tation, as osmotic demyelination and central pontine myelinolysis may result. ..... Iwatsuki S, Stieber AC, Marsh JW, Tzakis AG, Todo S,. Koneru B, Makowka L, ...
British Journal of Anaesthesia 1996; 77: 90–98
Fulminant and late onset hepatic failure A. E. S. GIMSON
For many years the definition of fulminant hepatic failure, first introduced by Trey and Davidson in 1970, has been used, describing a clinical syndrome of sudden massive hepatocyte dysfunction in the absence of prior liver disease and resulting in hepatic encephalopathy [93]. Although in many series mortality has continued to reach 80 %, those that do survive have full functional and structural regeneration without the development of chronic liver disease. In recent years there has been a renewed debate as to the definition of fulminant hepatic failure [12, 72]. Previous groups have restricted the diagnosis to those with encephalopathy developing between 3, 4 or 6 weeks [7, 9, 33, 41]. The King’s College Group has recently proposed a new terminology around the core term acute liver failure. Those patients presenting within 7 days of the onset of jaundice were defined as having hyperacute liver failure, those presenting within 8–28 days of jaundice defined as acute liver failure and those presenting between 29 and 72 days as having subacute liver failure. This definition is of importance as it categorizes groups with different aetiologies and, more importantly, different incidence of the major complication cerebral oedema. This is more common in those with hyperacute or acute liver failure and less common in those with the subacute variety. Similarly, there are differences in prognosis. In hyperacute liver failure with medical management alone the prognosis is relatively good (36 % survival) where as in those with subacute liver failure prognosis is poor with only a 14 % survival rate. All these studies have concluded that duration from onset of symptoms to encephalopathy is of prime importance in defining different prognostic groups, irrespective of the aetiology, and exemplify the fact that fulminant hepatic failure represents a heterogeneous group of conditions with diverse aetiologies and prognoses. Assessing the aetiology is, therefore, of crucial importance not only because of specific therapy directed to that aetiology but also in predicting subsequent outcome and need for additional nonmedical interventions such as orthotopic liver transplantation.
(Br. J. Anaesth 1996; 77: 90–98) Key words Liver, function. Complications, liver disease. Complications, jaundice. Complications, cerebral oedema.
Aetiology Fulminant hepatic failure is uncommon and the majority of cases are the result of drug hepatotoxicity or viral hepatitis (table 1).
DRUG HEPATOTOXICITY
Paracetamol hepatotoxicity, the most common cause of fulminant hepatic failure in the United Kingdom, usually occurs after consumption of more than 12 g of the drug. More recently the importance of inadvertent paracetamol hepatotoxicity often taken for an intercurrent illness and without suicidal intent has been stressed. Patients with enzyme induction due to alcohol abuse [61] or the consumption of enzyme-inducing drugs leads to induction of the cytochrome system and increased production of the toxic metabolite [57]. Hepatic metabolism of paracetamol initially occurs via sulphation and glucuronidation. When this metabolic pathway is saturated a cytochrome P450 mechanism may result in the formation of an unstable toxic nucleophilic compound N-acetyl-p-benzoquinone imine. This compound is detoxified by tissue glutathione and when stores of this are depleted hepatic damage occurs. Prior depletion of tissue glutathione due to oxidant stress or alcohol consumption will also aggravate hepatocyte injury. The antidote N-acetylcysteine (NAC) if given within 16 h of the overdose may act as a sulphydryl donor and neutralize the toxic metabolite. Recent evidence from retrospective analyses [47] as well as a prospective randomized controlled trial suggest that patients with significant hepatotoxicity and liver failure may benefit from NAC even when given more than 16 h after the initial overdose. In these important studies reduced organ dysfunction and significantly improved survival were observed [56]. While the mechanism of action of NAC at this later stage is likely to be different from that when given within the first 16 h it is clear that all patients who have taken a significant paracetamol overdose and have evidence of hepatotoxicity should be given a continuous NAC infusion until normalization of markers of hepatocyte damage. A wide range of other drug toxicities may occur leading to fulminant hepatic failure. Halothane hepatotoxicity is now rare, usually occurring in
A. E. S. GIMSON, FRCP, Hepatobiliary and Liver Transplant Unit, Addenbrooke’s Hospital NHS Trust, Hills Road, Cambridge CB2 2QQ.
Fulminant and late onset hepatic failure Table 1 Aetiology of fulminant hepatic failure Viral Acute hepatitis A (HAV) Acute hepatitis B (HBV) ± hepatitis D co-infection Hepatitis D (HDV) superinfection of a chronic HBV carrier Hepatitis B reactivation in a chronic HBV carrier Acute hepatitis C (HCV) ± other chronic viral carriage Acute hepatitis E (HEV) Indeterminate viral hepatitis Epstein-Barr virus infection, cytomegalovirus, herpes simplex, herpesvirus-6, varicella Drugs Paracetamol (intentional/unintentional; with/without enzyme induction) Halothane, isoflurane, enflurane Carbon tetrachloride Rare idiosyncratic drug reactions: isoniazid, rifampicin, sodium valproate, ketoconazole, erythromycin, sulphonamides, tricyclic antidepressants, propyl thiouracil, FIAU Others Acute fatty liver or pregnancy, pre-eclamptic syndromes Wilson’s disease Autoimmune chronic active hepatitis Budd-Chiari syndrome Malignancy; non-Hodgkin’s lymphoma, metastatic disease Heat stroke Amanita poisoning Circulatory shock Reye’s syndrome Sepsis
females up to 21 days after exposure. Multiple exposures are common but it has been reported after a single anaesthetic. Occasionally there may be other features of drug hypersensitivity including a rash, eosinophilia and liver kidney microsomal antibodies in 25 % of cases. A specific antibody against a halothane altered component of hepatocyte membranes suggests that the damage may be immunologically mediated. Hepatotoxicity has been reported on rare occasions following enflurane [104] and isofluorane as well as phenytoin, tricyclic antidepressant drugs and sodium valproate [23]. Recently, the importance of significant hepatotoxicity associated with anti-tuberculous medication has been stressed. In these patients oxidant stress and low tissue glutathione concentration as well as enzyme induction due to fasting or chronic alcohol abuse may also contribute to the likelihood of hepatic dysfunction [65].
VIRAL HEPATITIS
In most series fulminant viral hepatitis is the most common cause of acute liver failure. The reason for the development of liver failure in up to 1 % of cases is unclear but presumably includes host factors such as age, as well as the size of the inoculum and perhaps virus strains. Fulminant hepatitis A (HAV) is more common in the elderly [36] and i.v. drug users [1] and the mechanism of the damage remains unclear. The prognosis is relatively good with survival rates of up to 50 % with medical treatment alone. Fulminant hepatitis B (HBV) is an important cause of acute liver failure [40, 74], the risk of a fulminant presentation being higher than with HAV, and more common in women or after termination of
91 Table 2 Investigations in patients with fulminant hepatic failure Full blood count Prothrombin time/prothrombin ratio Serum electrolytes, creatinine and phosphate Serum bilirubin, albumin, transaminases, alkaline phosphatase, amylase Serum/urine for toxicological screen Viral serology HAV IgM anti-HAV HBV HBsAg, IgM anti-HBc, HBV DNA HCV Anti-HCV antibody, HCV mRNA HDV IgM anti-HDV HEV Anti-HEV antibody Serology for CMV, EBV, herpes, etc. and convalescent sera if available. Serum copper, caeruloplasmin. 24-h urinary copper and penicillamine challenge if appropriate Autoantibodies/immunoglobulins Chest x-ray Ultrasound scan of liver (size, texture, patency of portal/hepatic veins. Spleen size) Slit-lamp examination for Keyser-Fleischer rings
chemotherapy and immunosuppression in HBV carriers [16]. It may also occur with HBV reactivation, with HBe antigen/HBe antibody seroconversion and when there is associated delta HDV co-infection or super-infection of HBV carriers [34, 44]. Hepatitis C (HCV) has been considered only rarely as a cause of acute liver failure, on the basis on anti-HCV serology [43]. In contrast, recent studies have suggested that HCV may account for up to 30 % of cases of serologically indeterminate viral hepatitis when HCV mRNA is tested by polymerase chain reaction (PCR). In these studies the importance of multiple viral co-infection has also been stressed. Other viral causes include hepatitis E infection [3, 60], particularly in the Indian subcontinent and rarely Epstein-Barr virus [26], cytomegalovirus [49], herpes simplex [24], varicella [66] and herpesvirus-6 [73]. These cases often occur in immunocompromised individuals. A long list of rare causes of fulminant hepatic failure account for approximately 5 % of the cases but accurate diagnosis is essential (table 2). Liver failure associated with pregnancy may be caused by acute fatty liver of pregnancy or eclamptic syndromes [27, 80, 81]. The Budd-Chiari syndrome [78], disseminated malignancy (in particular non-Hodgkin’s lymphoma [102]) and Wilson’s disease may also present a fulminant course [8]. The clue is often the presence of hepatosplenomegaly. Reye’s syndrome is a further rare cause of acute liver failure but is more common in young children [31]. The cause is unknown but interest has centred on the role of salicylates and the use of these drugs in febrile children is no longer recommended. In such cases the primary lesion of diffuse microvascular fatty change within the liver is different from that observed in most other forms of fulminant hepatic failure. Liver failure has also been recorded in children treated with sodium valproate [103] or tetracycline hepatoxicity and Jamaican vomiting sickness. Recently the development of a diffuse microvascular infiltrate with hepatocellular necrosis
92
British Journal of Anaesthesia
has been observed following the use of nucleoside analogues and electron microscopic evidence has pointed to a primary mitochondrial damage [63].
Pathology The majority of causes of fulminant hepatic failure give rise to a severe and widespread hepatocellular necrosis [52]. This starts in a centrizonal distribution and progresses towards the portal tracts [20]. The degree of associated parenchymal inflammation is highly variable, being more prominent in those with a longer duration of the disease [46]. Canalicular cholestasis may also be apparent but usually is the consequence of sepsis. Initial studies by Horney and Galambos suggested that pathogenesis of fulminant viral hepatitis was due to an ischaemic infarction [50] which, in the context of fulminant hepatitis B, was considered to result from sinusoidal deposition of antigen–antibody complexes following an exaggerated immune response to the hepatitis B virus [40]. Previous suggestions that fulminant hepatic failure may be associated with an impaired hepatic regenerative response have been discounted with the finding of prominent immunostaining for proliferating cell nuclear antigen in surviving hepatocytes [38] and elevated concentrations of hepatocyte growth factor [42].
General management Management in an intensive care unit is mandatory. Patients require dextrose infusions, prophylaxis for upper gastrointestinal bleeding and close microbiological surveillance. Treatment of the coagulation deficit is needed only if there is overt bleeding. Attempts at treating fulminant hepatic failure with steroids, insulin and glucagon have been unsuccessful. Other modalities tried have included PGE1 [11, 88, 89] and interferon with cyclosporin A in patients with fulminant viral hepatitis [101]. These are either of no proved benefit or require further evaluation.
Organ dysfunction and treatment HEPATIC ENCEPHALOPATHY AND CEREBRAL OEDEMA
During fulminant hepatic failure progressive encephalopathy is subsequently associated with the Table 3 Classification of grades of hepatic encephalopathy Grade 1 Grade 2 Grade 3 Grade 4
Mild confusion, poor concentration occasionally dysphoria. Reversed sleep pattern. When roused fully coherent. Increasing confusion and disorientation but still rousable and able to be rational. Sleeping most of the time but can be roused to commands. May be markedly agitated occasionally aggressive. Not rousable to commands but may or may not be responsive to painful stimuli. Clinical features of cerebral oedema may be apparent during this stage, including hyperventilation, pupillary abnormalities, opisthotonus and extensor plantars. Abnormal respiratory pattern.
development of cerebral oedema. The clinical features range from minimal dysphoria and drowsiness in the initial stages to agitation and, later, unresponsiveness to all stimuli in grade 4 encephalopathy (table 3). The rate of progression through these grades varies significantly but is fastest with paracetamol-induced hepatotoxicity. Those patients with grade 4 encephalopathy who develop cerebral oedema have a very high mortality without treatment, compared with those who only develop grade 1 or 2 encephalopathy. The pathogenesis of hepatic encephalopathy in patients with acute liver failure remains unclear. The previous hypotheses centred around hyperammonaemia, changes in the proportional relationship between branch chain and aromatic amino acids, elevation of toxins such as mercaptans and short chain fatty acids with synergistic effects. Unfortunately these have not given consistent results in animal models and, more particularly, the visual evoked responses of animals exposed to these agents do not replicate the responses seen during liver failure. More recent evidence has pointed to the gamma amino butyric acid (GABA) pathway as the major cause of neuronal depression [67]. Although GABA concentrations are not elevated it has been postulated that benzodiazepine-like substances acting via a benzodiazepine receptor closely linked to the GABA receptor may be involved. Basile and colleagues have observed increased concentrations of 1,4-benzodiazepine in brain tissue in both animals and patients with acute liver failure [5, 6]. The relationship between these findings and changes in other neuroexcitatory and depressant pathways including serotinergic, dopaminergic and glutaminergic pathways, remains unclear. The use of a benzodiazepine receptor antagonist such as flumazenil has been associated with minor changes in coma grade for short periods of time but is of little clinical importance [45]. Opioidergic neurotransmission is also altered in animal models of liver failure with increased cerebral levels of Met-Leu encephalin. Cerebral oedema remains one of the major causes of early mortality in fulminant hepatic failure. During grade 4 encephalopathy it may be present in up to 80 % of cases and is associated with an elevated intracranial pressure, reduction in cerebral blood flow (CBF) and cerebral metabolic rate for oxygen (CMRO2). As intracranial pressure increases, critical impairment of cerebral oxygenation occurs, with the development of cerebral ischaemia, and tentorial herniation develops in about 25 % of cases. The pathogenesis of this cerebral oedema remains unclear and both cytotoxic and vasogenic hypotheses have been put forward. It is likely that both varieties of cerebral oedema share similar mechanisms at the endothelial level. Electron microscopic studies of brain from patients dying with fulminant hepatic failure have suggested a predominantly cytotoxic origin for the cerebral oedema [55]. This has been suggested to be the result of the presence of inhibitors of neuronal Na/K ATPase [87], although others have not confirmed these findings [75]. An alteration in the blood–brain barrier has also been
Fulminant and late onset hepatic failure observed in other animal models. It is most likely that these hypotheses are not mutually exclusive and that the increase in brain water content may initially be cytotoxic associated with glial swelling in cortical grey but not subcortical white matter, and subsequently be associated with alteration in the blood– brain barrier [54]. Cerebral oedema, as in many other pathological situations, is associated with changes in the normal cerebral blood flow autoregulation. Patients with grade 4 encephalopathy and fulminant hepatic failure have a low cerebral blood flow and do not exhibit the usual changes in cerebral blood flow with increases in PaCO2 [2]. This implies some uncoupling of the usual relationship between cerebral blood flow and CMRO2 [59]. It is also clear that there are pronounced regional differences in cerebral blood flow. The clinical detection of cerebral oedema is of critical importance [17, 62]. Reliance on such clinical features as systemic hypertension, bradycardia, opisthotonus, abnormal pupillary reflexes and decerebrate posturing only occur late and when therapeutic intervention may be ineffective. The use of computed tomography has variable sensitivity [68] but the most accurate assessment has been the use of an intracranial pressure monitor by the subdural route [18, 29, 62]. Complication rates are acceptably low and it allows the measurement of cerebral perfusion pressure, a critical measure of cerebral oxygen delivery. The increase in intracranial pressure to greater than 20 mm Hg, if untreated, is associated with the subsequent development of tentorial herniation. Transient increases in intracranial pressure may be associated with endotracheal suction, changes in patient position and painful stimuli. Management rests on maintaining normothermia, a head-up position of approximately 20⬚ to the horizontal [25] and the use of i.v. mannitol 0.5 g/kg body weight. Previous trials have demonstrated that dexamethasone and hyperventilation [30] confer no survival benefit but mannitol when given for the above specific indication significantly improves hospital survival [21]. Both mannitol and NAC have been shown to increase cerebral blood flow in patients with grade 4 encephalopathy and this increase in cerebral blood flow is accompanied by an increase in cerebral oxygen extraction [48]. It is important to note that in these circumstances hyperventilation may also result in a decrease in cerebral blood flow usually due to a decrease in cardiac output, and that this decrease in cerebral blood flow may be associated with a reduction in cerebral oxygen extraction [48]. There is no indication that prophylactic mannitol is of benefit and its use should be reserved for specific evidence of intracranial hypertension. Osmotic therapy is ineffective in reducing intracranial pressure in the presence of renal failure [21] unless combined with ultrafiltration of twice the volume of infused mannitol. Other agents including barbiturates may significantly lower intracranial pressure but have profound haemodynamic side effects [35]. It is best considered as a bridge to transplantation to maintain stability while the patient awaits a donor liver.
93 CARDIOVASCULAR AND PULMONARY DISTURBANCES
Fulminant hepatic failure is associated with profound haemodynamic changes, most particularly, of a marked reduction in systemic vascular resistance. Over 50 % of patients have episodes of hypotension during grade 4 encephalopathy despite an elevated cardiac output, and these abnormalities are of prognostic importance. Despite the elevated cardiac index and arterial oxygen delivery to the tissues (cardiac index arterial oxygen content, DaO2 ) Bihari and colleagues have proposed that an underlying covert tissue hypoxia is present [13]. Hyperlactataemia in the absence of systemic hypotension correlates inversely with systemic vascular resistance implying poor tissue perfusion despite apparently adequate delivery, and changes in the in vivo p50, a measure of the position of the oxygen–haemoglobin dissociation curve, are only associated with changes in peripheral oxygen extraction in patients who survive. In cases with an ultimately poor prognosis changes in in vivo p50 that might be expected to release more oxygen in the tissues are not associated with any change in oxygen extraction ratio, suggesting a profound disturbance in the control of peripheral circulation and oxygen homeostasis, with poor capillary perfusion [14]. This may result from an interruption to perfusion of some capillaries because of marginated platelets or activated white cells with a reflex arteriolar vasodilatation and luxury perfusion of remaining capillaries [15]. Increases in diffusion distance from capillary lumen to active respiring cells and a reduction in capillary transit time result in impaired oxygen extraction. These patients exhibit a close relationship between oxygen delivery and oxygen extraction by the tissues. Such supply dependency has been proposed in other states with a high cardiac output/low vascular resistance, although its existence remains controversial. In patients with severe liver disease, use of a peripheral vasodilator such as prostacyclin (PGI2) is associated with both an increased arterial oxygen delivery and oxygen consumption by the tissues [95]. Similarly NAC results in an increase in both oxygen delivery and oxygen extraction ratio [48]. Such a relationship between oxygen supply and extraction is also found at a tissue level. Changes in cerebral blood flow (using the xenon washout technique) are associated with corresponding changes in CMRO2. Both PGI2 and NAC increase cerebral oxygen delivery and CMRO2, whereas hyperventilation and vasoconstrictor drugs (despite increasing mean arterial pressure) both reduce CMRO2 ]96]. These findings carry important consequences for the management of patients with fulminant hepatic failure. Assessment of mean arterial pressure alone is inadequate and arterial oxygen delivery requires careful monitoring. Calculation of arterial oxygen content requires the use of a co-oximeter rather than a calculated arterial oxygen saturation because of significant changes in the position of the oxygen– haemoglobin dissociation curve. Haemodynamic goals of maintaining DaO2 above 700 ml min91 m2, have been proposed. Other measures to maximize
94 DaO2 should be attempted and the effect on oxygen extraction assessed. Pulmonary complications may occur in up to 50 % of cases [92]. The majority of cases have a low pulmonary vascular resistance and some increase in alveolar–arterial oxygen difference. In a recent review of cases with liver failure due to paracetamol hepatotoxicity, 33 % had severe lung injury (Murray score 2.5) with hypoxaemia contributing to the death of two patients [4]. Such hypoxaemia may have many causes including aspiration of gastric contents, pulmonary infection or a syndrome of noncardiogenic pulmonary oedema. Chest radiology significantly underestimates the severity of the pulmonary dysfunction. Endotracheal intubation is usually undertaken when grade 3 encephalopathy occurs and care must be taken to ensure that changes in ventilatory parameters and end-expiratory pressure do not compromise systemic and cerebral haemodynamics. ELECTROLYTE AND RENAL DYSFUNCTION
Hyponatraemia is a universal finding as a result of water retention and an intracellular sodium shift from inhibition of membrane Na/K ATPase. Saline should not be administered. Hypokalaemia related to the respiratory alkalosis, and hypophosphataemia [28] may also require correction. Hypoglycaemia due to reduced hepatic glycogen stores and hyperinsulinaemia require treatment with continuous glucose administration. Hyperlactataemia and metabolic acidosis occur in up to 30 % of cases, predominantly paracetamol induced, and carry a very poor prognosis. Either acute tubular necrosis or functional renal failure may occur in up to half of all cases [97]. In cases of toxic injury caused by paracetamol, carbon tetrachloride or solvent use, renal impairment may be out of proportion to the hepatic injury. Continuous haemodiafiltration is performed in order to minimize large shifts in solute [98]. Large changes in serum sodium concentration must be avoided particularly at the time of orthotopic liver transplantation, as osmotic demyelination and central pontine myelinolysis may result. BACTERIAL AND FUNGAL SEPSIS
A wide range of defects in host defences is present. Impaired opsonization, leucocyte chemotaxis [100] and intracellular killing [22] all contribute to a substantial risk of sepsis with up to 80 % of patients developing bacterial sepsis and 30 % developing fungal infection [83]. The sensitivity and specificity of the usual markers of infection are poor. The majority of infective episodes are related to Grampositive organisms. Prophylactic antibiotics may have a minor role, although there is no evidence that enteral decontamination is of any benefit [82]. More important is close microbiological surveillance. Fungal infection is particularly common in cases with prior bacterial sepsis, a low white cell count at presentation and renal failure. Patients require careful monitoring particularly in those proceeding to orthotopic liver transplantation.
British Journal of Anaesthesia DISORDERS OF COAGULATION AND FIBRINOLYSIS
Hepatocellular necrosis results in marked impairment in synthesis of many coagulation factors and their inhibitors, as well as those factors involved in the regulation of fibrinolysis. Only factor VIII concentrations are elevated. In addition to the reduced synthesis, the contribution of increased intravascular consumption of coagulant factors has been controversial for some years, but the recent finding of elevated thrombin–antithrombin III complexes and D-dimer concentrations both indicate intravascular activation of coagulation [58]. In contrast, activation of fibrinolysis is not a significant clinical problem [77]. Progressive thrombocytopenia is universal, associated with the loss of the larger more haemostatically active platelets [85]. Platelets also have reduced aggregation to ADP.
Assessment of prognosis Improvements in intensive medical management have resulted in a steady increase in survival rates from fulminant hepatic failure. Previous studies have demonstrated that the severity of the liver failure assessed by serial prothrombin times, number and type of organ system failures, and the aetiology of the hepatocellular necrosis are all important [10]. Assessing which patients have the worst prognosis and require consideration for other interventions, including orthotopic liver transplantation, must be undertaken early giving enough time to find an appropriate donor, and at a time when the patient is fit enough to withstand the procedure. The King’s College group has proposed that assessments of prognosis will be different for each aetiology [71]. Paracetamol-induced hepatotoxicity is best assessed by the presence of acidosis (arterial pH 7.3) and level of prothrombin time [76] (table 4). For all other aetiologies two static variables, age and aetiology, as well as dynamic variables of bilirubin, prothrombin time and time from onset of symptoms to development of encephalopathy are used (table 4). In contrast, Bernau and colleagues proposed that factor V concentrations and age were more discriminatory [10], and a recent study from Table 4 Criteria for consideration for orthotopic liver transplantation Paracetamol overdose Arterial pH 100 s Creatinine >300 µmol litre91 Grade 3 or 4 encephalopathy Prothrombin time increasing on day 4 Non-paracetamol overdose Any three of the following: Aetiology non-A-non-B hepatitis, halothane or drug reaction Age 40 years Jaundice to encephalopathy Serum bilirubin >300 µmol litre91 Prothrombin time >50 s or prothrombin time >100 s (Taken from ref. [71])
Fulminant and late onset hepatic failure
95
Table 5 Results of orthotopic liver transplantation for fulminant (FHF) and late onset hepatic failure (LOHP) % Grade 3/4 Author [Ref.]
Patients
FHF/LOHF
Encephalopathy
% Survival
O’Grady [69] Vickers [94] Schafer [86] Emond [32] Iwatsuki [53] Gallinger [37] Rakela [79]
31 16 24 19 42 21 8
16/15 16/0 24/0 19/0 42/0 9/12 8/0
35 100 50 84 64 81 88
61 56 58 58 50 72 63
Japan could not confirm the King’s College criteria [91], perhaps reflecting differences in aetiology and medical management. Each centre needs to develop criteria that can predict outcome as accurately as possible and use these to refer cases for orthotopic liver transplantation. This procedure is usually not performed in patients over the age of 65 years, and does require a satisfactory cardiopulmonary assessment.
Orthotopic liver transplantation For those patients with the worst prognosis orthotopic liver transplantation remains their only chance of long-term survival. Survival rates of up to 70 % have been reported in some series (table 5). Selection of the patient is important [99]. An upper age limit of 65 years is used in some units and the presence of two other organ system dysfunctions used as a contraindication. Reports of significant brain damage after transplantation related to preoperative cerebral ischaemia and cerebral oedema reflects the difficult issue of the significance of changes in cerebral blood flow and perfusion pressure in predicting neurological outcome [68]. Recent studies have demonstrated that survival without neurological deficit may occur even after periods of up to 3 h of low cerebral perfusion pressure presumably because of very low CMRO2. Possibly the use of jugular bulb cannulation and lactate/oxygen concentrations may give better discrimination. In those cases with potentially reversible liver dysfunction, such as paracetamol hepatotoxicity, the technique of auxiliary partial orthotopic liver transplantation with a hemihepatectomy of donor and recipient, and grafting of the left lobe of the donor only, have theoretical advantages [19]. If satisfactory regeneration of the native liver occurs then immunosuppression can be withdrawn and the graft then atrophies [64].
Artificial liver support In recent years the use of temporary liver support with perfusion of hepatocyte or hepatoblastoma cell lines encapsulated within hollow fibres has seen a resurgence of interest [84, 90]. Their use remains experimental and no evidence of survival advantage or basis for a “bridge” to transplantation has been reported. Previous techniques including high flux haemofiltration, charcoal haemoperfusion [39, 70]
and Amberlite XAD-7 perfusion [51]; all had some problems of bioincompatibility and were clinically ineffective. Indeed, the concept that the major problem in the late stages of fulminant hepatic failure is the result of the failure of the liver to clear “toxins” may be false. Studies demonstrating dramatic improvements in cerebral perfusion pressure, and systemic vascular resistance on exclusion of the liver from the circulation or hepatectomy, suggest that substances released by the necrotic organ may be just as important. Until more efficient biocompatible devices are available, artificial liver support will develop only slowly.
References 1. Akriviadis EA, Redeker AG. Fulminant hepatitis A in intravenous drug users with chronic liver disease. Annals of Internal Medicine 1989; 110: 838–839. 2. Almdal T, Schroeder T, Ranek L. Cerebral blood flow and liver function in patients with encephalopathy due to acute and chronic liver diseases. Scandinavian Journal of Gastroenterology 1989; 24: 299–303. 3. Asher LVS, Innis BL, Shrestha MP, Ticehurst J, Baze WB. Virus-like particles in the liver of a patient with fulminant hepatitis and antibody to hepatitis E virus. Journal of Medical Virology 1990; 31: 229–233. 4. Baudouin SV, Howdle P, O’Grady JG, Webster NR. Acute lung injury in fulminant hepatic failure following paracetamol poisoning. Thorax 1995; 50: 399–402. 5. Basile AS, Pannell L, Jaouni T, Gammal SH, Fales HM, Jones EA, Skolnick P. Brain concentrations of benzodiazepines are elevated in an animal model of hepatic encephalopathy. Proceedings of National Academy of Science USA 1990; 87: 5263–5267. 6. Basile AS, Hughes RD, Harrison PM, Jones EA, Williams R, Skolnick P. Elevated brain concentrations of 1,4-benzodiazepines in fulminant hepatic failure. New England Journal of Medicine 1991; 325: 473–478. 7. Benhamou JP. Fulminant and subfulminant hepatic failure: definition and causes. In: Williams R, Hughes RD, eds. Acute Liver Failure Improved Understanding and Better Therapy. London: Mitre Press, 1991; 6–10. 8. Berman DH, Leventhal RI, Gavaler JS, Cadoff EM, Van Thiel DH. Clinical differentiation of fulminant Wilsonian hepatitis from other causes of hepatic failure. Gastroenterology 1991; 100: 1129–1134. 9. Bernuau J, Rueff B, Benhamou J-P. Fulminant and subfulminant liver failure: definitions and causes. Seminars in Liver Disease 1986; 6: 97–106. 10. Bernuau J, Goudeau A, Poynard T, Dubois F, Lesage G, Yvonnet B, Degott C, Bezeaud A, Rueff B, Benhamou JP. Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology 1986; 6: 648–651. 11. Bernuau J, Babany G, Bezeaud A, Benhamou JP. Does prostaglandin E1 (PGE1) prevent further aggravation in severe, or early fulminant, hepatitis? A preliminary open trial (abstract). Journal of Hepatology 1989; 9: S114.
96 12. Bernuau J, Benhamou JP. Classifying acute liver failure. Lancet 1993; 342: 252. 13. Bihari D, Gimson AES. Waterson M, Williams R. Tissue hypoxia in fulminant hepatic failure. Critical Care Medicine 1985; 3: 1034–1039. 14. Bihari DJ, Gimson AES, Williams R. Cardiovascular, pulmonary and renal complications of fulminant hepatic failure. Seminars in Liver Disease 1986; 6: 119–128. 15. Bihari D, Wendon J. Tissue hypoxia in fulminant hepatic failure. In: Williams R, Hughes RD, eds. Acute Liver Failure: Improved Understanding and Better Therapy. London: Mitre Press, 1991: 4244. 16. Bird GLA, Smith H, Portmann B, Alexander GJM, Williams R. Acute liver decompensation on withdrawal of cytotoxic chemotherapy and immunosuppressive therapy in hepatitis B carriers. Quarterly Journal of Medicine 1989; 73: 895–902. 17. Blei AT. Cerebral edema and intracranial hypertension in acute liver failure: distinct aspects of the same problem. Hepatology 1991; 13: 376–379. 18. Blei AT, Olafsson S, Webster S, Levy R. Complications of intracranial pressure monitoring in fulminant hepatic failure. Lancet 1993; 341: 157–158. 19. Boudjema K, Cherqui D, Jaeck D, Chenard-Neu M-P. Auxiliary liver transplantation for fulminant and subfulminant hepatic failure. Transplantation 1995; 59: 218–223. 20. Boyer JL, Klatskin G. Pattern of necrosis in acute viral hepatitis. Prognostic value of bridging (subacute hepatic necrosis). New England Journal of Medicine 1970; 12: 1063–1071. 21. Canalese J, Gimson AES, Davis C, Mellon PJ, Davis M, Williams R. Controlled trial of dexamethasone and mannitol for the cerebral oedema of fulminant hepatic failure. Gut 1982; 23: 625–629. 22. Canalese J, Gove C, Gimson AES, Wilkinson SP, Wadle EN, Williams R. Reticuloendothelial system and hepatocyte function in fulminant hepatic failure. Gut 1982; 23: 265–269. 23. Carson JL, Strom BL, Duff A, Gupta A, Shaw M, Lundin FE, Das K. Acute liver disease associated with erythromycins, sulphonamides and tetracyclines. Annals of Internal Medicine 1993; 119: 576–583. 24. Connor RW, Lorts G, Gilbert DN. Lethal herpes simplex virus type 1 hepatitis in a normal adult. Gastroenterology 1979; 76: 590–594. 25. Davenport A, Will EJ, Davison AM. Effect of posture on intracranial pressure and cerebral perfusion in patients with fulminant hepatic and renal failure after acetaminophen selfpoisoning. Critical Care Medicine 1980; 18: 286–289. 26. Davies MH, Morgan-Capner P, Portmann B, Wilkinson SP, Williams R. A fatal case of Epstein-Barr virus infection with jaundice and renal failure. Postgraduate Medical Journal 1980; 56: 794–795. 27. Davies MH, Wilkinson SP, Hanid MA, Portmann B, Brudenell JM, Newton JR, Williams R. Acute liver disease with encephalopathy and renal failure in late pregnancy and the early puerperium. A study of fourteen patients. British Journal of Obstetrics and Gynaecology 1980; 87: 1005–1014. 28. Dawson DJ, Babbs C, Warnes TW, Neary RH. Hypophosphatemia in acute liver failure. British Medical Journal 1987; 295: 1312–1313. 29. Donovan JP, Shaw BW jr, Langnas AN, Sorrell MF. Brain water and acute liver failure: the emerging role of intracranial pressure monitoring. Hepatology 1992; 16: 267–268. 30. Ede RJ, Gimson AES, Bihari D, Williams R. Controlled hyperventilation in the prevention of cerebral oedema in fulminant hepatic failure. Journal of Hepatology 1986; 2: 43–51. 31. Ede RJ, Williams R. Reyes syndrome in adults. British Medical Journal 1988; 296: 517. 32. Emond JC, Aran PP, Whitington PF, Broelsch CE, Baker AL. Liver transplantation in the management of fulminant hepatic failure. Gastroenterology 1989; 96: 1583–1588. 33. European Association for the Study of the Liver. Randomised trial of steroid therapy in acute liver failure. Gut 1979; 20: 620–623. 34. Feray C, Gigou M, Samuel D, Reyes G, Bernuau J, Reynes M, Bismuth H, Brechot C. Hepatitis C virus RNA and hepatitis B virus DNA in serum and liver of patients with fulminant hepatitis. Gastroenterology 1993; 104: 549–555. 35. Forbes A, Alexander GJ, O’Grady JG, Keays R, Gullan R,
British Journal of Anaesthesia
36. 37.
38.
39. 40. 41. 42.
43.
44. 45.
46. 47.
48.
49. 50. 51. 52.
53.
54. 55. 56.
Dawling S, Williams R. Thiopental infusion in the treatment of intracranial hypertension complicating fulminant hepatic failure. Hepatology 1989; 10: 306–310. Forbes A, Williams R. Increasing age—an important adverse prognostic factor in hepatitis A virus infection. Journal of the Royal College of Physicians of London 1988; 22: 237–239. Gallinger S, Greig PD, Levy G, Blendis LM, Roberts EA, Superina RA, Taylor BR, Strasberg SM, Phillips MJ, Langer B. Liver transplantation for acute and subacute fulminant hepatic failure. Transplantation Proceedings 1989; 21: 2435– 2438. Gerber MA, Thung SN, Shen S, Stromeyer FW, Ishak KG. Phenotypic characterization of hepatic proliferation. Antigenic expression of proliferating epithelial cells in fetal liver, massive hepatic necrosis and nodular transformation of the liver. American Journal of Pathology 1983; 110: 70–74. Gimson AES, Braude S, Mellon P, Canalese J, Williams R. Earlier charcoal haemoperfusion in fulminant hepatic failure. Lancet 1982; ii: 681–683. Gimson AES, Tedder RS, White YS, Eddleston ALWF, Williams R. Serological markers in fulminant hepatitis B. Gut 1983; 24: 615–617. Gimson AES, O’Grady J, Ede R, Portmann B, Williams R. late-onset hepatic failure: clinical, serological and histological features. Hepatology 1986; 6: 228–294. Gohda E, Tsubouchi H, Nakayama H, Hirono S, Arakaki N, Yamamoto I, Hashimoto S, Daikuhara Y. Human hepatocyte growth factor in blood of patients with fulminant hepatic failure: basic aspects. Digestive Diseases and Sciences 1991; 36: 785–790. Gordon FD, Anastopoulos H, Khettry U, Loda M, Jenkins RL, Lewis WD, Trey C. Hepatitis C infection: a rare cause of fulminant hepatic failure. American Journal of Gastroenterology 1995; 90: 117–120. Govindarajan S, Chin KP, Redeker AG, Peters RL. Fulminant B viral hepatitis: role of delta agent. Gastroenterology 1984; 86: 1417–1420. Grimm G, Ferenci P, Katzenschlager R, Madl C, Schneeweiss B, Laggner AN, Lenz K, Gangl A. Improvement of hepatic encephalopathy treated with flumanzenil. Lancet 1991; 2: 1392–1394. Hanau C, Munoz SJ, Rubin R. Histopathological heterogeneity in fulminant hepatic failure. Hepatology 1995; 21: 345–351. Harrison PM, Keays R, Bray GP, Alexander GJM, Williams R. Late N-acetylcysteine administration improves outcome for patients developing paracetamol-induced fulminant hepatic failure. Lancet 1990; i: 1572–1573. Harrison PM, Wendon JA, Gimson AES, Alexander GJM, Williams R. Improvement by N-acetylcysteine of haemodynamics and oxygen transport in fulminant hepatic failure. New England Journal of Medicine 1991; 324: 1852–1857. Henson DE, Crimley PM, Strano AJ. Postnatal cytomegalovirus hepatitis: an autopsy and liver biopsy study. Human Pathology 1974; 5: 93–103. Horney JT, Galambos JT. The liver during and after fulminant hepatitis. Gastroenterology 1977; 73: 639–645. Hughes R, Williams R. Clinical experience with charcoal and resin hemoperfusion. Seminars in Liver Disease 1986; 6: 164–173. Ishak KG. Viral hepatitis: the morphologic spectrum. In: Gall EA, Mostofi FK, eds. The Liver. International Academy of Pathology Monographs No 13. Baltimore: Williams and Wilkins, 1973: 218–268. Iwatsuki S, Stieber AC, Marsh JW, Tzakis AG, Todo S, Koneru B, Makowka L, Gordon RD, Starzl TE. Liver transplantation for fulminant hepatic failure. Transplantation Proceedings 1989; 21: 2431–2434. Joo F. A unifying concept on the pathogenesis of brain oedemas. Neuropathology and Applied Neurobiology 1990; 13: 161–176. Kato M, Hughes RD, Keays RT, Williams R. Electron microscopic study of brain capillaries in cerebral edema from fulminant hepatic failure. Hepatology 1992; 15: 1060–1066. Keays R, Harrison PM, Wendon JA, Forbes A, Gove C, Alexander GJ, Williams R. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. British Medical Journal 1991; 303: 1026– 1029.
Fulminant and late onset hepatic failure 57. Kumar S, Rex DK. Failure of physicians to recognize acetaminophen hepatotoxicity in chronic alcoholics. Archives of Internal Medicine 1991; 151: 1189–1191. 58. Langley PG, Forbes A, Hughes RD, Williams R. Thrombinantithrombin III complex in fulminant hepatic failure: evidence for disseminated intravascular coagulation and relationship to outcome. European Journal of Clinical Investigation 1990; 20: 627–631. 59. Larsen FS, Knudsen GM, Paulson OB, Vilstrup H. Cerebral blood flow autoregulation is absent in rats with thioacetamideinduced hepatic failure. Journal of Hepatology 1994; 21: 491–495. 60. Liang TJ, Jeffers L, Reddy RK, Hasegawa K, Rimon N, Wands JR, Ben-Porath E. Fulminant or subfulminant non-A, non-B viral hepatitis: the role of hepatitis C and E viruses. Gastroenterology 1993; 104: 556–562. 61. Licht H, Seeff LB, Zimmerman HJ. Apparent potentiation of acetaminophen hepatotoxicity by alcohol. Annals of Internal Medicine 1980; 92: 511. 62. Lidofsky SD, Bass NM, Prager MC, Washington DE, Read AE, Wright TL, Ascher NL, Roberts JP, Scharschmidt BF, Lake JR. Intracranial pressure monitoring and liver transplantation for fulminant hepatic failure. Hepatology 1992; 16: 1–7. 63. McKenzie R, Fried MW, Sallie R, Conjeevaram H, Di Bisceglie AM, Park Y, Savarese B, Kleiner D, Tsokos M, Luciano C. Hepatic failure and lactic acidosis due to Fialuridine (FIAU), an investigational nucleoside analogue for chronic hepatitis B. New England Journal of Medicine 1995; 333: 1099–1105. 64. Metselaar HJ, Hesselink EJ, de Rave S, ten Kate FJ, Lameris JS, Groenland TH, Reuvers CB, Weimar W, Terpstra OT, Schalm SW. Recovery of failing liver after auxiliary heterotopic liver transplantation. Lancet 1990; 335: 1156–1157. 65. Mitchell I, Wendon J, Fitt S, Williams R. Anti-tuberculous therapy and acute liver failure. Lancet 1995; 345: 555–556. 66. Morishita K, Kodo H, Asano S, Fujii H, Miwa S. Fulminant varicella hepatitis following bone marrow transplantation. Journal of the American Medical Association 1985; 253: 511. 67. Mullen KD, Martin JV, Mendelson WB, Bassett ML, Jones EA. Could an endogenous benzodiazepine ligand contribute to hepatic encephalopathy? Lancet 1988; i: 457–459. 68. Munoz SJ, Robinson M, Northrup B, Bell R, Moritz M, Jarrell B, Martin P, Maddrey WC. Elevated intracranial pressure and tomography of the brain in fulminant hepatic failure. Hepatology 1991; 13s: 209–212. 69. O’Grady JG, Alexander GJM, Thick M, Potter D, Calne RY, Williams R. Outcome of liver transplantation in the aetiological and clinical variants of acute liver failure. Quarterly Journal of Medicine 1988; 69: 817–824. 70. O’Grady J, Gimson AES, O’Brien C, Pucknell A, Hughes RD, Williams R. Controlled trials of charcoal hemoperfusion and prognostic factors in fulminant hepatic failure. Gastroenterology 1988; 94: 1186–1192. 71. O’Grady JG, Alexander GJM, Hallyar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97: 439–445. 72. O’Grady JG, Schalm SW, Williams R. Acute liver failure; redefining the syndrome. Lancet 1993; 342: 273–275. 73. Osano Y, Yoshikawa T, Suga S, Yazaki T, Kondo K, Yamanishi K. Fatal fulminant hepatitis in an infant with human herpes virus-6 infection. Lancet 1991; 335: 862–863. 74. Papaevangelou G, Tassopoulos N, Roumeliotou-Karayannis A, Richardson C. Aetiology of fulminant viral hepatitis in Greece. Hepatology 1984; 4: 369–372. 75. Pappas S, Ferenci P, Jones EA. Evidence against the hypothesis that cerebral oedema in FHF is due to decreased neural Na-K ATPase activity. Hepatology 1983; 3: 848 (Abstract). 76. Pereira LMMB, Langley PG, Hayllar KM, Tredger JM, Williams R. Coagulation factor V and VIII/V ratio as predictors of outcome in paracetamol induced fulminant hepatic failure: relation to other prognostic indicators. Gut 1992; 33: 98–102. 77. Pernambuco R, Langley PG, Hughes R, Izumi S, Williams R. Activation of the fibrinolytic system in patients with fulminant liver failure. Hepatology 1993; 18: 1350–1356. 78. Powell-Jackson PR, Ede RJ, Williams R. Budd-Chiari
97
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
91.
92.
93.
94.
95.
96.
97.
98.
99.
syndrome presenting as fulminant hepatic failure. Gut 1986; 27: 1101–1105. Rakela J, Perkins JD, Gross JB jr, Hayes DH, Plevak DJ, Krom RA, Ludwig J. Acute hepatic failure: the emerging role of orthotopic liver transplantation. Mayo Clinic Proceedings 1989; 64: 424–428. Riely CA, Latham PS, Romero R, Duffy TP. Acute fatty liver of pregnancy: a reassessment based on observations in nine patients. Annals of Internal Medicine 1987; 106: 703–706. Rolfes DB, Ishak KG. Acute fatty liver of pregnancy: a clinicopathologic study of 35 cases. Hepatology 1985; 5: 1149–1158. Rolando N, Gimson AES, Wade J, Philpott-Howard J, Casewell M, Williams R. Prospective controlled trial of selective parenteral and enteral antimicrobial regimen in fulminant liver failure. Hepatology 1993; 17: 196–201. Roland N, Harvey F, Brahan J, Philpott-Howard J, Gimson AES, Fagan E, Williams R. Prospective study of bacterial infection in acute liver failure: an analysis of fifty patients. Hepatology 1990; 11: 49–53. Rozga J, Williams F, Ro MS, Neuzil DF, Giorgio TD, Backfisch G, Moscioni AD, Hakim R, Demetriou AA. Development of a bioartificial liver; properties and function of a hollow fibre module inoculated with liver cells. Hepatology 1993; 17: 258–265. Rubin MH, Weston MJ, Bullock G, Roberts J, Langley PG, White YS, Williams R. Abnormal platelet function and ultrastructure in fulminant hepatic failure. Quarterly Journal of Medicine 1977; 183: 339–352. Schafer DF, Shaw BW. Fulminant hepatic failure and orthotopic liver transplantation. Seminars in Liver Disease 1989; 9: 189–194. Seda HMW, Hughes RD, Gove C, Williams R. Reduced brain Na-K ATPase activity by serum from patients with fulminant hepatic failure. Hepatology 1984; 4: 74–79. Sheiner P, Sinclair S, Greig P, Logan A, Blendis LM, Levy G. A randomized controlled trial of prostaglandin E2 (PGE2) in the treatment of fulminant hepatic failure. Hepatology 1992; 16 (Suppl): S114 (abstract). Sinclair SB, Greig PD, Blendis LM, Abecassis M, Roberts EA, Phillips MJ, Cameron R, Levy GA. Biochemical and clinical response of fulminant viral hepatitis to administration of prostaglandin E: a preliminary report. Journal of Clinical Investigation 1989; 84: 1063–1069. Sussman NI, Gislason GT, Conlin CA, Kelly JH. The Hepatix extracorporeal liver assist device: initial clinical experience. Artificial Organs 1994; 18: 390–396. Takahashi Y, Kumada H, Shimizu M, Tanikawa K, Kumashiro R, Omato M. A multicentre study on the prognosis of fulminant viral hepatitis: Early prediction for liver transplantation. Hepatology 1994; 9: 1065–1071. Trewby PN, Warren R, Contini S, Crosbie WA, Wilkinson SP, Laws JW, Williams R. Incidence and pathophysiology of pulmonary edema in fulminant hepatic failure. Gastroenterology 1978; 74: 859–865. Trey C, Davidson CS. The management of fulminant hepatic failure. In: Popper H, Schaffner F, eds. Progress in Liver Diseases. Vol. III. New York: Grune & Stratton, 1970: 282–298. Vickers C, Neuberger J, Buckels J, McMaster P, Elias E. Transplantation of the liver in adults and children with fulminant hepatic failure. Journal of Hepatology 1986; 7: 143–150. Wendon JA, Gimson AE, Potter D. Oxygen uptake and delivery in fulminant hepatic failure. Care of the Critically Ill 1989; 5: 55–59. Wendon JA, Harrison PM, Keays R, Gimson AES, Alexander GJM, Williams R. Effects of vasopressor agents and epoprostenol on systemic hemodynamics and oxygen transport in patients with fulminant hepatic failure. Hepatology 1992; 15: 1067–1071. Wilkinson SP, Blendis LM, Williams R. Frequency and type of renal and electrolyte disorders in fulminant hepatic failure. British Medical Journal 1974; 1: 186–189. Wilkinson SP, Weston MJ, Parsons V, Williams R. Dialysis in the treatment of renal failure in patients with liver disease. Clinical Nephrology 1977; 8: 287–292. Williams R, Wendon J. Indications for orthotopic liver
98 transplantation in fulminant hepatic failure. Hepatology 1994; 20: 5S–10S. 100. Wyke RJ, Rajkovic IA, Eddleston ALWF, Williams R. Defective opsonisation and complement deficiency in serum from patients with fulminant hepatic failure. Gut 1981; 21: 643–649. 101. Yoshiba M, Sekiyama K, Inoue K, Fujita R. Interferon and cyclosporin A in the treatment of fulminant viral hepatitis. Journal of Gastroenterology 1995; 30: 67–73.
British Journal of Anaesthesia 102. Zafrani ES, Leclercq B, Vernant JP, Pinaudeau Y, Chomette G, Dhumeaux D. Massive blastic infiltration of the liver: a cause of fulminant hepatic failure. Hepatology 1983; 3: 428–432. 103. Zimmerman HJ, Ishak KG. Valproate-induced hepatic injury. Analysis of 23 fatal cases. Hepatology 1982; 2: 591–597. 104. Zimmerman H. Even enflurane (Editorial). Hepatology 1991; 13: 1251–1253.
