Etiology including geographical variation

Acetaminophen overdose, taken with deliberate suicidal intent, is the most common cause of ALF in the United Kingdom, accounting for 50 to 60 per cent of all cases referred (Spo0D.§L..a.D.d H§ry®y 199.3.). In England and Wales, the number of deaths attributed to acetaminophen increased from seven in 1968 to 66 in 1973 and 144

in 1977, and by the late 1980s there were over 500 deaths annually. However, in a recent review of the 547 deaths recorded in 1990, there was evidence of acute hepatic damage in only 150. In the remaining cases, death could not be directly attributed to acetaminophen although it was a component of the fatal overdose

(Smo_n_e_r__a_nd daryey..199.3.). The extensive press coverage afforded to fatal acetaminophen overdose cases in the United Kingdom coupled with the easy availability of the drug are the two most important factors underlying its use in suicide attempts. A recent study of overdose patients demonstrated that 63 per cent had chosen acetaminophen because it was easy to obtain and 53 per cent had obtained the drug specifically for the overdose; 36 per cent of the patient group knew that acetaminophen was dangerous and 78 per cent realized that it could be fatal.

Other countries have also recorded a substantial increase in the annual number of cases. The number of calls to poisons centers in the United States concerning acetaminophen overdoses increased from 60 000 in 1987 to 90 000 in 1993, although in the same year only 92 deaths were directly related to this cause. In France there are less than 109 deaths annually, which is thought to be the result of legally limiting the pack size to just 8 g. However, in one of the major liver centers in France the incidence of acetaminophen overdose as a cause of ALF has increased from less than 2 per cent of all cases before 1991 to 16 per cent currently.

Of considerable interest are the reports of severe hepatotoxicity following therapeutic doses of acetaminophen in patients who are concurrently taking enzyme-inducing drugs, such as phenytoin, or are chronic consumers of alcohol. In a series of 67 patients who developed hepatic injury after ingestion of acetaminophen taken with therapeutic intent, 64 per cent were considered to be 'alcoholic' or reported alcohol intakes above 80 g/day. The acetaminophen doses taken were within the recommended therapeutic range (< 4 g/day) in 40 per cent of cases. Almost 20 per cent of the patients died. Presumably, susceptibility is caused by induction of cytochrome P-4502EI by ethanol and depletion of glutathione by the effects of both alcohol and the frequently associated malnutrition.

The anesthetic agent halothane continues to feature among the drugs responsible for ALF, although much less frequently than previously. The exact mechanism of toxicity underlying this very rare idiosyncratic reaction is uncertain but appears to depend on both immunological and constitutional factors. A recent analysis of our case experience over the past 10 years revealed 18 cases of ALF due to halothane compared with 48 patients referred between 1965 and 1984. In many instances the recommended guidelines of the Committee on Safety of Medicines had been disregarded, with the patients having been re-exposed to halothane within a month of the last halothane anesthetic and despite having had documented reactions previously. Many other drugs, including monoamine oxidase inhibitors, non-steroidal anti-inflammatory drugs, gold, sodium valproate, cotrimoxazole, sulfonamides, disulfiram, ketoconazole, and phenytoin, may also rarely cause ALF. With the re-emergence of tuberculosis in many Western countries, an increasing number of cases of ALF from isoniazid-rifampicin-pyrazinamide hepatotoxicity are being encountered, usually as a result of a failure to monitor liver function properly after starting such therapy. A rare cause of acute hepatotoxicity in the United Kingdom, although it is relatively common in France, is ingestion of the poisonous mushroom Amanita phalloides.

During the past few years we have also seen cases of ALF following ingestion of ecstasy (3,4-methyldioxymethamphetamine). The spectrum of liver injury ranges from a heatstroke-type lesion to a more hepatitis-like injury.

Acute viral hepatitis accounts for up to 50 per cent of cases of ALF seen in mainland European centers and in North America. The increased incidence of viral hepatitis A as a cause reported from some countries may relate to a change in the time of exposure to the virus with infection occurring later in life. When ALF follows an acute infection with hepatitis B virus (HBV), viral replication has usually ceased by the time of presentation. Chronic HBsAg carriers who develop 'super-infection' with the delta virus (HDV) can develop ALF, and it is a rare development in carriers with a reactivation of HBV replication following immunosuppressive therapy for some other condition. The importance of mutant HBV strains in causing ALF, as demonstrated by molecular biology techniques, is the subject of conflicting reports. In many cases of presumed fulminant viral hepatitis, as referred to earlier, no specific viral hepatitis agent can be identified (i.e. hepatitis A, B, C, D, and E negative) despite the clinical presumption of viral hepatitis as the cause. In a recent study of 50 patients with seronegative non-A non-B fulminant hepatitis using the sensitive polymerase chain reaction analysis of hepatic DNA for detection of occult viral infection, negative results were obtained.

In general, the frequency with which the different viral hepatitis agents are responsible for ALF is related to the underlying prevalence of those infections in the country concerned. Thus hepatitis B is particularly common in the Far East, where carrier rates of HBV are high, but is rare in the United Kingdom where HBV infects less that 1 per cent of the population. Indeed, the proportion of ALF cases in the United Kingdom in which a viral etiology can be implicated is less than 30 per cent, with more than half of these having a seronegative hepatitis. In France, the proportion of viral-associated ALF is higher, with hepatitis B being the major viral agent

(Benhamou 1991), and the figures are similar in the United States, with viral hepatitis accounting for 62 per cent of cases. In the Indian subcontinent a high proportion of cases fall within the non-A non-B category. Hepatitis E is more frequently encountered in subtropical areas and is associated with high mortality, particularly in pregnant women. However, a recent study showed that hepatitis E virus could be implicated in a small proportion of sporadic cases of non-A non-B hepatitis in which there was no history of travel abroad.

There is also considerable geographical variation with respect to hepatitis C as a cause of ALF. Instances of infection are rarely found in the West, whereas in Japan over half the patients from one series with acute or subacute liver failure had evidence of infection with HCV. In another series from Japan, dual infection with HCV RNA was observed in a number of patients with HBV ALF. This is similar to a report from France in which almost half of the HBsAg-positive patients had detectable HCV RNA in serum. In Taiwan, 40 to 50 per cent of cases of fulminant viral hepatitis are related to HCV infection.

The contribution of the newly described GB viral agent and of hepatitis G (which appear to be different serotypes of the same virus with some homology to the flaviviruses, particularly hepatitis C) to the non-A to E category of fulminant viral hepatitis is probably smaller in the West, although in a recent study from Japan three of six cases with fulminant hepatitis of unknown etiology were found to have positive signals for GBV-C genome in serum. Further viral infections which rarely result in ALF include cytomegalovirus, Epstein-Barr, herpes simplex, Coxsackie B, and echovirus. Other rare causes of ALF, which are important because of the possibilities of specific treatment, are acute fatty liver of pregnancy, lymphoma, ischemic hepatitis, and acute Budd-Chiari syndrome. Rarely, Wilson's disease has a fulminant presentation and can be identified from the associated hemolysis, splenomegaly, and Kaiser-Fleischer rings. Finally, an autoimmune hepatitis can also occasionally present as a fulminant illness.

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