pro- Chicago, IL 60611, USA. E-mail: [email protected] posed. However, none of these systems has been accepted universally, and overlap in terms and time inter- Current Gastroenterology Reports 2003, 5:39–47 Current Science Inc. ISSN 1522-8037 vals among them is an obvious source of confusion Copyright © 2003 by Current Science Inc. (Table 1). Hepatic encephalopathy is the hallmark of FHF in all classifications and clearly marks the transition Fulminant hepatic failure (FHF) remains a rare but devastat- from a severe condition to a deadly disease. In the differ- ing disease. Viruses and drug-induced hepatotoxicity are ent classifications, the interval between the onset of the most common causes of the syndrome, but the rele- symptoms or jaundice and the appearance of encephal- vance of each differs depending on the geographic area. In a opathy allows grouping of patients with similar etiolo- large proportion of patients no cause for FHF can be identi- gies, clinical characteristics, and prognosis. fied. Good intensive care is critical for patient survival. Orthotopic liver transplantation (OLT) remains a definitive therapeutic option. Prognostic indices have helped to opti- Etiology mize patient selection and timing for performance of OLT. Viral hepatitis is the most common identifiable cause of However, the accuracy of these prognostic indices FHF worldwide, but the contribution of each etiologic decreases when they are applied to different populations, category to the total number of cases of FHF varies by probably because of regional differences in etiology and geographic region (Table 2). Thus, hepatitis B virus (HBV) peculiar native host factors. More accurate prognostic cri- is a common cause of FHF in the Far East, and hepatitis E teria and new therapeutic alternatives to OLT are required. 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]. Introduction Hepatitis A virus (HAV) is associated with a higher risk Fulminant hepatic failure (FHF) is a rare clinical syndrome of developing FHF if infection is acquired in older adult- with an estimated incidence of 2000 cases per year in the hood. Thus, vaccination is recommended for adults travel- United States [1]. For practical purposes, it is defined as the ing from developed countries to endemic areas. The appearance of hepatic encephalopathy in a patient with relevance of HAV as a cause of FHF in patients with preex- acute deterioration of liver function and no previous his- isting chronic liver disease has been recognized recently, tory of liver disease. Viruses, drugs, toxins, and miscella- and vaccination has also been suggested [15]. neous conditions such as cardiovascular and metabolic Acute HBV infection is diagnosed by detection of disorders are the main causes of FHF. IgM antibodies against hepatitis B core antigen Orthotopic liver transplantation (OLT) is used increas- (HbcAg) because a substantial number of patients have ingly to salvage patients with FHF. Although medical man- negative serum hepatitis B surface antigen (HBsAg) and agement of FHF has improved, early prediction of which serum HBV-DNA. Low or absent levels of HBsAg and patients need a liver transplant to survive is still the most HBV-DNA are associated with better prognosis and important task for the clinician. Between 10% and 30% of lower rate of recurrence after OLT [16]. The risk of patients on the waiting list for emergent OLT may recover developing FHF after infection by precore mutants spontaneously. In contrast, approximately 25% of patients remains controversial, with an increase reported by in the United States die while awaiting an organ [2]. These some authors [17] but not by others [18]. FHF follow- facts have prompted the search for more accurate prognos- ing reactivation of chronic hepatitis B has been tic criteria and for alternatives to OLT, including bioartifi- described mainly in male patients under diverse immu- cial liver-assist devices, auxiliary liver transplantation, and nosuppressant conditions; it usually has a subfulmi- hepatocyte transplantation. nant course and poor prognosis. 40 Liver

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 failure—hyperacute: within 10 days Acute liver failure—fulminant: 10 to 30 days Acute liver failure—not otherwise specified Subacute liver failure (development of ascites and/or HE from 5 to 24 weeks after onset of symptoms) Subclassification by etiology Hepatitis A–E 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 non–A-to-E cryptogenic etiology. FHF—fulminant hepatic failure; HE—hepatic encephalopathy.

Most studies indicate that hepatitis C virus (HCV) in adults, < 8 mg/kg in infants) may cause hepatotoxicity infection alone does not result in FHF. However, isolated if other concurrent factors exist, such as alcohol inges- cases of HCV-RNA in serum or tissue of patients with FHF tion, fasting, or malnutrition. Hepatotoxicity usually and negative markers for other viruses have been noted in develops 1 to 2 days after the overdose, with alanine ami- Western countries [11]. Involvement of HCV in FHF is notransferase levels and prothrombin time reaching their slightly more common in the Far East [19]. An increased peak around day 3. A continued increase of prothrombin risk of FHF in patients with chronic hepatitis B and super- time after day 3 is associated with a 90% mortality rate. infection by HCV has been suggested. Acetaminophen is also nephrotoxic, and renal failure Coinfection with HBV and hepatitis D virus (HDV), or may occur in the absence of liver necrosis. superinfection by HDV in patients with chronic hepatitis B, Other idiosyncratic drug reactions and toxins may can also cause FHF. The incidence of such coinfection is cause FHF. Isoniazid, pyrazinamide, antidepressants, higher in studies in which intravenous drug abuse is a rele- nonsteroidal anti-inflammatory drugs, and halothane vant risk factor. Diagnosis of acute infection by HDV is and its derivatives are most frequently implicated. Two made by the presence of HDV antigen, anti-HDV IgM anti- histologic patterns are usually distinguished, one charac- body, or HDV-RNA. terized by confluent necrosis (isoniazid or halothane) Infection by HEV is uncommon in Western countries and the other by hepatocyte microvesicular fatty change and is mainly diagnosed in travelers to endemic areas [11]. (valproic acid or tetracyclines). Reemergence of tubercu- Pregnant women infected by HEV seem to have a special losis in the last decade has increased the frequency of FHF propensity for developing FHF. Diagnosis is made by caused by isoniazid. Cotreatment with rifampin or detection of anti-HEV IgM antibodies. pyrazinamide may increase the risk. Mushroom poison- Acetaminophen overdose accounts for more than ing is relatively common in Europe. Florid muscarinic 70% of FHF in the UK. It has also become the most com- effects such as sweating or watery diarrhea occur early, mon cause in the United States based on a recent series with FHF usually occurring 4 to 8 days after mushroom [9], and its frequency is increasing in other Western ingestion. Other toxins (eg, carbon tetrachloride or yel- countries [11]. Even doses considered nontoxic (< 4 g/d low phosphorus) are rare causes of FHF. Etiology and Management of Fulminant Hepatic Failure • Vaquero and Blei 41 Indeterminate, % Indeterminate, Miscellaneous, % Miscellaneous, Drug ortoxin, Drug % Acetaminophen, % Acetaminophen, Other virus, % Other HAV, % HBV, % n Patients, Patients, Year 2002 315 8 2 2 17 12 17 43 for emergent liver transplantation. liver emergent for US 1995 60 15 8 0 18 15 5 38 UK 1994 1257 7.5 4.8 0.4 60.9 6.1 6.8 16 India 1996 423 28 1.7 13 0 4.5 0 53 Spain 1993 62 42 2 NR 0 8 6 44 Country countries * Nordic

[9] US 1999 295 10 7 NR 20 12 NR 15

[8] US 1994 115 19 NR 34 NR 14 2 31 et [7] US 1994 459 22.9 6.1 1.5 4.6 10.6 NR 29.9 [7] (children) US 1994 148 4.1 10.1 NR 2 8 2 73.6 et al. et al. et al. et al. et al. et al. et al. [14] [13] al. [12] [1] Wendon [10] Wendon Acharya Brandsaeter Detre Detre Dodson Hoofnagle Schiodt and Williams Williams [11]Castells UK 1996 342 2.4 2.4 NR 73 2.6 11.4 8.2 Study includes patients listed * Only HAV—hepatitis virus; A HBV—hepatitis B virus; reported. NR—not Table 2. Etiology of fulminant hepatic failure worldwide 42 Liver

Miscellaneous cardiovascular, metabolic, and other practitioners have administered the oral formulation intra- disorders account for 2% to 10% of cases of FHF. Acute venously after adequate filtering. liver ischemia secondary to hypotension, arrhythmia, or In amanita intoxication, beneficial effects have been heart failure can result in hepatocyte necrosis, but the reported with the use of penicillin G, silymarin, and forced prognosis is good if the primary condition can be cor- diuresis. Activated charcoal and cathartic agents may be rected. The prognosis is worse when other causes, such as useful if they are given early after mushroom ingestion. Budd-Chiari syndrome, veno-occlusive disease, or malig- Hepatitis secondary to Herpesvirus may be misdiag- nancies, are responsible for the alteration of blood flow. nosed because of the lack of specificity of symptoms at pre- Sporadically, the first manifestation of Wilson’s disease is sentation and the absence of typical mucocutaneous FHF, but underlying cirrhosis is always present. Death is lesions. If herpesvirus is suspected, treatment with acyclo- the universal result without OLT. Acute fatty liver of preg- vir or ganciclovir should be started. nancy is rare, occurring in the third trimester of preg- As noted previously, acute fatty liver of pregnancy usu- nancy, and responds well to fetal delivery. Other causes of ally responds to fetal delivery. Urgent chemotherapy is FHF are autoimmune hepatitis or Reye’s syndrome, the indicated for FHF caused by massive infiltration of the liver latter less commonly seen in the pediatric population by lymphoma. Acute Budd-Chiari syndrome may be ame- once aspirin use was curtailed. nable to thrombolytic therapy or to transjugular intrahe- In a large group of patients (20%–50% in adults and patic portosystemic shunt placement. 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 Prevention and Management found in serum and liver tissue of patients with FHF and of Complications negative serologic markers of HBV infection [20]. However, Nutrition and metabolism this is not a common situation in other series, probably Glycemia must be controlled frequently (every 1–2 hours) reflecting geographic differences. Small case reports of FHF in patients with deep encephalopathy. Constant infusion caused by Varicella or Herpes simplex virus in pregnant of 10% to 20% glucose is preferable to bolus administra- women, neonates, or immunosuppressed individuals, by tion for maintainance of euglycemia. parvovirus B19 in children, or by togavirus-like particles, FHF is a catabolic state, and protein-caloric malnutri- explain another small proportion of cases. Although these tion develops quickly. Thus, nutrition should be started causes are rare, they must be ruled out because some soon and adjusted individually to maintain an adequate patients may benefit from specific therapies. caloric intake. Enteral nutrition through a nasogastric or nasojejunal tube is preferred to parenteral nutrition. Cor- rection of hypomagnesemia, hypokalemia, or hypophos- Management of Fulminant Hepatic Failure phatemia is accomplished by supplementation of these Early referral to a transplant center is important. Patients substances. H2-receptor antagonists, proton-pump inhibi- with slight alteration of mental state may deteriorate rap- tors, or sucralfate are used to reduce the incidence of gas- idly, leaving no time for alternatives. Patients should be trointestinal ulceration. managed in a critical care unit for close surveillance of mental state. Coagulation When evaluation of mental state is not possible, evolution Specific therapies of coagulation parameters is the only way of assessing Elucidation of the cause of hepatic failure allows some improvement or worsening of liver function. Administra- patients to benefit from specific treatments and may influ- tion of fresh-frozen plasma does not increase survival and ence posttransplant management if a transplant is per- may cause volume overload. Thus, correction of coagulop- formed. N-acetylcysteine is used as specific antidote for athy is not indicated unless bleeding occurs or invasive acetaminophen overdose. If it is given in the first 8 to 10 procedures are to be performed. In those instances, 2 to 4 hours after overdose, it replenishes glutathione stores and units of fresh-frozen plasma should be administered every prevents the development of hepatotoxicity. The efficacy of 6 to 12 hours according to severity of coagulopathy and N-acetylcysteine declines progressively thereafter, but it transfusion of platelets, if the platelet count is below 50 × may be effective up to 72 hours after acetaminophen inges- 109/L. Recombinant activated factor VII offers advantages tion. It is used differently in Europe (intravenous, total of shorter half-life and avoidance of volume overload, dose of 300 mg/kg in 20 hours) than in the United States compared with fresh-frozen plasma, but reports are only (oral, total dose of 1330 mg/kg in 72 hours). The poor oral preliminary, and more studies are needed [21]. bioavailability of N-acetylcysteine explains the high doses used in the United States. Because it is not well tolerated Infection orally and the intravenous formulation is not approved by A high index of suspicion should be maintained concern- the US Food and Drug Administration (FDA), some US ing infection in FHF. Fever and leukocytosis are absent in Etiology and Management of Fulminant Hepatic Failure • Vaquero and Blei 43 up to 30% of infected patients. Infection must be suspected Kidney in the presence of any sudden clinical or biochemical dete- Frequent control of serum creatinine level, urinary output, rioration, and even more so if liver function has started to and urinary sodium concentrations is needed. Because of recover. Microbiologic cultures should be obtained from the risk of infection, a urinary catheter should be used only different sites, and empiric antibiotics covering both gram- in patients with oliguria and should be removed in anuric negative and gram-positive bacteria should be started. patients. Adequate volume repletion is essential to prevent There are no generally accepted guidelines regard- development of functional renal failure. Dopamine at ing use of prophylactic antibiotics. Their use may be diuretic doses (2–4 µg/kg/h) has been used traditionally to supported by recent studies in which infection and pro- improve renal perfusion, but it is not efficacious. Diuretics gression to deep encephalopathy were correlated are not helpful and usually impair renal function. Poten- [22••]. In the two studies that have compared prophy- tially nephrotoxic drugs, such as aminoglycosides, should lactic antibiotics to placebo [23,24], the patients not be used in FHF. If dialysis is needed, continuous hemo- treated with antibiotics had a lower rate of infection, filtration is preferred over intermittent hemodialysis to but there was no difference in survival. Both broad- avoid rapid fluid shifts that may aggravate brain edema. spectrum intravenous antibiotics and selective enteral bacterial-fungal decontamination seem to be efficient Brain for decreasing the rate of infection. Selective enteral Hepatic encephalopathy decontamination, however, does not add any benefit if Infection or any other precipitant factor must be identified the patient is already on intravenous antibiotics. Emer- and treated. The efficacy of lactulose in FHF has not been gence of meticillin-resistant Staphylococcus aureus and tested in clinical trials; it should be used with caution vancomycin-resistant enterococci has caused great con- because of the risk of hypernatremia and functional ileus. cern in recent years. Flumazenil (1 mg intravenously) may be useful if ingestion of benzodiazepines is suspected. Although monitor- Cardiovascular system ing of mental state is very important for assessing Arrhythmia occurs frequently if electrolyte abnormalities prognosis, sedation and intubation are usually required in are not corrected promptly. A hyperdynamic circulation advanced stages of encephalopathy. is characteristic of FHF, with systemic and splanchnic arterial vasodilation resulting in increased cardiac output Cerebral edema and decreased arterial pressure. Correction of these Brain edema and intracranial hypertension may develop abnormalities is difficult, especially in patients with very quickly in patients with deep encephalopathy. An arte- intracranial hypertension. Reposition of volume is rial ammonia level higher than 200 µg/dL in stage III and required to avoid or correct arterial hypotension, but IV encephalopathy is a strong predictor of brain herniation normalization of blood pressure is rarely achieved. Mon- [25••]. Monitoring of intracranial pressure should be lim- itoring of central venous pressure helps to guide the ited to specialized units and to patients awaiting OLT amount of fluid to be infused (target, 8–12 mmHg). In because it has not been shown to increase survival. Intra- the presence of persistent hypotension or worsening cranial pressure should be maintained below 15 mm Hg, renal function, sepsis needs to be ruled out. Placement of and cerebral perfusion pressure over 50 mm Hg. Most cen- a pulmonary artery catheter can improve management in ters prefer epidural to subdural or intraparenchymal trans- these patients, though invasive procedures entail risk. ducers because of the lower rate of complications [26]. There is controversy over which volume expander is best, Monitoring of jugular bulb oxygen saturation with a but blood, colloids or albumin are usually preferred over reversed jugular venous catheter can also guide interven- crystalloids. Isotonic or hypertonic, but not hypotonic, tions to avoid intracranial hypertension. Decreased satura- sodium-containing solutions should be used if acute vol- tions (< 55%) indicate cerebral ischemia, and high ume expansion is needed in patients at risk of brain saturations (< 85%) indicate either decreased metabolic edema. Adrenaline or noradrenaline are the vasopressors demands of the brain or cerebral hyperemia, more com- of choice, but caution should be exercised because they monly the latter. may impair tissue oxygenation or produce an unwanted Current recommendations include maintaining the increase of cerebral blood flow. patient’s head at a 20° angle to improve jugular venous outflow. In episodes of intracranial hypertension, a bolus Lung of 0.5 to 1 g/kg of mannitol can be administered intrave- Intubation and mechanical ventilation are usually required nously and repeated until plasma osmolarity reaches 310 in patients with agitation or deep encephalopathy to avoid mOsm/L. Patients with oliguria and renal failure may surges of intracranial pressure and pulmonary aspiration. require hemodialysis to avoid hyperosmolarity. Hyperven- Sedation must be maintained at the lowest possible level, tilation produces cerebral vasoconstriction and reduces but some patients require additional sedation during nurs- cerebral blood flow, but the effect is usually transient. ing manipulations. Finally, induction of barbiturate coma to decrease cerebral 44 Liver

Table 3. King’s College Hospital and Clichy liver transplantation criteria for fulminant hepatic failure King’s College criteria [31] FHF secondary to acetaminophen overdose pH less than 7.30 (irrespective of encephalopathy grade), or Hepatic encephalopathy grade III–IV, prothrombin time over 100 seconds (INR > 6.5), and serum creatinine over 300 µmol/ 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 µmol/L (17.6 mg/dL) Prothrombin time over 50 seconds (INR > 3.5) Clichy criteria [32] Presence of confusion or coma (stage III–IV 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

FHF—fulminant hepatic failure; HE—hepatic encephalopathy; INR–international normalized ratio. metabolic activity may be useful as a last resort, but such suboptimal when applied to different countries [9,13]. unwanted effects as myocardial depression or arterial Other prognostic parameters have been evaluated. Gc- hypotension limit its use. gammaglobulin levels are decreased in patients who do New therapies have been investigated. According to not spontaneously survive, although these values over- recent reports, mild hypothermia reduced intracranial lap considerably with those of survivors. Liver volume pressure and cerebral blood flow and improved cere- decreases with progression of the disease, and its mea- bral perfusion pressure both in patients with FHF [27•] surement with CT scanning may help to assess progno- and in experimental models [28]. Indomethacin also sis. Other proposed prognostic tools include the reduced cerebral blood flow and prevented brain proportion of necrosis in liver histology obtained by edema in experimental models, and it has been used in transjugular venous biopsy, the amount of fresh-frozen isolated cases in humans, with encouraging results plasma to correct coagulopathy, or the determination of [29]. In a recent controlled clinical trial, a prophylactic somatosensory evoked potentials. Recently, high-serum infusion of phenytoin decreased the incidence of sub- phosphate and blood lactate have been proposed as clinical seizure activity and appeared to prevent brain markers of poor prognosis in patients with acetami- edema [30]. However, clinical experience with these nophen-induced FHF [33,34]. agents remains scarce, and their efficacy and safety should be explored further. Medical therapy N-acetylcysteine is used in Europe to treat established FHF of any cause, based on clinical reports from the King’s Col- Management of Liver Failure lege group. Benefits of N-acetylcysteine on survival, brain Liver transplantation edema, hemodynamics, oxygen delivery, and oxygen con- Liver transplantation is the only measure that can radically sumption were found in patients with established FHF influence the course of FHF. However, it is an expensive [35]; however, these effects were not confirmed by other and high-risk procedure with considerable morbidity and groups [36]. Moreover, N-acetylcysteine had deleterious represents a commitment to indefinite immunosuppres- effects in patients with critical illnesses other than FHF sion. Moreover, patients transplanted for FHF have a worse [37]. A randomized, controlled trial of N-acetylcysteine by outcome than those transplanted for other causes in most the US Acute Liver Failure Study Group in patients with series, in part because of their poor clinical condition at the non-acetaminophen–induced FHF is currently underway time of the procedure. and should clarify these issues. Early identification of which patients would die if Preliminary reports of increased survival of patients OLT were not performed is thus a very important objec- treated with prostaglandin-E1 in uncontrolled studies tive. Both the King’s College and the Clichy criteria are were very encouraging, but no clear benefit supporting used most often to identify such patients (Table 3). the use of this agent has been found in subsequent con- However, some reports suggest that these criteria may be trolled trials [38]. Etiology and Management of Fulminant Hepatic Failure • Vaquero and Blei 45

Artificial liver-assist devices except in patients with disease caused by acetaminophen Several modalities of artificial liver support have shown a overdose (n=39; 37% vs 70%, P<0.05). The final results benefit in FHF. Charcoal hemoperfusion consists of the of this trial are anxiously awaited. passage of plasma through columns of activated charcoal or resins with the goal of clearing lipophilic toxins. Clin- Hepatocyte transplantation ical benefit was found in early reports, but randomized, The rationale behind hepatocyte transplantation is to controlled trials failed to confirm such results [39]. deliver a sufficient supply of hepatocytes to maintain liver High-volume plasmapheresis has been used extensively function until regeneration of native liver occurs or a graft in Copenhagen, and improvement of mental state, cor- becomes available. Human hepatocytes from livers not rection of hyperdynamic circulation, and lowering of used for transplantation can be cryopreserved, making ammonia were reported [40]. A few reports have also them readily available if needed. noted beneficial hemodynamic effects and lowering of Experimental studies in models of FHF showed ammonia levels with the Molecular Adsorbent Recircu- engraftment and function of transplanted hepatocytes, lating System (MARS) [41]. In this system, water-soluble with increased survival. Hepatocyte transplantation has and albumin-bound toxins are cleared by dialysis of also been performed on a few occasions in humans. Bilir blood against an albumin-containing dialysate. However, et al. [45•] reported engraftment of donor hepatocytes no randomized clinical trials of the last two techniques in five patients with stage III and IV encephalopathy and in FHF are available. severe coagulopathy. In this and other reports from small studies, improvements in encephalopathy score Bioartificial liver-assist devices and hemodynamics have been noted as well as Several bioartificial liver-assist devices are currently under- decreased serum ammonia and bilirubin levels [45•,46]. going clinical trials. Most of these devices use hollow-fiber Pulmonary embolism of hepatocytes occurred in cartridges housing hepatocytes in the extraluminal space. patients in whom the injection was intraportal but not Blood or plasma is circulated through the hollow fibers, in those with hepatocytes injected into the splenic artery allowing exchange of substances by diffusion between [45•]. Other concerns about this technique include plasma and hepatocytes. The cells used in these devices are transplantation and acquisition of an adequate number primary porcine hepatocytes (Bioartificial Liver Device of hepatocytes (only 0.15–80 g have been injected com- [BAL]) or human hepatoblastoma C3a line cells (Extra cor- pared with 300 g [20% of normal liver mass required] to poreal Liver Assist Device [ELAD]). replace liver function), use of immunosuppression in The two systems with the most clinical experience are FHF, and the need for a 48-hour period for engraftment the BAL (Circe Biomedical HepatAssist, Lexington, MA) and function. Methods that reversibly immortalize and the ELAD (Vitagen, San Diego, CA). In the ELAD, human hepatocytes are important to supply a sufficient whole blood is perfused through the hollow fibers of the amount of hepatocytes for transplantation or for biore- bioreactor. A controlled clinical trial of 24 patients actors and to avoid the risks of tumorigenesis and showed improvement in galactose elimination time, xenotransplantation [47•]. encephalopathy, intracranial pressure, and hemodynamics in the group treated with the ELAD, compared with Auxiliary liver transplantation standard medical therapy, but no difference in survival Auxiliary liver transplantation involves transplantation of a was noted [42]. In the BAL system, plasma is separated hepatic lobe from a living or cadaveric donor, leaving the from blood and is circulated through a charcoal column whole liver or part of the liver of the recipient in situ. In and then through the bioreactor. In several case reports, auxiliary partial orthotopic liver transplantation (APOLT), significant improvements in blood glucose, serum one hepatic lobe of the recipient is resected, and the auxil- ammonia, and bilirubin levels; decrease of intracranial iary graft is placed in its original position. In heterotopic pressure; increase of cerebral perfusion pressure; and auxiliary liver transplantation (HALT), the donor graft is bridging to OLT were reported [43]. An interim analysis placed below the unresected liver of the recipient. A mini- of the largest controlled clinical trial using a bioartificial mum ratio of graft volume to recipient standard liver vol- liver-assist device was presented at the annual meeting of ume of 35% is necessary for the graft to support the the American Association for the Study of Liver Diseases, metabolic activity in FHF. In this potentially reversible con- November 9–10, 2001 in Dallas, TX [44•]. One-hundred dition, auxiliary transplantation has the advantage of and forty-seven patients with FHF and 24 with primary allowing regeneration of the native liver, after which the graft nonfunction were randomly assigned to standard graft can be surgically removed or left to atrophy following medical treatment alone or to standard medical treat- withdrawal of immunosuppression. Thus, auxiliary trans- ment plus BAL. No significant differences were found in plantation may be especially valuable in young patients the endpoint (30-day survival) between standard medi- and in those with potentially reversible causes of FHF (ie, cal treatment and BAL (59% vs 70%, not significant), HAV, HBV, or drug-induced). 46 Liver

In studies reported in the past 3 years, 1-year survival 7. Detre K, Belle S, Beringer K, Daily OP: Liver transplantation rates with auxiliary liver transplantation have been similar for fulminant hepatic failure in the United States: October 1987 through December 1991. Clin Transplant to those for OLT [48,49]. However, incidence of portal vein 1994, 8:274–280. thrombosis and primary nonfunction are significantly 8. Dodson SF, Dehara K, Iwatsuki S: Liver transplantation for higher with auxiliary transplantation (more with HALT fulminant hepatic failure. ASAIO J 1994, 40:86–88. than APOLT), reflecting the technical difficulties of these 9. Schiodt FV, Atillasoy E, Shakil AO, et al.: Etiology and outcome for 295 patients with acute liver failure in the United States. procedures. Sixty-five percent of patients surviving auxil- Liver Transpl Surg 1999, 5:29–34. iary liver transplantation for 1 year without retransplanta- 10. 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Brandsaeter B, Hockerstedt K, Friman S, et al.: Fulminant Conclusions hepatic failure: outcome after listing for highly urgent liver FHF continues to be a major challenge for the clinician transplantation—12 years experience in the Nordic coun- because of its high mortality rate and the requirement for a tries. Liver Transpl 2002, 8:1055–1062. 15. Vento S, Garofano T, Renzini C, et al.: Fulminant hepatitis multidisciplinary approach. The geographic area in which associated with hepatitis A virus superinfection in patients the patient has acquired the disease is an important con- with chronic hepatitis C. N Engl J Med 1998, 338:286–290. sideration, and efforts should be made to reach an etio- 16. Bernuau J, Goudeau A, Poynard T, et al.: Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology logic diagnosis. Regional differences may influence the 1986, 6:648–651. application of prognostic indices as well. New prognostic 17. 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