Hepatitis B Virus HBV

HBV is one of a group of viruses known as Hepadnaviruses which affect humans (HBV) and certain animals such as the woodchuck (WHV), ground squirrel (GSHV) and duck (DHV). All of these cause liver disease: acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma, in their respective hosts. In humans, transmission is mainly via blood or blood products, contaminated instruments, male homosexual contact and, most important, from mother to infant at birth. HBV is a partly double-stranded DNA virus possessing a genome consisting of four open reading frames which encode for four different proteins, surface

Table 2 Aetiology of hepatocellular carcinoma (male :female=2-4:1)

Agent

Prevalence

Magnitude

of risk

HBV

High

High

HCV

High

High

Alcohol

High

Low

Chemicals and

High

Low

drugs

Aflatoxin

Low

Moderate

Membranous obstruction

Low

Moderate

of IVC

Haemochromatosis

Moderate

Moderate

AAT deficiency

Low

Low

Tyrosinaemia

Low

High

Glycogen storage

Low

Low

disease

Porphyria

Low

Low

(HBsAg) and core (HBcAg) antigens, DNA polymerase and the X protein. The 'e' antigen (HBeAg) is closely associated with HBcAg. Replication takes place through reverse transcriptase and the virus is capable of integration into the host cell's genome. Most of the antigens and antibodies directed against them are demonstrable in the serum at one time or another during acute and chronic infections and the pattern of their presence is predictive of course, stage of disease and outcome. Levels of these 'marker' proteins decline in time as replication ceases and the virus becomes undetectable, but it remains in an integrated form in the nuclei of liver cells. The risk of malignant transformation relates both to the infective, replicative phase when continuing liver cell damage leads to hepatitis and cirrhosis, and to the non-replicative, integrated phase when carcinogenic events occur (Idilman et al., 1998; Chen and Chen, 1999; Schafer and Sorrell, 1999).

Chronic HBV infection is common in tropical Africa, South-East Asia and Oceania; it is uncommon in Western Europe, North America and Australia and an intermediate prevalence is seen in the Mediterranean countries, the Middle East and India. Indeed, maps can be constructed to show almost identical frequencies of HBV carriage rates and incidence of hepatocellular carcinoma, as this virus accounts for up to two-thirds of all cases of the tumour and more in some areas. It is generally accepted that a particularly high risk of chronic infection, with the subsequent development of cirrhosis and hepatocellular carcinoma, is associated with infection at or near birth or in childhood, which happens in tropical Africa and South-East Asia. Elsewhere, those most commonly affected are adults in high-risk groups, e.g. intravenous drug addicts, homosexuals, prostitutes and inmates of prisons or mental institutions. Individuals who received transfusions of blood and blood products prior to the institution of effective screening of donors in the 1980s are also at risk. Most of those who have chronic infection remain symptomless for many years and are known as carriers.

The strength of the association of HBV and hepato-cellular carcinoma, however, rests on multiple lines of evidence which are listed in Table 3. Numerous case-control studies were carried out in the 1970s and 1980s to show a much higher prevalence of HBV markers in the blood of patients with hepatocellular carcinoma than in controls, whether these were healthy individuals or hospital patients with other types of diseases including cancer. Infection precedes the development of the tumour by two to three decades on average and long-term follow-up studies established the measure of the risk. The best known of these was carried out on government employees in Taiwan, a high-incidence area for both HBV infection and hepatocellular carcinoma. They were chosen because all had life insurance policies provided by the State and an accurate record of causes of illness and death was readily available. The relative risk of developing the tumour, by

Table 3 Hepatitis viruses and hepatocellular carcinoma

HBV

HCV

Infection is associated

Yes

Yes

with tumour (case/control)

Infection precedes

Yes

Yes

tumour (follow-up)

Tumour DNA contains viral

Yes

No

genomic element (integration)

Tumour in culture produces

Yes

No

viral component

Virus transforms cells in culture

No

No

Virus produces tumours in

Yes

Yes

transgenic mice

Virus induces tumours in animals

Yes

No

Eradication of virus leads to

Yes

Not known

decrease of tumour decrease of tumour those who tested positive for HBV markers at the outset over those who did not, turned out to be nearly 100-fold 10 years later (Beasley, 1988), a much higher figure than the relative risk of lung cancer in smokers over non-smokers. Replicative HBV is not detectable in hepatocellular carcinoma tissue or cell lines but antigenic components such as HBsAg rarely are. The virus is not directly oncogenic in the sense that it does not transform cells in culture. However, it does produce hepatocellular carcinomas when its genome is incorporated in the germ line of mice in transgenic experiments. HBV-like hepadnaviruses also produce the tumour in their respective hosts, particularly the woodchuck. The most important event in hepatic carcinogenesis by HBV is its integration in the DNA of liver cell nuclei. No consistent site exists and it appears to be random and multiple. However, insertion of HBV in the genome leads to its destabilization and chromosomal abnormalities are common, a process known as insertional mutagenesis. In addition, two transactivating proteins have been identified; one is encoded for in the pre-S2 region of the gene coding for HBsAg and the other is the HBX protein. Of the two, the latter is of greater interest (Feitelson and Duan, 1997; Idilman et al., 1998; Chen and Chen, 1999). Transactivation in this context means the ability to modify the action of host genes at a distance from the integration site. Most hepatocellular carcinomas contain oncogenes (e.g. ras, myc, fos) and/or anti-onco-genes or tumour suppressor genes (e.g. p53, Rb) which have been made by HBX to be overexpressed or inactivated. These events, in turn, lead to changes in growth factors, cell cycle regulators and DNA repair which are relevant to carcinogenesis but no coherent pathway has yet been elucidated. Mass vaccination of infants against HBV in high-risk areas such as Taiwan and the Gambia began in the mid-1980s and has proved to be effective in preventing chronic infection, with a fall in the number of childhood hepatocellular carcinomas to a quarter of the previous level. (See the chapter Human DNA Tumour Viruses.)

A Disquistion On The Evils Of Using Tobacco

A Disquistion On The Evils Of Using Tobacco

Among the evils which a vitiated appetite has fastened upon mankind, those that arise from the use of Tobacco hold a prominent place, and call loudly for reform. We pity the poor Chinese, who stupifies body and mind with opium, and the wretched Hindoo, who is under a similar slavery to his favorite plant, the Betel but we present the humiliating spectacle of an enlightened and christian nation, wasting annually more than twenty-five millions of dollars, and destroying the health and the lives of thousands, by a practice not at all less degrading than that of the Chinese or Hindoo.

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