KINESIOL 1Y03 Lecture Notes - Lecture 15: Ribavirin, Aflatoxin B1, Hbeag
23 Jun 2018
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Viral hepatitis and HCC
Epi of HCC
Worldwide = 625000 case per year -2002, 5th commonest in the world
Highest in W.Africa / E.Asia > southern Europe > northern europe
Incidence = mortality i.e. most dies
Increasing
M>F by 4:1!
Worldwide geographical distribution of hep B and HCC similar
HCC commonest complication of compensated viral cirrhosis; linear association between
years of cirrhosis and HCC risk –Alberti et al 2004
Hep B and hep C co-infection has highest risk of HCC
Hep A not a cause of liver disease as only acute
Hepatitis B and HCC
Neonatal infection is more likely to cause chronic infection (95-100%) c.f. 5% persistent
infection in exposed adults
Hepatitis B has direct as well as indirect carcinogenic mechanisms i.e. cirrhosis is not
required to cause HCC; this is proven as DNA titre correlates with HCC risk independent of
other risk factors– Chen et al 2006; biological gradient of HCC risk by HBV DNA level from
undetectable upwards – risk increases significantly above 100, 000cml, and is present
>10cml
HBsAg can be derived from mature virions and defective particles, not just actively
replicating infected cells (unlike HepB DNA)
REVEAL study showed it to correlate with HCC risk useful in inactive carriers with low HepB
DNA
Genotype C (and B and F) may be associated with increased risk of HCC
Gentyope B affects yunounger non-cirrhotic patient c.f. genotype C
Pathogenesis – direct viral effect:
1. HBV DNA integrates within the chromosomes of infected hepatocytes. If it integrates within
critical location e.g. retinoic acid receptor alpha gene or human cyclin A gene (which are
crucial in cell growth) this has a pro-carcinogenic effect
2. Produces HBx protein (a transcriptional activator) which activates the Ras-Ras-MAPK
pathway, interacting with p53
- duck Hep B (DHBV) lacks an equivalent to HBx and doesn’t cause HCC
3. HBV mutants emerge due to errors in reverse transcription and anti-viral therapy:
- dual mutations in basal core promoter (BCP): has OR of 10.6 for HCC progression c.f.
inactive carriers
- Pre-S mutation: OR of 3.73 - deletions cause accumulation of surface protein in ER ER
stress oxidative damage induces mutagenesis in host genome HCC
Pathogenesis – indirect viral effect:
Pathogenesis thought to lie in persistant infection inflammation increased cell turnover in
cirrhosis forming an opportunity for mutations
Evidence for:
70% HBV-associated HCC occurs in cirrhosis
Cirrhosis of any cause associated with HCC
N.B. in animal models, only woodchuck hepatitis B (WHV) causes HCC
find more resources at oneclass.com
find more resources at oneclass.com
Document Summary
Worldwide = 625000 case per year -2002, 5th commonest in the world. Highest in w. africa / e. asia > southern europe > northern europe. Worldwide geographical distribution of hep b and hcc similar. Hcc commonest complication of compensated viral cirrhosis; linear association between years of cirrhosis and hcc risk alberti et al 2004. Hep b and hep c co-infection has highest risk of hcc. Hep a not a cause of liver disease as only acute. Neonatal infection is more likely to cause chronic infection (95-100%) c. f. Hbsag can be derived from mature virions and defective particles, not just actively replicating infected cells (unlike hepb dna) Reveal study showed it to correlate with hcc risk useful in inactive carriers with low hepb. Genotype c (and b and f) may be associated with increased risk of hcc. Gentyope b affects yunounger non-cirrhotic patient c. f. genotype c. Pathogenesis direct viral effect: hbv dna integrates within the chromosomes of infected hepatocytes.
