See articles on pages 473 and 480
Despite the relative infrequency of acute liver failure (ALF), this syndrome remains a major challenge in hepatological practice worldwide. It is a well-recognized entity characterized by rapidly developing encephalopathy, coagulopathy, and jaundice, occurring in previously healthy individuals. While some variations occur in nomenclature, existing definitions are essentially similar to that promulgated by Bernuau et al., who have defined fulminant hepatic failure as the occurrence of encephalopathy within 2 weeks of the onset of jaundice, and employ the term ‘subfulminant hepatic failure’ where the jaundice-encepalopathy interval is between 2 and 12 weeks. 1 Although the signs of acute liver failure are readily apparent, its causes remain only partly determined, and treatment remains a significant therapeutic challenge. Some of the current controversies may relate to geographically differing aetiology, courses and outcomes. The articles by Ostapowicz and Lee 2 and Acharya et al.3 in this issue of the journal highlight the discrepancies in acute liver failure by contrasting the Western and Eastern clinical experience.
Mortality in acute liver failure in the West may approach 80%; 4 even with the introduction of orthotopic liver transplantation, mortality remains 20–40%. 5 In the East the prognosis is similar, with mortality rates of 66% reported previously. 6 Despite this similarity in prognosis, underlying aetiologies do differ. In one recent United States series, paracetamol (acetaminophen) overdose accounted for 20% of acute liver failure, cryptogenic acute liver failure (‘hepatitis X’) for 15% of cases, idiosyncratic drug reactions for 12% of cases, and viral hepatitis for 17% of cases. 7 It should be noted, however, that variation in aetiology does occur even between Western countries. This is highlighted by the considerable differences in reported rates of acute liver failure due to paracetamol between the United Kingdom, where overdosage with this drug is the most common cause of ALF, 8 versus France, where toxicity is far less common. 1 While chronic alcohol ingestion has long been known to contribute to paracetamol toxicity, 9 the syndrome of ‘accidental overdose’, occurring in the susceptible chronic alcoholic patient, 10 may well be an emerging contributor to this group. 11
Viral hepatitis in the West has been variously described to account for 20–50% of cases of acute liver failure, and is attributable almost entirely to hepatitis A and B infection. In the East, hepatitis A is an endemic cause of childhood hepatitis, but given the almost universal population exposure to the virus, it is relatively uncommon in adults; hepatitis B and hepatitis E, therefore, account for the majority of ALF cases. Hepatitis E is both an endemic and epidemic virus, which appears to exhibit a predilection for pregnant women, and leads to increased rate of fulminant hepatitis: the prevalence of pregnancy among women with ALF in India is approximately 25–30%, compared to a background prevalence of 3% among women in the general population. 6 The reasons for this discrepancy remain to be explained; however, the outcome of pregnancy (with ALF) has not been shown to be significantly different. 6
Globally, hepatitis C is a rare cause of acute liver failure, and its presence should be interpreted as coinfection. Patients with ALF and hepatitis C coinfection may have a worse outcome, although the current evidence is inconclusive. Interestingly, as the current review by Acharya et al. demonstrates, in the East, a significant proportion of patients with presumed acute liver failure secondary to viral hepatitis were not diagnosable by standard methods. 3 The application of molecular methods, however, allowed a number of patients to be diagnosed with hepatitis B infection, some with pre-core or core mutants. While this may account for a significant number of cases of acute liver failure of cryptogenic origin, other hepatotropic viruses are almost certainly also involved. Hepatitis G does not appear to be a significant cause of acute liver failure, 12–16 and while the role of the TT-DNA virus remains to be determined, 17 recent studies have not shown a significant relationship with post-transfusion hepatitis. 18,19 Other possible candidate viruses almost certainly remain to be discovered.
Interesting differences exist between the East and the West in the time course of acute liver failure. This is not wholly explicable by differing aetiologies. In multiple Western studies, delayed onset of encephalopathy following jaundice is well described, and indeed has been demonstrated to correlate with prognosis. In contrast, rapid onset of encephalopathy within a week of jaundice has been demonstrated to signify a better outcome. In the Eastern setting, however, it would appear that delayed onset of encephalopathy is rare, and the timing of its onset is not related to prognosis. Aetiological considerations may partly explain this discrepancy: paracetamol overdose and hepatitis A both lead to rapid acute liver failure, but are more likely to spontaneously improve. In contrast, hepatitis B acute liver failure, which is more common in the East, carries a worse prognosis. Further, hepatitis B virus infection in the East has a higher percentage of precore mutants, which may be associated with a worse outcome, although the evidence regarding this is inconsistent. 20 Although these aetiological factors may partly explain the differences in presentation, this does not wholly explain the paucity of cases with delayed onset of encephalopathy occurring in the East. In the East, acute liver failure would also appear to be more rapidly fatal, with two-thirds of deaths occurring within the first 72 hours of hospitalization, despite intensive therapy. It is possible that this may be at least partially explained by delayed presentation in this setting, and consequent high rates of cerebral oedema at presentation.
With the advent of orthotopic liver transplantation as a viable treatment for this condition, prognostic markers have been extensively studied in both East and West, in order to predict patients who will require hepatic transplantation to survive. In the West, schemata such as the King’s College Criteria 21 have indicated that parameters such as coagulation, patient age, aetiology, delay until onset of encephalopathy, and serum bilirubin, are useful in predicting outcome. In contrast, in the East, as noted above, the timing of onset of encephalopathy is not helpful as a prognostic marker; in addition, the aetiology of acute liver failure does not appear to play a role in determining outcome. In common with data from the West, however, factors such as age, coagulopathy, and elevated bilirubin do appear to be useful predictive markers.
The differences in the aetiology, prognostic indicators, and apparent rapidity of the clinical course of ALF between the East and West are summarized in Table 1. Despite these differences, the complications of this condition are common throughout the world. The essentials of management are, therefore, universal. Early referral to a specialist centre for management of this rare condition is mandatory, whether or not liver transplantation is available. The main causes of mortality remain cerebral oedema and sepsis. Management of cerebral oedema is best carried out prospectively, with aggressive attention to hydration status, to avoid over hydration, and intubation for grade III to IV encephalopathy. Sepsis is also an important cause of mortality. In the East, sepsis is more commonly due to Gram-negative organisms. 3 In the West, it has been often been reported as being due to Gram-positive organisms, however, Gram-negative sepsis does occur. 5 The prevalence of Gram-positive sepsis in the West may be due, at least in part, to the use of invasive monitoring of this condition. Fungal sepsis may also occur. The frequency of this complication in acute liver failure, its often cryptic presentation, and its adverse effects on outcomes mean that aggressive monitoring and rapid treatment for sepsis should be carried out in all patients with acute liver failure.
|Commonest single agent||Hepatitis E virus||Hepatitis B virus (HBV)|
|Role of ‘mutant’ HBV||Yes||No (?)|
|Multiple viral coinfections||Up to 6%||Rare|
|Drug reactions||≤ 5%||2–20%|
|Timing of onset of encephalopathy||No||Yes|
|Cause of death|
|Survival without transplantation||20–30%||20–30%|
|Availability of transplantation||Limited||Yes|
In the West, orthotopic liver transplantation has been an accepted treatment for acute liver failure for over a decade, albeit limited by donor organ availability in all centres. The emergence of transplant facilities in various Eastern locations will hopefully allow this treatment modality to become available to a wider population. Other methods of hepatic support, such as bioartificial liver support, and high performance plasma exchange haemofiltration remain of unproven benefit, but are an area of ongoing research. 22
In conclusion, there are major differences in the aetiology and presentation of acute liver failure between the East and the West, as highlighted by the two papers in this issue. With N-acetyl cysteine being the only specific treatment for a major cause of acute liver failure (paracetamol hepatotoxicity), supportive treatment and transplantation remain the mainstay of treatment. Given that 90–95% of cases of acute liver failure are due to viral hepatitis in the East, and form a significant fraction of the cohort in the West, it is expected that vaccination will become the focus of prevention globally.