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Message - August 26, 2001
Viral Load May Not Be Linked to Liver Damage



Increased intrahepatic hepatitis C virus (HCV) load may not be associated with more severe liver injury, according to a report from Australia.

The pathogenesis of HCV induced hepatic injury remains unidentified and could be attributable to either direct cytopathic damage by HCV or immune-mediated hepatic injury induced by HCV. It is also possible that both could act simultaneously.

"One way to identify whether liver damage is attributable to direct cytopathic damage is to examine whether the degree of viral load correlates with the degree of liver injury," researcher Peter H. McGuinness and colleagues wrote ("Intrahepatic HCV RNA Levels Do Not Correlate with Degree of Liver Injury in Patients with Chronic Hepatitis C," Hepatology, April 1996;23(4):676-687).

"Most studies addressing this question have measured the amount of HCV in serum. Ideally, HCV RNA viral load should be estimated directly from liver tissue itself, because serum levels of virus may be contributed to and influenced by extrahepatic sources. Also, the presence of serum immune complexes may introduce further variables. Doubt has also been raised as to the validity of HCV RNA quantitation in serum compared with plasma."

HCV has been shown to consist of many distinct genotypes, and while some investigations have found a link between genotype and the severity of liver disease, others have not.

"This may be because of the geographical difference in genotype populations, " McGuinness and colleagues wrote. "Most studies may be biased toward a subset of genotypes. This may obscure relationships between genotypes and pathogenicity.

"Many researchers have compared HCV load with genotype in blood. Most have demonstrated that genotype 1b tends to be associated with the highest HCV RNA levels. In contrast, there has been no analysis of the effect of different genotypes on intrahepatic HCV RNA levels. Therefore, an analysis of intrahepatic HCV RNA levels must take into account the effect of these genotypes."

In this study McGuinness et al. attempted to determine whether there was a correlation between liver HCV RNA load and the degree of liver injury and to examine the effect of interferon alpha (INF-(alpha)) treatment on hepatic HCV RNA load.

Liver tissues (n = 56) were obtained from 47 patients with chronic HCV (nine before and after IFN-(alpha) therapy). Total RNA was isolated and quantitated for specific HCV RNA by dot-blot polymerase chain reaction (DB-PCR) using a standard curve created from synthetic HCV RNA of known titer to calculate actual RNA levels.

A multivariate analysis was undertaken to determine the relationship of intrahepatic HCV RNA levels with risk factors, length of HCV exposure, and histological injury scores. The confounding effect of HCV genotype was examined by direct sequencing of the NS5b region. Liver HCV RNA ranged from 10(2) to 3.1x10(7) molecules per microgram total liver RNA.

"The multiple regression analysis showed no effect of length of HCV exposure, risk factors, degree of bile duct damage, steatosis, or total Scheuer or Knodell score on RNA levels," McGuinness et al. wrote. "No significant confounding effect of HCV genotype on the degree of liver injury was observed. However, genotype 1b had a significantly higher mean intrahepatic HCV RNA load compared with the other genotypes detected."

In the nine patients who received IFN-(alpha) treatment, seven had no detectable HCV after treatment. This was associated with a significant decrease in intrahepatic HCV RNA levels (7.57 +/- 2.53x10(5) to 1. 82 +/-1.80x10(3) molecules per microgram total liver RNA +/- SEM, n = 9m P = ..0005).

The authors conclude that intrahepatic viral load appears to be significantly increased in patients with genotype 1b, but their results do not support the hypothesis that increased intrahepatic HCV load is associated with more severe liver injury.

"These data suggest that the HCV virus does not cause liver injury by simply expanding the viral load and thus resulting in a cytopathic process," McGuinness et al. wrote. "The role of intrahepatic anti- HCV-specific and nonspecific immune responses therefore needs to be examined. It is clear that anti-HCV-specific and nonspecific immune responses are detected in this disease. Their role and the role of intrahepatic cytokine responses in the induction of chronic HCV liver injury clearly require further investigation. Careful sequential studies that simultaneously examine both the virus and the immune response in liver tissue and serum are also clearly needed."

The corresponding author for this study is Geoffrey W. McCaughan, The A.W. Morrow Gastroenterology and Liver Center, Royal Prince Alfred Hospital, Missenden Road, Camperdown NSW 2050, Australia.

Hepatitis Weekly, 05-06-1996, pp 2.


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