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High Levels of Hbsag Increase HCC Risk in Patients with Low HBV Load
http://www.gastrojournal.org/article/S0016-5085(12)00172-2/abstract

Abstract
Background & Aims
Patients with chronic hepatitis B virus (HBV) infection have a high risk for developing hepatocellular carcinoma (HCC). Patients with lower levels of hepatitis B surface antigen (HBsAg) have higher chances of losing HBsAg than those with high levels. However, little is known about whether higher levels of HBsAg increase the risk for HCC.

Methods
We followed 2688 Taiwanese HBsAg-positive patients without evidence of cirrhosis for a mean time period of 14.7 years. In addition to known risk factors of HCC, we investigated association between levels of HBsAg and the development of HCC.

Results
Of the patients followed, 191 developed HCC, with an average annual incidence rate of 0.5%. Baseline levels of HBsAg and HBV were associated with the development of HCC, and risk increased with level. Compared to HBsAg level, by receiver operating characteristic curve analysis, HBV DNA level better predicted the development of HCC over 10-year and 15-year periods (both P<.001). However, when we evaluated hepatitis B e antigen (HBeAg)-negative patients with levels of HBV DNA <2000 IU/mL, factors that determined HCC risk included sex, age, and levels of alanine aminotransferase (ALT) and HBsAg (≧1000 IU/mL), but not level of HBV DNA. Multivariate analysis showed that the adjusted hazard ratio for HCC in patients with levels of HBsAg ≧1000 vs <1000 IU/mL was 13.7 (95% confidence interval, 4.8–39.3).

Conclusions
Among patients infected with HBV genotypes B or C, determinants of HCC risk include their sex, age, HBeAg status, HBV genotype and levels of ALT and HBV DNA, but not level of HBsAg. Among HBeAg-negative patients with low viral loads, HCC risk is determined by levels of HBsAg and ALT and age, but not HBV DNA.

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Interesting. This is a very fine observation. I wonder what it is telling us.
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i link this study to other studies posted long time ago where it was found that decrease of hbsag to more than 50 or 70%, dont remember exactly, was followed by HCC reduction too

i think there is one thing inaccurate in this study, but maybe it is present in full article.hbsag mutations levels and hbsag wild type levels, because we do know some hbsag mutations increase HCC risk very much

hbsag mutants are also more common on hbeag negative although we have few studies on hbsag mutants, i just read some italian studies on this
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Studies showed reducing hbv dna reduces the risk of HCC. This study said within low hbv dna, reducing HBsAg reduces the risk of HCC further. But why?
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But why?

i think no study has yet explained why hbsag can increase hbsag risk.

my guess is:
hbsag like hbvdna is produced with errors and mutations, maybe some type of hbsag is not secreted by the cells and remaining inside cells increases oxidative stress damaging dna, if dna is not repaired this can foolow up with HCC

i am sorry this is italian but this study on hbsag types (wild/mutant present at same time) can be of some interest

Mutazioni a carico della regione pre-s del genoma di hbv non influenzano i livelli di HbsAg sierico nei portatori HBeAg negativi, ma correlano con l'età e lo stadio di malattia

Mutations in the pre-S region of the genome of hbv dont affect the levels of serum HBsAg in HBeAg negative carriers, but  are correlated with age and stage of disease

http://www.tigicongress.com/tigicongress/relazioni-online/visualizzavideo/891/xi-riunione-annuale-et/28-mutazioni-a-carico-della-regione-pre-s-del-genoma-di-hbv-non-influenzano-i-livelli-di-hbsag-sierico-nei-portatori-hbeag-negativi-ma-correlano-con-leta-e-lo-stadio-di-malattia
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how about the other mentioned indicators ALT and AGE ? are this corelate with HBsAg ?
and also do you know a similar study regarding other genotypes ? (HBsAg > 1000 UI/ml is high in case of B and C but in caze of D high can be > 10.000, how about A ....)
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i dont think these studies are so important, in case of geno b and c tdf or etv and then interferon add on should be used anyway to lower hbsag and reduce hcc risk to minimum

as regards d genotype only fibrosis/cirrhosis increase hcc risk from statistical studies.
those ones who clear hbsag with crrhosis and no fibrosis regression are at increased risk for HCC anyway, while those clearing hbsag and regressing liver damage to mild or no fibrosis have insignificant hcc risk

on geno d it looks like hcc is the same in those with insignificant fibrosis and hbsag+ but hbvdna und and those who cleared hbsag and hbvdna und, so i d say that fibrosis and hbvdna are the most important hcc risks on geno d
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