Hepatocellular Carcinoma Research – Prof Michael Kew
Prof Michael Kew
Department of Medicine, Groote Schuur Hospital
Title of the project
The Aetiology and Pathogenesis of Hepatocellular carcinoma in Southern African blacks
Highlights of the project
There have been a number of highlights. We have provided the first evidence for the occurrence of occult hepatitis B virus infection in Black Africans with hepatocellular carcinoma (reference 5). By using very sensitive molecular techniques for detecting hepatitis B virus DNA we showed that the great majority of our Black patients with this tumour who showed serological evidence of past (but not present hepatitis B virus infection) were still actively infected with the virus (albeit at a low level).
It is now evident that about 90% of hepatocellular carcinomas in southern African Blacks are related to hepatitis B virus infection, making the causal association between the virus and the tumour even closer than was initially thought. We have continued with our research into possible mechanisms at the molecular level by which the hepatitis B virus causes hepatocellular carcinoma. We have shown that the G to T mutation at position 1862 in the bulge of the RNA encapsidation signal that causes a valine to phenyl alanine substitution in the hepatitis B virus e antigen (that we have previously found in Black African patients with hepatocellular carcinoma) results in a 54% reduction in the secretion of the e antigen from hepatocytes, with the mutant antigen accumulating in the endoplasmic reticulum, ERGI and Golgi and finally causing intracytoplasic aggresomes, which may play a contributory role in the genesis of chronic hepatic damage and possibly contribute to hepatitis B virus-induced malignant transformation (reference 4).
We have been the first to show that hepatic iron overload acts synergistically with alcohol in hepatic mutagenesis (reference 6). This is relevant in the African context because the iron overload results from the ingestion of home-brewed alcoholic beverages that have a high iron content. Iron overload is an important cause of hepatocellular carcinoma in sub-Saharan Africa. In following up our earlier observation that the hepatic mutagenesis in dietary iron overload is largely the result of the generation of reactive oxygen species and the consequent oxidative damage, we have examined the role of anti-oxidants in combating the mutagenesis induced by excess hepatic iron storage (reference 7).
We showed that administration of vitamins A and E did not prevent the hepatic mutagenesis. Because chronic hepatitis B virus and HIV infections are common in sub-Saharan Africa and the two infections often co-exist and may interact in the causation of hepatocellular carcinoma, we felt it important to establish to what extent occult hepatitis B virus infection was present in individuals chronically infected with HIV. We showed that occult hepatitis B virus infection was present in 88% of individuals with HIV who were positive for hepatitis B virus antibodies but negative for hepatitis B surface antigen (reference 9). Thus the association between the two viruses increased from 4.8% with overt hepatitis B virus infection to 15% with overt and occult infection.
- Kramvis A, Arakawa K, Yu MC, Noqueira R, Stram DO, Kew MC. Relationship of serological subtype, basic core promoter and precore mutations to genotypes/subgenotypes of hepatitis B virus. J Med Virol 2008; 80: 27-46.
- Kew MC. Hepatitis B virus infection: Burden of disease in South Africa. S Afr J Epidemiol Infect. 2008.
- Francois G, Mphahlele MJ, Leroux-Roels G, Kew MC, van der Heever J, Meheus A (eds). Childhood vaccination programmes in South Africa and Belgium: public health issues. S Afr J Epidemiol Infect 2008; 23: 1-60.
- Chen A, Kew MC, Crowther C, Kramvis A. A valine to phenylalanine mutation in the precore region of hepatitis B virus causes intracellular retention and impaired secretion of hepatitis B virus e antigen. Hepatol Res 2008; 38: 50-592.
- Kew MC, Welschinger R, Viana R. Occult hepatitis B virus infection in southern African Blacks with hepatocellular carcinoma. J Gastroenterol Hepatol 2008; 23: 1426-1430.
- Asare GA, Bronze M, Naidoo V, Kew MC. Synergistic interaction between excess hepatic iron and alcohol ingestion in hepatic mutagenesis. Toxicology 2008; 254: 11-18.
- Asare GA, Kew MC, Mossanda KS, Paterson AC, Siziba K, Kahler-Venter CP. Effects of endogenous antioxidants on dietary iron overload. J Clin Biochem Nutr 2009; 44: 85-94.
- Kew MC. Hepatic iron overload and hepatocellular carcinoma. In: Hepatocellular Carcinoma: Translational Research in Hepatocarcinogenesis. Cancer Letters. 2009. In press.
- Firnhaber C, Viana R, Reyneke A, Schultz D, Malope B, Sanne I, MacPhail AP, Dikisi AM, Kew MC. Occult hepatitis B virus infection in HIV positive patients in a Johannesburg HIV clinic. Int J Infect Dis. 2009. In press.
- Singh J, Pahal V, Kumar R, Chaudhary Kramvis A, Kew MC. First Report of Genotype E of Hepatitis B Virus in Indian Population. Intervirology. 2009. In press.
- Liu J, Kew MC, Arbuthnot P, Feitelson MA. Increased expression of c-erbB-2 in liver is associated with Hepatitis B x antigen and shorter survival of patients with liver cancer. Internat J Cancer. 2009. In press.
- Kew MC. Hepatocellular carcinoma: molecular biology and genesis. In: Principles and Practice.of Gastrointestinal Oncology. Kelsen DP, Levin B, Daly JM, Tepper JE, Kern E, Van Custem E, eds. Wolters Kluwer/ Lippincott, Williams & Wilkens. 2008; 405-418.
- Kew MC. Prevention. In: Hepatocellular carcinoma. JW Lau (ed). New Jersey: World Scientific. 2008; 85-128.
- Kew MC. Liver Cancer. In: International Encyclopedia of Public Health. Vol 4. Heggenhougen HK, Quah SR, eds. San Diego, Acadeomic Press. 20078: 105-114.
- Kew MC. Hepatitis B virus and hepatocellular carcinoma. In: Human Virus Guides 1. Hepatitis B virus. 2nd ed. Lai CL, Locarnini S, eds. London: Medical Press International. Chapter 14. 2008: 14.1-14.12.
How was this project of value in the struggle against cancer?
This project has been of value in the struggle against cancer in southern Africa in a number of ways. Not only is hepatocellular carcinoma among the most common malignant tumours in the Black African population, but it also carries a particularly grave prognosis in this population, the annual fatality ratio being 0.97 (the highest annual fatality ratio of any human tumour). The tumour is seldom amenable to operative intervention and is largely unresponsive to existing anti-cancer agents. Prevention of hepatocellular carcinoma is thus an urgent priority.
This project, which is directed towards ascertaining the causes and the pathogenetic mechanisms responsible for the malignant transformation with the ultimate aim of being able to prevent the tumour, is therefore important in the South African context. The research done to date in this project has uncovered the causes of most (but not all) the hepatocellular carcinomas that occur in the Black population and has created opportunities to prevent the tumour. This is best shown by the discovery that the single most important cause of hepatocellular carcinoma in Black Africans is chronic hepatitis B virus, by showing that this infection can be prevented by early immunization, and that this intervention will in due time have an enormous impact on the occurrence of this devastating tumour.
The research has also shed light on the other causes of the tumour (which often act synergistically with the hepatitis B virus). These causes include dietary exposure to aflatoxin B1 and dietary iron overload in the African. Both of the latter risk factors are preventable and the results of the local research can be used to encourage governmental agencies to take the necessary steps prevent these causes. Although we have defined the role of the hepatitis C virus in the causation of the tumour, no vaccine against this virus has yet been developed. It is therefore important that measures to prevent the spread of this virus should be introduced and the research done into this virus will be helpful ammunition in this regard.
Future plans with the project
With my re-location to the University of Cape Town I am continuing with my research programme into the Aetiology and Pathogenesis of Hepatocellular Carcinoma in southern African Blacks. It will take some time before the research programme is at the same level that it was in Johannesburg, but progress is being made and a number of new avenues into the causes of hepatocellular carcinoma in the Black African population are being researched.