1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence and aetiology
  6. Clinical features
  7. Haemodynamic, respiratory and renal instability
  8. Coagulopathy
  9. Infection
  10. Specific therapies in ALF
  11. Prognostication to guide OLT in ALF
  12. Conclusions
  13. Acknowledgement
  14. References

Aliment Pharmacol Ther31, 345–358


Background  Acute liver failure is a devastating clinical syndrome with a persistently high mortality rate despite critical care advances. Orthotopic liver transplantation (OLT) is a life-saving treatment in selected cases, but effective use of this limited resource requires accurate prognostication because of surgical risks and the requirement for subsequent life-long immunosuppression.

Aim  To review the aetiology of acute liver failure, discuss the evidence behind critical care management strategies and examine potential treatment alternatives to OLT.

Methods  Literature review using Ovid, PubMed and recent conference abstracts.

Results  Paracetamol remains the most common aetiology of acute liver failure in developed countries, whereas acute viral aetiologies predominate elsewhere. Cerebral oedema is a major cause of death, and its prevention and prompt recognition are vital components of critical care support, which strives to provide multiorgan support and ‘buy time’ to permit either organ regeneration or psychological and physical assessment prior to acquisition of a donor organ. Artificial liver support systems do not improve mortality in acute liver failure, whilst most other interventions have limited evidence bases to support their use.

Conclusion  Acute liver failure remains a truly challenging condition to manage, and requires early recognition and transfer of patients to specialist centres providing intensive, multidisciplinary input and, in some cases, OLT.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence and aetiology
  6. Clinical features
  7. Haemodynamic, respiratory and renal instability
  8. Coagulopathy
  9. Infection
  10. Specific therapies in ALF
  11. Prognostication to guide OLT in ALF
  12. Conclusions
  13. Acknowledgement
  14. References

Acute liver failure (ALF) is a rare disorder characterized by catastrophic loss of liver cell function. It remains one of the most challenging medical emergencies, because of the multiorgan nature of the disease, the rapid evolution of the clinical condition, the need for multidisciplinary supportive interventions and the requirement for the clinician to prognosticate accurately to best utilize orthotopic liver transplantation (OLT) as a life-saving treatment. Despite advances in supportive care, spontaneous survival without OLT is as low as 20%; therefore, early recognition and prompt transfer of potential transplant candidates to tertiary centres with intensive care and liver transplantation expertise are vital.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence and aetiology
  6. Clinical features
  7. Haemodynamic, respiratory and renal instability
  8. Coagulopathy
  9. Infection
  10. Specific therapies in ALF
  11. Prognostication to guide OLT in ALF
  12. Conclusions
  13. Acknowledgement
  14. References

Acute liver failure refers to the abrupt loss of hepatic cellular function in a patient without pre-existing liver disease, with the subsequent development of coagulopathy, jaundice and encephalopathy. In 1970, Trey and Davidson defined fulminant hepatic failure as a ‘potentially reversible condition, the consequence of severe liver injury, with an onset of encephalopathy within 8 weeks of the appearance of the first symptoms and in the absence of pre-existing liver disease’.1 However, as the initial symptoms of liver failure are frequently nonspecific and open to subjective bias, ALF was redefined based on the time taken to develop hepatic encephalopathy (HE) after the first appearance of jaundice, with the terms ‘hyperacute’, ‘acute’ and ‘subacute’ liver failure referring to a jaundice-to-encephalopathy interval of 0–7, 8–28 and 29–84 days respectively.2 This distinction is useful in guiding prognosis as, paradoxically, the time to onset of encephalopathy is negatively correlated with outcome despite the increased incidence of cerebral oedema in hyperacute liver failure. Hepatitis A and B, paracetamol and ischaemic insults typically present as hyperacute liver failure, and have a relatively good spontaneous survival rate of 36%, whereas idiosyncratic drug reactions and indeterminate causes present later, with only a 14% survival rate without OLT.3 Severe acute liver injury, with elevated transaminases and coagulopathy, typically precedes hyperacute liver failure but it is HE, the cardinal feature of the progression to ALF, which defines the condition and is of major prognostic significance.

Incidence and aetiology

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence and aetiology
  6. Clinical features
  7. Haemodynamic, respiratory and renal instability
  8. Coagulopathy
  9. Infection
  10. Specific therapies in ALF
  11. Prognostication to guide OLT in ALF
  12. Conclusions
  13. Acknowledgement
  14. References

The accurate reporting of ALF is hampered by the heterogeneous nature of the syndrome and by the lack of an International Classification of Diseases code for ALF. This means that the incidence is probably underreported but has been estimated at 2800 cases per annum in the US or approximately 3.5 deaths per million population.4, 5 Within Scotland, the incidence of paracetamol-induced ALF has been estimated at 8.4 cases per annum per million population.6 The syndrome of ALF is not a single clinical entity, and may be precipitated by a wide variety of hepatic insults (Table 1).7 These insults have a marked geographical and socioeconomic variation, with the most common aetiologies in Europe and North America being paracetamol and idiosyncratic drug reactions, whereas developing countries have a higher preponderance of acute viral aetiologies (Table 2). Specific insults also demonstrate geographical variation, with staggered accidental paracetamol overdoses predominating in the US, whereas single, intentional, overdoses are more common in the UK.8, 9 The early identification, where possible, of the underlying aetiology of ALF is crucial as several causes of ALF, such as paracetamol (N-acetyl cysteine, NAC), Amanita phalloides poisoning (penicillin and silibinin), fulminant hepatitis B (lamivudine), herpes simplex virus (HSV) (acyclovir) and pregnancy (delivery), have specific treatments and the prognosis between different aetiologies varies considerably.10–14

Table 1.   Selected aetiologies of acute liver failure
Aetiological categorySpecific causes
  1. HAV, hepatitis A virus; HBV, hepatitis B virus; HDV, hepatitis delta virus; HEV, hepatitis E virus; HSV, herpes simplex virus; CMV, cytomegalovirus; EBV, Epstein–Barr virus; VZV, Varicella zoster virus; HLLP, haemolysis, elevated liver enzymes and low platelets; HAART, Highly Active Anti-Retroviral Treatment.

ViralHAV, HBV +/− HDV, HEV, HSV, human herpes virus 6, CMV, EBV, VZV, parvovirus B19, yellow fever
Drug/toxin induced (dose-dependent)Paracetamol, Amantina phalloides, tetracyclines, Bacillus cereus, CCl4
Drug/toxin induced (idiosyncratic)Halothane, anti-tuberculous therapy, sulphonamides, coamoxiclav, macrolides, valproate, NSAIDs, disulfiram, thalidomide, β-interferon, HAART, Ecstasy, cocaine, herbal remedies, etc.
VascularIschaemic hepatitis, Budd–Chiari, right heart failure, veno-occlusive disease
MetabolicWilson’s disease, acute fatty liver of pregnancy, HELLP
MiscellaneousAutoimmune hepatitis, malignant infiltration, sepsis, heat stroke
Table 2.   Aetiologies of acute liver failure by geographical location
  1. * Patients listed for orthotopic liver transplantation only.

  2. † Paediatric patients only.

No. cases31030881315363267278037180
Paracetamol (%)433915177203600
Nonparacetamol drug reactions (%)813121021147680.6
Hepatotropic viruses (%)7123012333737142768 (44 Hep E)
Indeterminate (%)30172743183244343831
Other causes (%)1219161721151110270

Clinical features

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence and aetiology
  6. Clinical features
  7. Haemodynamic, respiratory and renal instability
  8. Coagulopathy
  9. Infection
  10. Specific therapies in ALF
  11. Prognostication to guide OLT in ALF
  12. Conclusions
  13. Acknowledgement
  14. References

The initial clinical features of ALF may be nonspecific and may include anorexia, fatigue, abdominal pain, jaundice and fever before progressing to HE.15 The ‘type A’ HE associated with ALF (types B and C HE are associated with portosystemic bypass and cirrhosis respectively) is graded from 1 to 4 on clinical features and neurological signs (Table 3).16 This grading is clinically robust, and increasing grades of HE have a strong negative correlation with outcome. The pathogenesis of HE (and subsequent cerebral oedema) in ALF is incompletely understood, and differs from the encephalopathy observed in chronic liver disease, but hyperammonaemia, systemic inflammation and loss of cerebral blood flow (CBF) autoregulation all appear to accelerate progression.17–19 Ammonia, produced from glutamine by enterocytes, enters the systemic circulation via the portal vein, but is poorly cleared by the failing liver, and this is exacerbated by the coexistent renal failure, reduced hepatic urea synthesis and impaired skeletal muscle function observed in ALF.20 Astrocytes detoxify ammonia by converting it to glutamine which leads to osmotic swelling; this cytotoxic process appears to be the main pathophysiological driver of cerebral oedema in ALF.3, 21, 22 Hyponatraemia, frequently seen in patients with ALF, may potentiate this process, possibly via aquaporin-4.23, 24 In additio, cerebral hyperaemia, potentially mediated by pro-inflammatory cytokines, increases intracranial blood volume, further compromising cerebral perfusion.25, 26 Interestingly, case reports have directly implicated liver-derived toxins in this process.27

Table 3.   Classification of hepatic encephalopathy148
HE GradeMental statusNeurological signsEEGGCS
  1. EEG, electroencephalogram; GCS, glasgow coma scale.

ITrivial lack of awareness; euphoria or anxiety; shortened attention span; impairment of addition/subtractionSlight tremor; apraxia; incoordinationUsually normal15
IILethargy or apathy; disorientation for time; obvious personality change; inappropriate behaviourAsterixis; ataxia; dysarthriaGeneralized slowing11–15
IIISomnolence to semi-stupor; responsive to stimuli; confused; gross disorientation; bizarre behaviourAsterixis; ataxiaAbnormal8–11
IVComa; unable to test mental stateDecerebrationAbnormal<8

The evolution to grade III/IV HE is a grave prognostic sign as this group is at risk of intracranial hypertension and subsequent brain herniation.28 In addition, intracranial hypertension compromises cerebral perfusion pressure (CPP), defined as the difference between mean arterial pressure and intracranial pressure (ICP). A CPP >60 mmHg is considered crucial to maintain normal neurological functioning and periods >2 h with a CPP <40 mmHg is considered by some centres to preclude liver transplantation.5 Clinical signs suggestive of increasing ICP include worsening of HE, systemic hypertension and bradycardia (Cushing reflex), altered pupillary reflexes and decerebrate rigidity. All of these clinical signs occur late in the clinical course, when therapeutic interventions may be ineffective, and this has led to the direct monitoring of ICP in patients with ALF.

Intracranial pressure monitoring

The use of ICP monitoring in ALF remains controversial, because of the lack of consensus over treatment goals, the associated risks of bleeding and infection and the lack of randomized trial data supporting improved survival. However, continuous monitoring permits rapid, targeted treatment to be initiated and several groups now include ICP monitoring as part of their standard ALF protocol, particularly in potential OLT candidates.5, 29 Intracerebral bleeding occurs in 8–10% of cases, although fatal bleeds occur considerably less frequently.30, 31 Calculation of cerebral oxygen consumption using a jugular bulb catheter may provide additional information through continuous, indirect assessment of CBF.32 This involves the retrograde passage of a fine-bore catheter into the jugular vein until the tip reaches the jugular bulb; venous saturations >85% (normal range 55–70%) represent a hyperaemic cerebral circulation.

Treatment for raised ICP

The goal of medical management of cerebral oedema should be to maintain the ICP <20 mmHg and the CPP >70 mmHg, by reducing brain volume or CBF. Basic manoeuvres include elevation of the head of the bed to no more than 30° and minimizing painful stimuli including suctioning.33 Hyperventilation produces, at best, a transient restoration of CBF autoregulation by lowering PaCO2; however, its prolonged use in ALF patients has been questioned.34 Established therapies for raised ICP include the use of mannitol and barbituates such as thiopentone.35, 36 More limited evidence supports the use of hypertonic saline, propofol sedation and indomethacin.37, 38 Unrandomized studies from Edinburgh have advocated the use of moderate hypothermia (32–33 °C) in advanced ALF as a means of reducing ICP prior to, and during, transplantation, and this appears to offer a therapeutic option which targets many of the proposed triggers for elevated ICP in ALF.20, 39–41 Further studies are required to clarify the optimal extent and duration of hypothermia and to exclude a negative impact from hypothermia upon sepsis, coagulopathy and cardiac stability.

Haemodynamic, respiratory and renal instability

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence and aetiology
  6. Clinical features
  7. Haemodynamic, respiratory and renal instability
  8. Coagulopathy
  9. Infection
  10. Specific therapies in ALF
  11. Prognostication to guide OLT in ALF
  12. Conclusions
  13. Acknowledgement
  14. References

Acute liver failure is characterized by a hyperdynamic circulation, with markedly reduced systemic vascular resistance, increased cardiac output and hypotension, which frequently necessitates vasopressor support in addition to fluid repletion.42 As yet, the optimal fluid and vasopressor strategy remains uncertain, but most centres use crystalloid resuscitation followed by norepinephrine infusions to maintain adequate perfusion pressures and cerebral oxygenation, although this strategy may not significantly improve oxygen delivery.43 Overzealous norepinephrine use should be avoided as this may exacerbate cerebral hyperaemia because of the loss of CBF autoregulation in ALF.44 Terlipressin, a vasopressin synthetic analogue, has been evaluated in two small studies which produced conflicting results regarding its effects on CBF, ICP and systemic haemodynamic parameters.45, 46

Critical illness-related corticosteroid insufficiency (CIRCI) may exacerbate the haemodynamic instability seen in ALF, with a negative correlation between illness severity and the response to short synacthen testing in a cohort of 45 patients with acute liver injury.47 Corticosteroid treatment of patients with low baseline cortisol levels (‘hepatoadrenal syndrome’) in a liver intensive care unit resulted in reduced vasopressor requirements and mortality, but it is worth noting that adrenal insufficiency was commoner in patients with chronic liver disease or post-OLT in this study than in the ALF patients.48 There is insufficient evidence at this stage to recommend routine treatment of CIRCI in liver patients, and the use of synacthen tests to diagnose CIRCI is not recommended.49

Radiographic changes suggestive of pulmonary oedema occur in a high proportion of ALF cases, and the development of severe acute lung injury is associated with a poor prognosis.50, 51 Treatment of ARDS using a protective ventilatory strategy is more problematic in ALF because increases in positive end expiratory pressure may exacerbate cerebral oedema and hepatic congestion.7

Renal failure in ALF is multifactorial, and is related to acute tubular necrosis, hypoperfusion, use of contrast agents and, in paracetamol-induced ALF, direct nephrotoxicity.52 The systemic inflammatory response syndrome (SIRS) has recently been shown to predict renal dysfunction in nonparacetamol-induced ALF.53 Management should focus on prevention of renal failure by maintaining adequate systemic blood pressure, prompt identification and treatment of infections and judicious use of contrast agents, because once established, the prognosis is considerably poorer. Continuous, rather than intermittent, methods of extracorporeal support are preferred to minimize circulatory and cerebral fluctuations.54 Hypophosphataemia is associated with renal failure in ALF and may also be linked to hepatic regeneration; persistently elevated phosphate levels may reflect failure of this regenerative process and have been associated with a poorer prognosis in paracetamol-induced ALF.55, 56 Reduced hepatic glycogen stores and hyperinsulinaemia contribute to hypoglycaemia, which complicates up to 40% of ALF cases, and continuous glucose administration is frequently required. Oral or enteral feeding is vital, but the markedly increased energy expenditure observed in ALF makes adequate nutritional support difficult to institute effectively in established liver failure.57


  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence and aetiology
  6. Clinical features
  7. Haemodynamic, respiratory and renal instability
  8. Coagulopathy
  9. Infection
  10. Specific therapies in ALF
  11. Prognostication to guide OLT in ALF
  12. Conclusions
  13. Acknowledgement
  14. References

The coagulopathy of ALF is complex and remains poorly characterized, but is undoubtedly of prognostic significance.58–60 ALF is characterized by prolongation of prothrombin time and quantitative and qualitative platelet dysfunction and, in paracetamol-induced ALF, hypofibrinogenaemia and reductions in coagulation factors II, V, VII and X.61 However, despite the severity of the coagulopathy, clinically significant spontaneous bleeding is relatively unusual in ALF, even during liver transplantation.62, 63 The defective production of procoagulant factors is compensated for in part by underproduction of anticoagulant proteins protein C, protein S and antithrombin III, whilst factor VIII production is upregulated, possibly in extrahepatic sites.64, 65 Plasminogen activator inhibitor-1 levels are grossly elevated in ALF, suggesting hypofibrinolysis; this was supported by a recent murine study where heparin pre-treatment significantly reduced hepatic fibrin deposition following paracetamol poisoning and significantly attenuated paracetamol-induced hepatotoxicity.66, 67 The bleeding risk in ALF has been overstated, and the prophylactic administration of large volumes of fresh frozen plasma (FFP) in ALF is unnecessary, interferes with prognostic scoring systems and may worsen cerebral oedema or volume overload.68, 69 Several pilot studies have suggested that recombinant factor VII may be superior to FFP for clinically significant bleeding in ALF, but further evaluation is required before this expensive treatment can be universally recommended.70, 71 At present, FFP, platelet and cryoprecipitate infusions should be reserved for use in actively bleeding patients or prior to planned invasive procedures.72


  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence and aetiology
  6. Clinical features
  7. Haemodynamic, respiratory and renal instability
  8. Coagulopathy
  9. Infection
  10. Specific therapies in ALF
  11. Prognostication to guide OLT in ALF
  12. Conclusions
  13. Acknowledgement
  14. References

The SIRS and, when precipitated by infection, sepsis have been shown to have a strong negative impact on HE progression, renal function and mortality in ALF.19, 53, 73 Bacteraemia is present in up to 80% of ALF patients who have enhanced susceptibility to infection because of the presence of indwelling lines and catheters, impaired complement and opsonization function and impaired innate immunity.74 The majority of infections are caused by Gram-negative enteric organisms, staphylococci and fungal infections.75, 76 The role of bacterial gut translocation, important in cirrhosis, is unclear at present, as prospective randomized trials of oral and enteral gut decontamination in ALF have failed to add additional benefit over parenteral antibiotic regimens alone.77–79 Fungal infections are commonly underrecognized and are particularly important in ALF patients who have received prolonged courses of antibiotics or have renal dysfunction.76 Close surveillance for infection should be maintained in all ALF patients with frequent chest radiographs and cultures of blood, urine and sputum, but prophylactic antibiotics should probably be reserved for patients with high-grade encephalopathy and renal dysfunction or for those awaiting OLT.69, 78

Specific therapies in ALF

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence and aetiology
  6. Clinical features
  7. Haemodynamic, respiratory and renal instability
  8. Coagulopathy
  9. Infection
  10. Specific therapies in ALF
  11. Prognostication to guide OLT in ALF
  12. Conclusions
  13. Acknowledgement
  14. References

N-acetyl cysteine

When used early as an antidote after a single, intentional paracetamol overdose, NAC is extremely effective at replenishing hepatic glutathione stores and preventing severe N-acetyl-p-benzoquinone imine-induced hepatotoxicity and liver failure.10 The evidence for NAC in patients with established hepatotoxicity or ALF is less robust, and is based on a retrospective study from King’s College Hospital and a small randomized controlled trial from the same centre.80, 81 Initial studies suggested that NAC improved oxygen delivery and consumption in ALF, but this assertion has subsequently been challenged.82, 83 Furthermore, the optimal duration of NAC therapy in these patients is unclear, as prolonged NAC therapy was recently shown to impair murine liver regeneration and worsen outcome following paracetamol poisoning.84 The benefit of NAC in nonparacetamol-induced ALF is also unclear, and although it appears to confer benefit in children, a recent multicentre randomized-controlled trial (RCT) in adults only demonstrated improvement in spontaneous survival in a subgroup of patients with Grade I–II HE.85, 86

Penicillin and silibinin

Mycetismus (mushroom poisoning), most commonly from Amanita genus mushrooms, is a medical emergency. Amantinin toxin, recycled via the enterohepatic circulation, interrupts hepatocyte messenger RNA synthesis and causes dose-dependent hepatotoxicity. Initial promising reports describing charcoal haemoperfusion in the treatment of Amanita poisoning have not been replicated.87 Penicillin G (250 mg/kg/day) and silibinin (20–50 mg/kg/day), although never subjected to an RCT, appear to be effective when administered early in the course of the disease, but severe cases may require emergency OLT.11, 88


A small proportion of patients with acute hepatitis B proceed to develop ALF, which occasionally necessitates OLT. Previous case reports utilized foscarnet in the treatment of fulminant hepatitis B, but increasing attention is being given to nucleoside analogues in this condition.13, 89–91 However, an RCT of lamivudine involving 71 patients with acute hepatitis B (three of whom had HE) failed to demonstrate any significant clinical benefit in the lamivudine arm.12

Delivery of pregnant ALF patients

The syndrome of haemolysis, elevated liver enzymes and low platelets (HELLP) and acute fatty liver of pregnancy (AFLP) are the pregnancy-related liver disorders most commonly associated with ALF, although pre-eclampsia can occasionally result in hepatic rupture and infarction. There is increasing evidence that pre-eclampsia, HELLP and AFLP represent a spectrum of the same disease, with similar clinical and pathophysiological correlations including increased vascular tone and platelet aggregation.92 Foetal deficiency of the mitochondrial enzyme long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) results in maternal accumulation of medium- and long-chain fatty acids, and similar mutations of the mitochondrial trifunction protein have been linked to both HELLP and AFLP.93–95 Pre-eclampsia, HELLP and AFLP all carry significant risk of both maternal and foetal mortality, and severe cases should be managed in tertiary centres capable of dealing with the potential obstetric and hepatic complications. The mainstay of treatment of all the three conditions is delivery, but close postpartum observations of both mother and infant are important to detect any haemorrhagic complications or continued clinical or biochemical deterioration, which can occasionally necessitate postpartum emergency OLT.96–99


Whilst HSV has high seroprevalence amongst the general population, HSV-related hepatitis is a rare cause of ALF (1.4% in one 13-year cohort study) and is most commonly, but not exclusively, seen amongst immunosuppressed and pregnant patients.100 The diagnosis of HSV-ALF is frequently made late, with a resultant high mortality rate. As the characteristic vesicles are often absent, a high index of suspicion must be maintained to screen for potential cases amongst young, immunosuppressed, or pregnant individuals presenting with fever and transaminitis, as prompt treatment with intravenous acyclovir is safe and has shown benefit in several cases.14, 101

Plasmapheresis and d-penicillamine

Fulminant Wilson’s disease represents a rare, but important cause of ALF, and the diagnosis can be intimated by the presence of a low alkaline phosphatase to bilirubin ratio, AST:ALT ratio >2.2 and haemolytic anaemia.102, 103 Isolated cases report the successful use of plasmapheresis and chelation therapy in the treatment of fulminant Wilson’s disease, although these remain a bridge to transplantation rather than definitive therapies.104, 105 Plasmapheresis appears to reduce arterial ammonia levels, and has occasionally been utilized in the treatment of aetiologies of ALF other than Wilson’s disease, but the side effects of treatment can be significant and no mortality benefit has been demonstrated to date.106–108

Other treatments

Other treatments such as insulin/glucagon, prostaglandin E2 and corticosteroids (even in fulminant autoimmune hepatitis) have failed to show significant benefit in ALF and are not recommended.82, 109–112 A recent RCT of l-ornithine–l-aspartate (LOLA) in ALF patients, predominantly with acute viral hepatitis, found LOLA to be ineffective in reducing either ammonia levels or mortality rates, with a trend towards increased seizure rates in the LOLA arm.113

Artificial and bioartificial liver devices

Liver assist devices have received much attention over recent years in the hope that they can provide an effective ‘bridge’ to transplantation or recovery of liver function. The initial artificial liver support devices were essentially filters designed to remove toxins through haemodialysis or adsorption using charcoal, and failed to show a survival benefit in ALF.114 The MARS (Molecular Absorbent and Recirculating System) utilizes a hollow fibre, double-sided, albumin-impregnated dialysis membrane to extract protein-bound toxins into the albumin dialysate.108 Initial reports suggested improvements in both systemic and cerebral haemodynamic parameters and improvements in HE in patients with ALF and acute-on-chronic liver failure.115–118 More advanced systems, such as Prometheus, involve fractionated plasma separation and adsorption, whilst bioartificial liver systems include living human or porcine hepatocytes incorporated in an extracorporeal circuit to add synthetic function to the process of detoxification. At least 12 RCTs of these devices have been performed and they have been systematically reviewed twice; overall, these devices improve HE but have no mortality benefit in ALF, but may improve outcome in acute-on-chronic liver failure.119, 120

Liver transplantation

Although never subjected to an RCT, OLT has been recommended for the treatment of ALF since 1983.121 Emergency OLT for ALF now accounts for 5–12% of all liver transplantation activity and is the only treatment to date to alter substantially the mortality resulting from the condition.122 Patient survival following OLT for ALF is generally poorer than that in those transplanted for chronic liver failure, particularly in the setting of pre-transplant renal failure, but is of the order of 65–80% 1 year survival.123–125 Alternatives to standard OLT are being refined, including living donor grafts and auxiliary liver transplantation (where part of the native liver is left in situ after partial liver transplantation in the hope that native liver regeneration can permit later cessation of immunosuppression).126, 127 Whilst a promising therapy for paracetamol-induced ALF, auxiliary transplantation fails to remove the diseased native liver, leading to concerns over continuing haemodynamic and neurological instability. The limited timescales and the dramatic nature of the disease progression involved mean that the possibility of coercion of potential living donors in the setting of ALF is of significant ethical concern. In addition, ALF patients are at particular risk of small-for-size syndrome and therefore the larger right lobe from the donor is usually transplanted, increasing the risk of donor morbidity or mortality.128

Prognostication to guide OLT in ALF

  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence and aetiology
  6. Clinical features
  7. Haemodynamic, respiratory and renal instability
  8. Coagulopathy
  9. Infection
  10. Specific therapies in ALF
  11. Prognostication to guide OLT in ALF
  12. Conclusions
  13. Acknowledgement
  14. References

The decision to list emergently an ALF patient for OLT is rarely easy – the inherent risks associated with delaying listing for OLT must be balanced against the potential for spontaneous recovery with medical therapy alone, the risks of surgery in the context of an acute critical illness, the scarcity of donor grafts and the requirement (except after auxiliary liver transplantation) for life-long immunosuppression.127 Furthermore, up to 60% of paracetamol-induced ALF patients meeting poor prognostic criteria are deemed unsuitable to undergo OLT because of coexistent psychiatric or medical conditions that are likely to preclude long-term graft and/or patient survival, such as resistant alcohol or drug dependence, or previous persistent treatment noncompliance.129 Accurate prognostication in ALF is therefore vital, and many proposed mathematical, serological, radiological and histological variables have been proposed, including the MELD (Model for End-stage Liver Disease) score, which has improved organ allocation in chronic liver disease (Table 4).130, 131 Major methodological flaws exist with many of these studies, which are often unblinded, retrospective and prone to spectrum bias.132 Furthermore, many authors equate liver transplantation with death, falsely elevating the positive predictive value of the test in question.133 In 1989, O’Grady et al. developed the ‘King’s College criteria’ from a retrospective cohort of 588 patients with grade II–IV HE admitted to that institution.58 The criteria recognize the prognostic importance of the aetiology of ALF, with separate criteria for paracetamol-induced ALF and other aetiologies (Table 5). These criteria are remarkable for their robustness and accuracy despite numerous attempts to improve their diagnostic accuracy (Table 4). The paracetamol criteria have recently been modified by the addition of lactate, although several authors have questioned the overall benefit of this modification.134–136 The King’s College criteria have also been criticized for its low sensitivity and negative predictive value, particularly for nonparacetamol aetiologies.137

Table 4.   Alternative prognostic variables suggested for use in acute liver failure
Prognostic variableAetiologyPredictor of poor prognostic outcomeSensitivitySpecificityRefs
  1. KCC, King’s College Hospital poor prognostic criteria; MELD, Model for End-stage Liver Disease; HE, hepatic encephalopathy; APACHE II, Acute Physiology and Chronic Health Evaluation II; AFP, alpha fetoprotein.

KCCAllSee Table 5699258
Clichy criteriaAllHE + Factor V < 20% (age <30 year) or <30% (age >30 year)  Grade III–IV HE + Factor V < 20%–  86–  7614960
Factor V; factor VIII/V ratioParacetamolFactor VIII/V ratio >30  Factor V < 10%91  9191 100150
PhosphateParacetamolPO43− > 1.2 mmol/L on day 2 or 3 postoverdose89100 56, 151
Gc-globulinAllGc-globulin <100 mg/L  Paracetamol  Nonparacetamol73  3068 100152
LactateParacetamolAdmission arterial lactate >3.5 or >3.0 mmol/L after fluid resuscitation8195134
α-FetoproteinParacetamolAFP <3.9 μg/L 24 h postpeak ALT10074153
MELDParacetamol  NonparacetamolMELD >33 at onset of HE  MELD >3260  7669  67154 155
Table 5.   The KCH poor prognostic criteria for paracetamol and nonparacetamol acute liver failure aetiologies as applied in the UK as transplant criteria58, 134
ParacetamolModified criteria
  1. HE, hepatic encephalopathy; OLT, orthotopic liver transplantation; PT, prothrombin time.

List for transplantation if:  Arterial pH <7.3 Or all 3 of the following occur within a 24-h period:  Grade III–IV HE  PT >100 s (INR >6.5)  Serum creatinine >300 μmol/LStrongly consider listing for OLT if:  Arterial lactate >3.5 mmol/L after early fluid resuscitation
List for transplantation if:  Arterial pH <7.3, or arterial lactate >3.0 mmol/L after adequate fluid resuscitation
List for transplantation if all 3 of the following occur within a 24-h period:  Grade III–IV HE  PT >100 s (INR >6.5)  Serum creatinine >300 μmol/L
List for transplantation if:  PT >100 s (INR >6.5) irrespective of HE grade Or any 3 of 5 of the following:  Unfavourable aetiology: (seronegative hepatitis, Wilson’s disease, idiosyncratic drug reaction, halothane)  Age <10 or >40 years  Jaundice to encephalopathy interval >7 days  PT >50 s (INR >3.5)  Bilirubin >300 μmol/L


  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence and aetiology
  6. Clinical features
  7. Haemodynamic, respiratory and renal instability
  8. Coagulopathy
  9. Infection
  10. Specific therapies in ALF
  11. Prognostication to guide OLT in ALF
  12. Conclusions
  13. Acknowledgement
  14. References

Acute liver failure remains a truly challenging condition to manage, and requires close surveillance for incipient organ failure and early transfer of patients to specialist centres offering intensive multidisciplinary input to manage effectively the myriad complications of the syndrome, and, in some cases, to offer liver transplantation. The rarity of the syndrome presents difficulties in performing RCTs and developing a true evidence base for many of the interventions outlined in this review. The future challenges are to further elucidate the pathophysiology behind liver cell death and the ensuing multiorgan failure of ALF, which in turn may help improve prognostic models. Further multicentre controlled trials of artificial and bioartificial liver support systems are needed before recommendations can be made regarding their clinical utility in ALF. Effective reduction of ammonia levels remains an attractive, but currently elusive, therapeutic goal in ALF.


  1. Top of page
  2. Abstract
  3. Introduction
  4. Definition
  5. Incidence and aetiology
  6. Clinical features
  7. Haemodynamic, respiratory and renal instability
  8. Coagulopathy
  9. Infection
  10. Specific therapies in ALF
  11. Prognostication to guide OLT in ALF
  12. Conclusions
  13. Acknowledgement
  14. References
  • 1
    Trey C, Davidson CS. The management of fulminant hepatic failure. Prog Liver Dis 1970; 3: 28298.
  • 2
    O’Grady JG, Schalm SW, Williams R. Acute liver failure: redefining the syndromes. Lancet 1993; 342: 273.
  • 3
    Gimson AES. Fulminant and late onset hepatic failure. Br J Anaesth 1996; 77: 908.
  • 4
    Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology 2005; 41: 117997.
  • 5
    Hoofnagle JH, Carithers RL Jr, Shapiro C, Ascher N. Fulminant hepatic failure: summary of a workshop. Hepatology 1995;21:24052.
  • 6
    Newsome PN, Bathgate AJ, Henderson NC, et al. Referral patterns and social deprivation in paracetamol-induced liver injury in Scotland. Lancet 2001; 358: 16123.
  • 7
    Sass DA, Shakil AO. Fulminant hepatic failure. Liver Transpl 2005; 11: 594605.
  • 8
    Larson AM, Polson J, Fontana RJ, et al. Acetaminophen-induced acute liver failure: results of a United States multicenter, prospective study. Hepatology 2005; 42: 136472.
  • 9
    Makin AJ, Wendon J, Williams R. A 7 year experience of severe acetaminophen-induced hepatotoxicity (1987-1993). Gastroenterology 1995; 109: 190716.
  • 10
    Heard KJ. Acetylcysteine for acetaminophen poisoning [see comment]. N Engl J Med 2008; 359: 28592.
  • 11
    Klein AS, Hart J, Brems JJ, Goldstein L, Lewin K, Busuttil RW. Amanita poisoning: treatment and the role of liver transplantation [see comment]. Am J Med 1989; 86: 18793.
  • 12
    Kumar M, Satapathy S, Monga R, et al. A randomized controlled trial of lamivudine to treat acute hepatitis B. Hepatology 2007; 45: 97101.
  • 13
    Miyake Y, Iwasaki Y, Takaki A, et al. Lamivudine treatment improves the prognosis of fulminant hepatitis B. Intern Med 2008; 47: 12939.
  • 14
    Montalbano M, Slapak-Green GI, Neff GW. Fulminant hepatic failure from herpes simplex virus: post liver transplantation acyclovir therapy and literature review. Transplant Proc 2005; 37: 43936.
  • 15
    Shakil AO, Kramer D, Mazariegos GV, Fung JJ, Rakela J. Acute liver failure: clinical features, outcome analysis, and applicability of prognostic criteria. Liver Transpl 2000; 6: 1639.
  • 16
    Ferenci P, Lockwood A, Mullen K, Tarter R, Weissenborn K, Blei AT. Hepatic encephalopathy – definition, nomenclature, diagnosis, and quantification: final report of the working party at the 11th World Congresses of Gastroenterology, Vienna, 1998. Hepatology 2002; 35: 71621.
  • 17
    Butterworth RF. Pathophysiology of hepatic encephalopathy: a new look at ammonia. Metab Brain Dis 2002; 17: 2217.
  • 18
    Bernal W, Hall C, Karvellas CJ, Auzinger G, Sizer E, Wendon J. Arterial ammonia and clinical risk factors for encephalopathy and intracranial hypertension in acute liver failure. Hepatology 2007; 46: 184452.
  • 19
    Rolando N, Wade J, Davalos M, Wendon J, Philpott-Howard J, Williams R The systemic inflammatory response syndrome in acute liver failure. Hepatology 2000; 32: 734.
  • 20
    Wendon J, Lee W. Encephalopathy and cerebral edema in the setting of acute liver failure: pathogenesis and management. Neurocrit Care 2008; 9: 97102.
  • 21
    Haussinger D, Kircheis G, Fischer R, Schliess F, Vom Dahl S. Hepatic encephalopathy in chronic liver disease: a clinical manifestation of astrocyte swelling and low-grade cerebral edema? J Hepatol 2000; 32: 10358.
  • 22
    Ranjan P, Mishra AM, Kale R, Saraswat VA, Gupta RK. Cytotoxic edema is responsible for raised intracranial pressure in fulminant hepatic failure: in vivo demonstration using diffusion-weighted MRI in human subjects. Metab Brain Dis 2005; 20: 18192.
  • 23
    Cordoba J, Gottstein J, Blei AT. Chronic hyponatremia exacerbates ammonia-induced brain edema in rats after portacaval anastomosis. J Hepatol 1998; 29: 58994.
  • 24
    Rama Rao KV, Norenberg MD. Aquaporin-4 in hepatic encephalopathy. Metab Brain Dis 2007; 22: 26575.
  • 25
    Wright G, Shawcross D, Olde Damink SW, Jalan R. Brain cytokine flux in acute liver failure and its relationship with intracranial hypertension. Metab Brain Dis 2007; 22: 37588.
  • 26
    Antoniades CG, Berry PA, Davies ET, et al. Reduced monocyte HLA-DR expression: a novel biomarker of disease severity and outcome in acetaminophen-induced acute liver failure. Hepatology 2006; 44: 3443.
  • 27
    Jalan R, Pollok A, Shah SH, Madhavan K, Simpson KJ. Liver derived pro-inflammatory cytokines may be important in producing intracranial hypertension in acute liver failure. J Hepatol 2002; 37: 5368.
  • 28
    Clemmesen JO, Larsen FS, Kondrup J, Hansen BA, Ott P. Cerebral herniation in patients with acute liver failure is correlated with arterial ammonia concentration. Hepatology 1999; 29: 64853.
  • 29
    Keays RT, Alexander GJ, Williams R. The safety and value of extradural intracranial pressure monitors in fulminant hepatic failure. J Hepatol 1993; 18: 2059.
  • 30
    Blei AT, Olafsson S, Webster S, Levy R. Complications of intracranial pressure monitoring in fulminant hepatic failure. Lancet 1993; 341: 1578.
  • 31
    Vaquero J, Fontana RJ, Larson AM, et al. Complications and use of intracranial pressure monitoring in patients with acute liver failure and severe encephalopathy. Liver Transpl 2005; 11: 15819.
  • 32
    Goetting MG, Preston G. Jugular bulb catheterization: experience with 123 patients. Crit Care Med 1990; 18: 12203.
  • 33
    Davenport A, Will EJ, Davison AM. Effect of posture on intracranial pressure and cerebral perfusion pressure in patients with fulminant hepatic and renal failure after acetaminophen self-poisoning. Crit Care Med 1990; 18: 2869.
  • 34
    Ede RJ, Gimson AE, Bihari D, Williams R. Controlled hyperventilation in the prevention of cerebral oedema in fulminant hepatic failure. J Hepatol 1986; 2: 4351.
  • 35
    Canalese J, Gimson AE, 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: 6259.
  • 36
    Forbes A, Alexander GJ, O’Grady JG, et al. Thiopental infusion in the treatment of intracranial hypertension complicating fulminant hepatic failure. Hepatology 1989; 10: 30610.
  • 37
    Murphy N, Auzinger G, Bernel W, Wendon J. The effect of hypertonic sodium chloride on intracranial pressure in patients with acute liver failure. Hepatology 2004; 39: 46470.
  • 38
    Tofteng F, Larsen FS. The effect of indomethacin on intracranial pressure, cerebral perfusion and extracellular lactate and glutamate concentrations in patients with fulminant hepatic failure. J Cereb Blood Flow Metab 2004; 24: 798804.
  • 39
    Jalan R, O Damink SW, Deutz NE, Lee A, Hayes PC. Moderate hypothermia for uncontrolled intracranial hypertension in acute liver failure. Lancet 1999; 354: 11648.
  • 40
    Jalan R, Olde Damink SW, Deutz NE, Hayes PC, Lee A. Moderate hypothermia in patients with acute liver failure and uncontrolled intracranial hypertension. Gastroenterology 2004; 127: 133846.
  • 41
    Jalan R, Olde Damink SW, Deutz NE, et al. Moderate hypothermia prevents cerebral hyperemia and increase in intracranial pressure in patients undergoing liver transplantation for acute liver failure. Transplantation 2003; 75: 20349.
  • 42
    Bihari D, Gimson AE, Waterson M, Williams R. Tissue hypoxia during fulminant hepatic failure. Crit Care Med 1985; 13: 10349.
  • 43
    Wendon JA, Harrison PM, Keays R, Gimson AE, Alexander GJ, Williams R. Effects of vasopressor agents and epoprostenol on systemic hemodynamics and oxygen transport in fulminant hepatic failure. Hepatology 1992; 15: 106771.
  • 44
    Larsen FS, Strauss G, Knudsen GM, Herzog TM, Hansen BA, Secher NH. Cerebral perfusion, cardiac output, and arterial pressure in patients with fulminant hepatic failure. Crit Care Med 2000; 28: 9961000.
  • 45
    Shawcross DL, Davies NA, Mookerjee RP, et al. Worsening of cerebral hyperemia by the administration of terlipressin in acute liver failure with severe encephalopathy. Hepatology 2004; 39: 4715.
  • 46
    Eefsen M, Dethloff T, Frederiksen HJ, Hauerberg J, Hansen BA, Larsen FS. Comparison of terlipressin and noradrenalin on cerebral perfusion, intracranial pressure and cerebral extracellular concentrations of lactate and pyruvate in patients with acute liver failure in need of inotropic support. J Hepatol 2007; 47: 3816.
  • 47
    Harry R, Auzinger G, Wendon J. The clinical importance of adrenal insufficiency in acute hepatic dysfunction. Hepatology 2002; 36: 395402.
  • 48
    Marik PE, Gayowski T, Starzl TE, Hepatic Cortisol Research and Adrenal Pathophysiology Study Group. The hepatoadrenal syndrome: a common yet unrecognized clinical condition. Crit Care Med 2005;33:12549.
  • 49
    Marik PE, Pastores SM, Annane D, et al. Recommendations for the diagnosis and management of corticosteroid insufficiency in critically ill adult patients: consensus statements from an international task force by the American College of Critical Care Medicine [see comment]. Crit Care Med 2008; 36: 193749.
  • 50
    Trewby PN, Warren R, Contini S, et al. Incidence and pathophysiology of pulmonary edema in fulminant hepatic failure. Gastroenterology 1978;74(5 Pt 1):85965.
  • 51
    Baudouin SV, Howdle P, O’Grady JG, Webster NR. Acute lung injury in fulminant hepatic failure following paracetamol poisoning. Thorax 1995; 50: 399402.
  • 52
    Blantz RC. Acetaminophen: acute and chronic effects on renal function. Am J Kidney Dis 1996; 28(Suppl. 1): S36.
  • 53
    Leithead JA, Ferguson JW, Bates CM, et al. The systemic inflammatory response syndrome is predictive of renal dysfunction in patients with non-paracetamol-induced acute liver failure. Gut 2009; 58: 4439.
  • 54
    Davenport A, Will EJ, Davidson AM. Improved cardiovascular stability during continuous modes of renal replacement therapy in critically ill patients with acute hepatic and renal failure. Crit Care Med 1993; 21: 32838.
  • 55
    Knochel JP. Does hypophosphatemia play a role in acute liver failure?. Hepatology 1989; 9: 5045.
  • 56
    Schmidt LE, Dalhoff K. Serum phosphate is an early predictor of outcome in severe acetaminophen-induced hepatotoxicity. Hepatology 2002; 36: 65965.
  • 57
    Walsh TS, Wigmore SJ, Hopton P, Richardson R, Lee A. Energy expenditure in acetaminophen-induced fulminant hepatic failure. Crit Care Med 2000; 28: 64954.
  • 58
    O’Grady JG, Alexander GJ, Hayllar KM, Williams R. Early indicators of prognosis in fulminant hepatic failure. Gastroenterology 1989; 97: 439.
  • 59
    Harrison PM, O’Grady JG, Keays RT, Alexander GJ, Williams R. Serial prothrombin time as prognostic indicator in paracetamol induced fulminant hepatic failure. BMJ 1990; 301: 9646.
  • 60
    Izumi S, Langley PG, Wendon J, et al. Coagulation factor V levels as a prognostic indicator in fulminant hepatic failure. Hepatology 1996; 23: 150711.
  • 61
    Kerr R, Newsome P, Germain L, et al. Effects of acute liver injury on blood coagulation. J Thromb Haemost 2003; 1: 754.
  • 62
    Munoz SJ, Rajender Reddy K, Lee W, Acute Liver Failure Study G. The coagulopathy of acute liver failure and implications for intracranial pressure monitoring. Neurocrit Care 2008;9:1037.
  • 63
    De Boer MT, Molenaar IQ, Hendriks HG, Slooff MJ, Porte RJ. Minimizing blood loss in liver transplantation: progress through research and evolution of techniques. Dig Surg 2005; 22: 26575.
  • 64
    Lisman T, Leebeek FW. Hemostatic alterations in liver disease: a review on pathophysiology, clinical consequences, and treatment. Dig Surg 2007; 24: 2508.
  • 65
    Hollestelle MJ, Poyck PP, Hollestelle JM, Marsman HA, Mourik JA, Gulik TM. Extra-hepatic factor VIII expression in porcine fulminant hepatic failure. J Thromb Haemost 2005; 3: 227480.
  • 66
    Pernambuco JR, Langley PG, Hughes RD, Izumi S, Williams R. Activation of the fibrinolytic system in patients with fulminant liver failure. Hepatology 1993; 18: 13506.
  • 67
    Ganey PE, Luyendyk JP, Newport SW, et al. Role of the coagulation system in acetaminophen-induced hepatotoxicity in mice. Hepatology 2007; 46: 117786.
  • 68
    Caraceni P, Van Thiel DH. Acute liver failure. Lancet 1995; 345: 1639.
  • 69
    Stravitz RT. Critical management decisions in patients with acute liver failure. Chest 2008; 134: 1092102.
  • 70
    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: 3789.
  • 71
    Shami VM, Caldwell SH, Hespenheide EE, Arseneau KO, Bickston SJ, Macik BG. Recombinant activated factor VII for coagulopathy in fulminant hepatic failure compared with conventional therapy. Liver Transpl 2003; 9: 13843.
  • 72
    Fontana RJ Acute liver failure including acetaminophen overdose. Med Clin North Am 2008 viii; 92:76194.
  • 73
    Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RM, Sibbald WJ. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis [see comment]. Crit Care Med 1992;20:86474.
  • 74
    Wyke RJ, Rajkovic IA, Eddleston AL, Williams R. Defective opsonisation and complement deficiency in serum from patients with fulminant hepatic failure. Gut 1980; 21: 6439.
  • 75
    Rolando N, Harvey F, Brahm J, et al. Prospective study of bacterial infection in acute liver failure: an analysis of fifty patients. Hepatology 1990; 11: 4953.
  • 76
    Rolando N, Harvey F, Brahm J, et al. Fungal infection: a common, unrecognised complication of acute liver failure. J Hepatol 1991; 12: 19.
  • 77
    Balzan S, De Almeida Quadros C, De Cleva R, Zilberstein B, Cecconello I. Bacterial translocation: overview of mechanisms and clinical impact. J Gastroenterol Hepatol 2007; 22: 46471.
  • 78
    Rolando N, Gimson A, 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: 196201.
  • 79
    Rolando N, Wade JJ, Stangou A, et al. Prospective study comparing the efficacy of prophylactic parenteral antimicrobials, with or without enteral decontamination, in patients with acute liver failure. Liver Transplantation & Surgery 1996; 2: 813.
  • 80
    Harrison PM, Keays R, Bray GP, Alexander GJ, Williams R. Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetylcysteine. Lancet 1990; 335: 15723.
  • 81
    Keays R, Harrison PM, Wendon JA, et al. Intravenous acetylcysteine in paracetamol induced fulminant hepatic failure: a prospective controlled trial. Br Med J 1991; 303: 10269.
  • 82
    Harrison PM, Wendon JA, Gimson AE, Alexander GJ, Williams R. Improvement by acetylcysteine of hemodynamics and oxygen transport in fulminant hepatic failure. N Engl J Med 1991; 324: 18527.
  • 83
    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: 133240.
  • 84
    Yang R, Miki K, He X, Killeen ME, Fink MP. Prolonged treatment with N-acetylcystine delays liver recovery from acetaminophen hepatotoxicity. Crit Care 2009; 13: R55.
  • 85
    Kortsalioudaki C, Taylor RM, Cheeseman P, Bansal S, Mieli-Vergani G, Dhawan A. Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure. Liver Transpl 2008; 14: 2530.
  • 86
    Lee WM, Hynan LS, Rossaro L, et al. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 2009 864.e1;137:856; Se-864.
  • 87
    Wauters JP, Rossel C, Farquet JJ. Amanita phalloides poisoning treated by early charcoal haemoperfusion. Br Med J 1978; 2: 1465.
  • 88
    Broussard CN, Aggarwal A, Lacey SR, et al. Mushroom poisoning – from diarrhea to liver transplantation [see comment]. Am J Gastroenterol 2001; 96: 31958.
  • 89
    Price JS, France AJ, Moaven LD, Welsby PD. Foscarnet in fulminant hepatitis B. Lancet 1986; 2: 1273.
  • 90
    Hedin G, Weiland O, Ljunggren K, et al. Treatment of fulminant hepatitis B and fulminant hepatitis B and D coinfection with foscarnet. Prog Clin Biol Res 1987; 234: 30920.
  • 91
    Tillmann HL, Hadem J, Leifeld L, et al. Safety and efficacy of lamivudine in patients with severe acute or fulminant hepatitis B, a multicenter experience. J Viral Hepat 2006; 13: 25663.
  • 92
    Rahman TM, Wendon J. Severe hepatic dysfunction in pregnancy. QJM 2002; 95: 34357.
  • 93
    Wilcken B, Leung KC, Hammond J, Kamath R, Leonard JV. Pregnancy and fetal long-chain 3-hydroxyacyl coenzyme A dehydrogenase deficiency. Lancet 1993; 341: 4078.
  • 94
    Treem WR, Rinaldo P, Hale DE, et al. Acute fatty liver of pregnancy and long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency. Hepatology 1994; 19: 33945.
  • 95
    Ibdah JA, Bennett MJ, Rinaldo P, et al. A fetal fatty-acid oxidation disorder as a cause of liver disease in pregnant women. N Engl J Med 1999; 340: 172331.
  • 96
    Lee NM, Brady CW. Liver disease in pregnancy. World J Gastroenterol 2009; 8: 897906.
  • 97
    Pereira SP, O’Donohue J, Wendon J, Williams R. Maternal and perinatal outcome in severe pregnancy-related liver disease. Hepatology 1997; 26: 125862.
  • 98
    Ockner SA, Brunt EM, Cohn SM, Krul ES, Hanto DW, Peters MG. Fulminant hepatic failure caused by acute fatty liver of pregnancy treated by orthotopic liver transplantation. Hepatology 1990; 11: 5964.
  • 99
    Gill EJ, Contos MJ, Peng TC. Acute fatty liver of pregnancy and acetaminophen toxicity leading to liver failure and postpartum liver transplantation. A case report. J Reprod Med 2002; 47: 5846.
  • 100
    Ichai P, Roque Afonso AM, Sebagh M, et al. Herpes simplex virus-associated acute liver failure: a difficult diagnosis with a poor prognosis. Liver Transpl 2005; 11: 15505.
  • 101
    Levitsky J, Duddempudi AT, Lakeman FD, et al. Detection and diagnosis of herpes simplex virus infection in adults with acute liver failure. Liver Transpl 2008; 14: 1498504.
  • 102
    Sallie R, Katsiyiannakis L, Baldwin D, et al. Failure of simple biochemical indexes to reliably differentiate fulminant Wilson’s disease from other causes of fulminant liver failure. Hepatology 1992; 16: 120611.
  • 103
    Korman JD, Volenberg I, Balko J, et al. Screening for Wilson disease in acute liver failure: a comparison of currently available diagnostic tests. Hepatology 2008; 48: 116774.
  • 104
    Rodriguez Farina E, Tremosa Llurba G, Xiol Quingles X, et al. D-penicillamine and plasmapheresis in acute liver failure secondary to Wilson’s disease. Rev Esp Enferm Dig 2003 ;95:602. 63–5.
  • 105
    Asfaha S, Almansori M, Qarni U, Gutfreund KS. Plasmapheresis for hemolytic crisis and impending acute liver failure in Wilson disease. J Clin Apheresis 2007; 22: 2958.
  • 106
    Clemmesen JO, Kondrup J, Nielsen LB, Larsen FS, Ott P. Effects of high-volume plasmapheresis on ammonia, urea, and amino acids in patients with acute liver failure. Am J Gastroenterol 2001; 96: 121723.
  • 107
    Lepore MJ, Martel AJ. Plasmapheresis with plasma exchange in hepatic coma. Methods and results in five patients with acute fulminant hepatic necrosis. Ann Intern Med 1970; 72: 16574.
  • 108
    Barshes NR, Gay AN, Williams B, Patel AJ, Awad SS. Support for the acutely failing liver: a comprehensive review of historic and contemporary strategies. J Am Coll Surg 2005; 201: 45876.
  • 109
    Woolf GM, Redeker AG. Treatment of fulminant hepatic failure with insulin and glucagon. A randomized, controlled trial. Dig Dis Sci 1991; 36: 926.
  • 110
    Cattral MS, Altraif I, Greig PD, Blendis L, Levy GA. Toxic effects of intravenous and oral prostaglandin E therapy in patients with liver disease. Am J Med 1994; 97: 36973.
  • 111
    Tygstrup N, Juhl E. Randomised trial of steroid therapy in acute liver failure.Report from the European Association for the Study of the Liver (EASL). Gut 1979; 20: 6203.
  • 112
    Ichai P, Duclos-Vallee JC, Guettier C, et al. Usefulness of corticosteroids for the treatment of severe and fulminant forms of autoimmune hepatitis. Liver Transpl 2007; 13: 9961003.
  • 113
    Acharya SK, Bhatia V, Sreenivas V, Khanal S, Panda SK. Efficacy of L-ornithine L-aspartate in acute liver failure: a double-blind, randomized, placebo-controlled study. Gastroenterology 2009; 136: 215968.
  • 114
    O’Grady JG, Gimson AE, O’Brien CJ, Pucknell A, Hughes RD, Williams R. Controlled trials of charcoal hemoperfusion and prognostic factors in fulminant hepatic failure. Gastroenterology 1988; 94: 118692.
  • 115
    Ben Abraham R, Szold O, Merhav H, et al. Rapid resolution of brain edema and improved cerebral perfusion pressure following the molecular adsorbent recycling system in acute liver failure patients. Transplant Proc 2001; 33: 28979.
  • 116
    Sorkine P, Ben Abraham R, Szold O, et al. Role of the molecular adsorbent recycling system (MARS) in the treatment of patients with acute exacerbation of chronic liver failure. Crit Care Med 2001; 29: 13326.
  • 117
    McIntyre CW, Fluck RJ, Freeman JG, Lambie SH. Use of albumin dialysis in the treatment of hepatic and renal dysfunction due to paracetamol intoxication. Nephrol Dial Transplant 2002; 17: 3167.
  • 118
    Schmidt LE, Wang LP, Hansen BA, Larsen FS. Systemic hemodynamic effects of treatment with the molecular adsorbents recirculating system in patients with hyperacute liver failure: a prospective controlled trial. Liver Transpl 2003; 9: 2907.
  • 119
    Kjaergard LL, Liu J, Als-Nielsen B, Gluud C. Artificial and bioartificial support systems for acute and acute-on-chronic liver failure: a systematic review. JAMA 2003; 2: 21722.
  • 120
    Liu JP, Gluud LL, Als-Nielsen B, Gluud C. Artificial and bioartificial support systems for liver failure. Cochrane Database Syst Rev 2004; 1: CD003628.
  • 121
    Schmid R. National Institutes of Health Consensus Development Conference Statement: liver transplantation – June 20–23, 1983. Hepatology 1984; 4(1 Suppl.): 107S10S.
  • 122
    O’Grady JG. Acute liver failure. Postgrad Med J 2005; 81: 14854.
  • 123
    Farmer DG, Anselmo DM, Ghobrial RM, et al. Liver transplantation for fulminant hepatic failure: experience with more than 200 patients over a 17-year period. Ann Surg 2003; 237: 66675; discussion 675–6.
  • 124
    Barshes NR, Lee TC, Balkrishnan R, Karpen SJ, Carter BA, Goss JA. Risk stratification of adult patients undergoing orthotopic liver transplantation for fulminant hepatic failure. Transplantation 2006; 81: 195201.
  • 125
    Lidofsky SD. Liver transplantation for fulminant hepatic failure. Gastroenterol Clin North Am 1993; 22: 25769.
  • 126
    Campsen J, Blei AT, Emond JC, et al. Outcomes of living donor liver transplantation for acute liver failure: the adult-to-adult living donor liver transplantation cohort study. Liver Transpl 2008; 14: 127380.
  • 127
    Chenard-Neu MP, Boudjema K, Bernuau J, et al. Auxiliary liver transplantation: regeneration of the native liver and outcome in 30 patients with fulminant hepatic failure – a multicenter European study. Hepatology 1996; 23: 111927.
  • 128
    Umeshita K, Fujiwara K, Kiyosawa K, et al. Operative morbidity of living liver donors in Japan. Lancet 2003; 362: 68790.
  • 129
    Simpson KJ, Bates CM, Henderson NC, et al. The utilization of liver transplantation in the management of acute liver failure: comparison between acetaminophen and non-acetaminophen etiologies. Liver Transpl 2009; 15: 6009.
  • 130
    Wiesner RH. MELD/PELD and the allocation of deceased donor livers for status 1 recipients with acute fulminant hepatic failure, primary nonfunction, hepatic artery thrombosis, and acute Wilson’s disease. Liver Transpl 2004; 10(Suppl. 2): S1722.
  • 131
    Zaman MB, Hoti E, Qasim A, et al. MELD score as a prognostic model for listing acute liver failure patients for liver transplantation. Transplant Proc 2006; 38: 20978.
  • 132
    Ding GK, Buckley NA. Evidence and consequences of spectrum bias in studies of criteria for liver transplant in paracetamol hepatotoxicity. QJM 2008; 101: 7239.
  • 133
    Bailey B, Amre DK, Gaudreault P. Fulminant hepatic failure secondary to acetaminophen poisoning: a systematic review and meta-analysis of prognostic criteria determining the need for liver transplantation. Crit Care Med 2003; 31: 299305.
  • 134
    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: 55863.
  • 135
    Schmidt LE, Larsen FS. Prognostic implications of hyperlactatemia, multiple organ failure, and systemic inflammatory response syndrome in patients with acetaminophen-induced acute liver failure. Crit Care Med 2006; 34: 33743.
  • 136
    Bates CM, Kochar N, Davidson JS, Hayes PC, Simpson KJ. Blood lactate as a predictor of poor prognosis in acute liver failure in acetaminophen overdose. Hepatology 2007; 46: 615A.
  • 137
    Renner EL. How to decide when to list a patient with acute liver failure for liver transplantation? Clichy or King’s College criteria, or something else? J Hepatol 2007; 46: 5547.
  • 138
    Bernal W, Cross TJ, Auzinger G, et al. Outcome after wait-listing for emergency liver transplantation in acute liver failure: a single centre experience. J Hepatol 2009; 50: 30613.
  • 139
    Ostapowicz G, Fontana RJ, Schiodt FV, et al. Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med 2002; 137: 94754.
  • 140
    Tessier G, Villeneuve E, Villeneuve JP. Etiology and outcome of acute liver failure: experience from a liver transplantation centre in Montreal. Can J Gastroenterol 2002; 16: 6726.
  • 141
    Brandsaeter B, Hockerstedt K, Friman S, et al. Fulminant hepatic failure: outcome after listing for highly urgent liver transplantation-12 years experience in the nordic countries. Liver Transpl 2002; 8: 105562.
  • 142
    Ichai P, Samuel D Etiology and prognosis of fulminant hepatitis in adults. Liver Transpl 2008; 14(Suppl. 2): S6779.
  • 143
    Escorsell A, Mas A, De La Mata M, Spanish Group for the Study of Acute Liver Failure. Acute liver failure in Spain: analysis of 267 cases. Liver Transpl 2007; 13: 138995.
  • 144
    Uribe M, Buckel E, Ferrario M, et al. Epidemiology and results of liver transplantation for acute liver failure in Chile. Transplant Proc 2003; 35: 25112.
  • 145
    Gow PJ, Jones RM, Dobson JL, Angus PW. Etiology and outcome of fulminant hepatic failure managed at an Australian liver transplant unit. J Gastroenterol Hepatol 2004; 19: 1549.
  • 146
    Mudawi HM, Yousif BA. Fulminant hepatic failure in an African setting: etiology, clinical course, and predictors of mortality. Dig Dis Sci 2007; 52: 32669.
  • 147
    Khuroo MS, Kamili S. Aetiology and prognostic factors in acute liver failure in India. J Viral Hepat 2003; 10: 22431.
  • 148
    Amodio P, Montagnese S, Gatta A, Morgan MY. Characteristics of minimal hepatic encephalopathy. Metab Brain Dis 2004; 19: 25367.
  • 149
    Bernuau J, Goudeau A, Poynard T, et al. Multivariate analysis of prognostic factors in fulminant hepatitis B. Hepatology 1986; 6: 64851.
  • 150
    Pereira LM, 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: 98102.
  • 151
    Chung PY, Sitrin MD, Te HS. Serum phosphorus levels predict clinical outcome in fulminant hepatic failure. Liver Transpl 2003; 9: 24853.
  • 152
    Schiodt FV, Bondesen S, Petersen I, Dalhoff K, Ott P, Tygstrup N. Admission levels of serum Gc-globulin: predictive value in fulminant hepatic failure. Hepatology 1996; 23: 7138.
  • 153
    Schmidt LE, Dalhoff K. Alpha-fetoprotein is a predictor of outcome in acetaminophen-induced liver injury. Hepatology 2005; 41: 2631.
  • 154
    Schmidt LE, Larsen FS. MELD score as a predictor of liver failure and death in patients with acetaminophen-induced liver injury. Hepatology 2007; 45: 78996.
  • 155
    Dhiman RK, Jain S, Maheshwari U, et al. Early indicators of prognosis in fulminant hepatic failure: an assessment of the Model for End-Stage Liver Disease (MELD) and King’s College Hospital criteria. Liver Transpl 2007; 13: 81421.