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Despite the identification of hepatitis C virus (HCV) as an aetiological agent of blood borne non-A, non-B (NANB) hepatitis a decade ago, its role in fulminant NANB hepatitis is still uncertain.1 In the West, HCV is only infrequently associated with NANB fulminant hepatitis. Thus, in studies from the USA, positive serum HCV RNA was reported in none of 15 cases by Wright and colleagues2 and in only two (12%) of 17 cases by Liang et al.3 Similarly, none of the 23 and 30 NANB cases in the French and English series, respectively, was positive for HCV infection.4 5 In contrast, the prevalence of serological markers of HCV infection in NANB fulminant hepatitis is much higher in the Oriental countries. In an early study from Japan, Muto et al found that seven (58%) of 12 patients with NANB fulminant hepatitis were anti-HCV (anti-C100–3) positive6; findings which were later confirmed by Yangi et al who reported detectable serum HCV RNA in 43% (3/7) of cases of NANB fulminant hepatitis.7 In Taiwan—geographically close to Japan—HCV RNA was detected in 45–50% of patients with NANB fulminant hepatitis8 9 and in the Republic of China, more than 50% of patients with various types of fulminant viral hepatitis had anti-HCV.10
The cause of this discrepancy between findings in the West and East is uncertain. Views of the pathogenesis of fulminant viral hepatitis suggest that an aggressive early host immune response to the virus is the cause of massive hepatocellular necrosis. Levels of the causative virus in the serum and liver may be high before the “peak” of liver damage and due to immune clearance, the viral load could be below the detection limit of currently available assays when the patients are first seen at the time of severe liver damage.11 Hence, in the absence of serial serum samples, in particular those preceding the patient’s admission to hospital, early HCV viraemia may have been missed. In many series the diagnosis has been based on the presence of anti-HCV rather than HCV RNA in the serum and unlike HCV RNA, anti-HCV is usually not detectable for two to three months after the initial exposure and infection. With the short time course of illness, patients with fulminant hepatic failure may not survive long enough to develop detectable anti-HCV in the serum. In most of the studies tackling the issue of HCV aetiology in NANB fulminant hepatitis, serial serum samples during and after the illness are lacking. However, in a recent study by an NIH group, the level of HCV viraemia, as measured by branched-chain DNA assay, increased in parallel with serum alanine aminotransferase concentrations and the degree of hepatocellular necrosis, indicative perhaps of a direct cytopathic effect of the virus.12Accordingly, a single negative test for HCV RNA, by PCR, in a patient with fulminant hepatitis would rule out HCV as the cause. This finding certainly requires further validation.
As the various HCV genotypes have geographical preferences: 1b in Oriental countries and 1a in the USA, another possibility would be that the differences between East and West in fulminant NANB hepatitis are related to distinct HCV genotypes. This possibility was explored in the prospective study reported in this issue by Chuet al (see page 613). One hundred and nine consecutive HCV RNA positive patients with acute hepatitis admitted to a Taiwan hospital were investigated. Eleven patients (10.1%) developed fulminant hepatic failure but no correlation could be detected between the occurrence of fulminant hepatitis and HCV genotype. Other viral factors such as HCV viral load and coinfection with hepatitis G virus (HGV) were also investigated and were not found to be related to the occurrence of a fulminant course. One shortcoming was the lack of cases with genotype 1a in the current series which could have weakened the significance of the findings. In a recent human-to-chimpanzee transmission experiment, the same HCV strain, genotype 1a, which had been associated with two episodes of fulminant hepatic failure in a single patient, caused severe hepatitis in the chimpanzee. This suggested that genotype 1a—as most frequently found in the USA—can be directly related to the occurrence of severe liver damage.13
One important finding in the study by Chu et al was the presence of concomitant chronic hepatitis B virus (HBV) infection, as defined by positive HBV surface (HBsAg) and negative IgM anti-HBV core (HBc) antigens in nine (82%) of 11 subjects who developed fulminant hepatic failure compared with only 30/98 (31%) of those with non-fulminant acute HCV hepatitis (p<0.05). This is in keeping with a study from France which showed that eight (47%) of 17 HBsAg positive patients with fulminant hepatic failure were also HCV RNA positive, although on no occasion in that series was HCV infection alone demonstrable. Furthermore, Wright et al detected HBV DNA by PCR in the liver specimen from six of 12 patients with “NANB” fulminant hepatic failure treated by transplantation who had negative HBV serological markers and undetectable serum HBV DNA in the serum by PCR.2 It has also been shown that acute hepatitis C infection in patients with chronic HBV can suppress markers of HBV infection and even displace HBsAg from serum.14 15 Hence, in some instances of HCV superinfection of HBV carriers or concomitant dual infection, HBV serological markers may not be detectable and the severe liver damage may be attributed to HCV alone. It is also possible that without the co-factor of HBV infection—much more likely in areas of high prevalence as in the East—HCV will less frequently be the cause of fulminant hepatic failure. Whatever the inter-relation between HCV and HBV infection in the East, it is clear that in the West there is still a significant percentage of cases of fulminanthepatic failure from presumed viral hepatitis where no markers of hepatitis viral infection can currently be identified.
See article on page 613
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