1. Exposure Data

1.1. Taxonomy, structure, and biology

1.1.1. Taxonomy

The hepatitis B virus (HBV) is the prototype member of a family of hepatotropic DNA viruses, the Hepadnaviridae, that replicate by reverse transcription of an RNA pregenome. HBV infects humans, whereas other hepadnaviruses infect mammals (orthohepadnaviruses) or birds (avihepadnaviruses) (Schaefer, 2007a).

HBV comprises eight genotypes (A to H) with distinct virological characteristics and geographic distributions (Kramvis et al., 2005; Schaefer, 2007a; see Section 1.2.3). Each genotype differs from the others by more than 8% of its nucleotide sequence. Genotypes may influence the disease caused, although further analysis of this association is required. The variability of the HBV genome may be further increased by recombination among genotypes, especially B/C and A/D.

HBV genotypes, with the exception of genotypes E and G, are divisible into subgenotypes. Each subgenotype differs from the others by more than 4% of its nucleotide sequence. The number of subgenotypes per genotype described to date ranges from three to five (Kramvis et al., 2005; Schaefer, 2007a).

1.1.2. Structure of the virion

HBV is an enveloped virus, measuring 42–47 nm in diameter, with an icosahedral nucleocapsid that encloses a partially double-stranded relaxed-circular (rc) DNA genome covalently bound to the viral polymerase. The envelope comprises a small amount of lipid of cellular origin and three hepatitis B surface proteins (HBs): large (LHB), medium, (MHB), and small (SHB), which form disulfide-linked homo- and heterodimers. The serum of infected individuals contains, in addition, two types of subviral particles: small spherical particles with a diameter of approximately 20 nm and filamentous particles also with a diameter of about 20 nm but of variable length. These non-infectious subviral particles lacking genomic DNA greatly outnumber the infectious viral particles, and have a composition similar to that of the viral envelope (Kann, 2002).

The nucleocapsid is formed by multiple copies of core protein. Of the total 183–185 amino acids (depending upon genotype), the N-terminal 149–151 amino acids are responsible for self-assembly of the nucleocapsid. Although the steps in its assembly remain to be clarified, the first step is the formation of homodimers linked by disulfide bridges. The nucleocapsid contains pores that allow the diffusion of nucleotides during the synthesis of the DNA genome. The C-terminal amino acids of the core protein play a role in the packaging of the pregenome–polymerase complex within the nucleocapsid (Bruss, 2007).

1.1.3. Structure of the viral genome

HBV has a partially double-stranded but not covalently closed circular (ccc) DNA genome composed of between 3182–3248 nucleotides, depending on the genotype. The genome consists of a complete minus-DNA strand with a short-terminal redundancy, and a shorter plus-DNA strand that leaves a single-stranded gap of variable length in mature nucleocapsids and released viruses (Kann, 2002; Jilbert et al., 2002). Base-pairing of plus- and minus-strands in the cohesive overlap region of the genome maintains the circular configuration. The 5′end of the minus-strand is covalently linked to the N-terminal portion of the viral polymerase. At its 5′end, the plus-strand is linked to a capped RNA oligonucleotide that is derived from the 5′end of the RNA pregenome, and serves as the primer for plus-strand-DNA synthesis.

The genome consists of four partially overlapping open reading frames (ORFs) (Kann, 2002) that express surface, precore/core, polymerase, and X proteins. Each ORF overlaps at least one other ORF, with the polymerase ORF overlapping all of the others, and every nucleotide is part of at least one ORF. Translation of preS1, preS2, and S ORFs leads to the expression of the surface proteins, LHB, MHB, and SHB, respectively (Fig. 1.1).

Fig. 1.1

Transcriptional and translational map of HBV

Four promoters (preC/C, preS1, S, and X) and two enhancers (Enh1 and Enh2) overlap the ORFs (Kann, 2002). The promoters initiate the transcription of messenger (m) RNAs of 3.5, 2.4, 2.1 and 0.9 kb that allow, by the use of different start codons, the expression of seven proteins. All are of positive orientation, possess a 5′cap, are polyadenylated at their 3′ends, and serve as mRNAs for viral gene products. Enh1, which stimulates the transcription of all viral RNAs, is located between the S and X ORFs, and Enh2, a less potent enhancer, overlaps the preC/C promoter.

In addition to the enhancers, other regulatory elements have been identified: a glucocorticoid responsive element (GRE) is located between Enh1 and Enh2; a CCAAT element regulates the transcription of the upstream preS1 promoter, and activates the transcription of S mRNA; and a negative regulatory element (NRE) appears to inhibit only the precore/core mRNA (Kann, 2002).

1.1.4. Host range

HBV primarily infects humans, although chimpanzees, Chacma baboons, and tree shrews are also susceptible to infection (Hu et al., 2000; Cao et al., 2003).

1.1.5. Target cells

HBV is primarily an hepatotropic virus, and hepatocytes are the only confirmed site of replication for all members of this virus family. Although the virus has been detected in other cells such as bile duct epithelial cells, peripheral blood mononuclear cells and cells in the pancreas and kidneys, the evidence for viral replication in these cells is controversial (Seeger & Mason, 2000).

1.1.6. Function of the gene products

(a) Surface proteins

The HBV surface protein: small (SHB), medium (MHB) and large (LHB), together with cellular lipid material, form the viral envelope (Kann, 2002).

SHB antigen which represents 85% of hepatitis B surface antigen (HBsAg), is highly immunogenic and provokes the host’s immune response to HBV. Excess surface protein circulating in subviral particles is thought to dilute the host’s immunological response to the virus.

LHB, in contrast to MHB, is essential for infection and viral morphogenesis. It represents 10–30% of the HBsAg of virions and filaments. LHB plays a role in viral entry into hepatocytes, although SHB may also be needed in this process (Kann, 2002).

(b) Core protein and ‘e’ antigen

Core protein (C) is the major structural component of the nucleocapsid. The preC/C ORF is transcribed into a precore/core fusion protein. During entry into the endoplasmic reticulum, 19 amino acids are cleaved from the N-terminal end of the precore protein by a signal peptidase. When transported into the Golgi compartment, additional amino acids are removed from the C-terminal end by intra-Golgi proteases to form HBe antigen. This antigen is secreted into the serum. The biological function of HBe remains unsolved (Kann, 2002).

(c) Polymerase protein

Polymerase (P) has four domains: a terminal domain, which serves as a protein primer for reverse transcription of pregenomic viral RNA; a spacer region without apparent function; the polymerase domain, which has reverse transcription activity; and the RNase H domain, which is responsible for the degradation of the RNA template during reverse transcription (Kann, 2002).

(d) X protein

The X protein (HBx) has been shown to be a promiscuous regulator of transcription that is essential for viral replication. Although not binding itself to DNA, it regulates transcription from HBV enhancers/promoters, and from the promoters of cellular genes, including oncogenes, cytokines, growth factors, and several genes involved in cell-cycle control and progression, DNA repair, apoptotic cell death, and cellular adhesion. HBx also forms complexes with several signal transduction proteins and regulators of cell growth and survival (Murakami, 1999; Feitelson et al., 2005; Benhenda et al., 2009). It is suspected to play a central role in HBV regulation and pathogenesis (see Section 4).

1.1.7. Viral life cycle

During both acute and persistent infection, high levels of infectious HBV particles (virions) circulate in the bloodstream, together with an excess of empty particles.

Hepatocytes, the major targets of the virus, are separated from the bloodstream by endothelial and Kupffer cells that line the sinusoids of the liver. Liver sinusoidal endothelial cells have long cytoplasmic components that contain fenestrations with a diameter of 50–100 nm. Virions are thought to pass through these fenestrations from the sinusoids of the liver to the space of Disse, which is immediately adjacent to the surface of the hepatocytes. Infectious virions bind by means of the PreS1 domain of LHBs (and perhaps by the envelope lipid) to specific, as yet unidentified, receptors on the hepatocyte surface (Seeger & Mason, 2000; Jilbert et al., 2002; Beck & Nassal, 2007; Kann et al., 2007).

HBV then proceeds following a characteristic replication strategy shared by all the members of the hepadnaviridae family (Fig. 1.2; Seeger & Mason, 2000; Jilbert et al., 2002; Beck & Nassal, 2007; Kann et al., 2007). The nucleocapsid is released into the cytoplasm and translocated by microtubules to the microtubule-organizing centre (MTOC) near the nucleus. How the nucleocapsid gets from the MTOC to the nucleus is not known at the time of writing. Access to the nucleus is gained through nuclear pores (Kann et al., 2007), and may be mediated by polymerase or heat shock proteins. The exact stage and mechanism by which the viral genome is released from the nucleocapsid is not currently known. In the nucleus, rc-DNA is converted into cccDNA, the key template in HBV replication. The steps in achieving this conversion are uncertain, but they include completion of the positive DNA strand by polymerase; removal of the covalently linked polymerase, the 5′capped oligonucleotide primer (and the terminal redundancy), and ligation of the 5′ and 3′ends of the positive and negative DNA strands.

Fig. 1.2

Replication cycle of Hepanaviral genome

Several genomic and subgenomic RNAs are transcribed by cellular RNA polymerase II using cccDNA as the transcriptional template. Of these, the polyadenylated pregenomic RNA, with a length corresponding to the entire genome length plus a terminal redundancy of 120 nucleotides, is selectively packaged into nucleocapsids. It is then reverse-transcribed by the co-packaged polymerase into new rc-DNA genomes. Following encapsidation of the pregenomic RNA-polymerase complex, polymerase initiates negative-strand DNA synthesis by reverse transcription (Jilbert et al., 2002).

The synthesis of polymerase and core proteins is accomplished by two translation events (Jilbert et al., 2002). The mechanism that allows translation from the downstream polymerase protein start codon is not yet known, but may include a direct internal ribosomal entry-site-like binding of the ribosomal subunits at, or near to, the polymerase start codon, “leaky’ scanning of the ribosomes that allow passage to the downstream start codon, or the presence of a ‘minicistron’ upstream of the polymerase ORF that is translated (Jilbert et al., 2002).

1.2. Epidemiology of infection

HBV is one of the most common infectious viruses worldwide. It is estimated that more than two billion people are infected. Approximately 360 million of these are chronically infected (Lee, 1997; Chen et al., 2007a; Dienstag, 2008). Approximately one million people die each year from HBV-related chronic liver disease, including liver cirrhosis and hepatocellular carcinoma (HCC) (Mahoney, 1999). HCC is one of the most common cancers in the world, and chronic HBV infection is responsible for 50–90% of HCC in high-risk areas (Chen et al., 1997).

1.2.1 Prevalence, geographic distribution

There is a wide variation of HBV infection in the world as shown in Fig. 1.3 (Custer et al., 2004; CDC, 2012). Approximately 45% of the world population lives in areas where chronic HBV infection is highly endemic (> 8% of the population are HBsAg-positive); 43% live in areas where endemicity is intermediate (2–7% HBsAg-positive); and 12% live in areas where endemicity is low (< 2% HBsAg-positive). The prevalence of chronic HBV infection is lowest in North America, Northern and Western Europe, Australia and New Zealand; intermediate in Japan, the Middle East, Eastern and Southern Europe and parts of South America; and highest in sub-Saharan Africa, the Amazon Basin, the People’s Republic of China, the Republic of Korea, Taiwan (China), and several other countries in South-east Asia (Chen et al., 2000; Custer et al., 2004).

Fig. 1.3

Prevalence of chronic infection with hepatitis B virus, 2006

The worldwide variation in the endemicity of HBV infection is influenced primarily by the predominant age at which infection occurs and the modes of transmission by which it occurs. In areas of high endemicity, the lifetime risk of HBV infection is more than 60%, and most infections are acquired from perinatal and child-to-child transmission, when the risk of developing chronic infection is greatest. In these areas, acute hepatitis B is uncommon because most perinatal and early childhood infections are asymptomatic. However, rates of liver cancer and cirrhosis in adults are very high. Chronic carriage is thought to result from vertical transmission in China, Taiwan (China), and the Republic of Korea (Chen et al., 2000). Of note, HBV infection in newborns is less common in Africa. A lower prevalence of HBeAg positivity has been observed in mothers from sub-Saharan Africa compared with mothers in Asia. Child-to-child horizontal transmission accounts for high hepatitis B infection in this region of Africa.

In areas where endemicity is intermediate, mixed patterns of transmission exist, including infant, early childhood, and adult transmission. In low endemicity areas, most HBV infections occur in adolescents and young adults with relatively well defined high-risk groups, including injection drug users, homosexual males, health care workers, and patients who require regular blood transfusion or haemodialysis. In countries where adult horizontal transmission patterns are the principal transmission routes, the incidence of HBV infection is highest in adults (Custer et al., 2004).

HBV is a prototype member of the hepadnavirus family. Currently, eight genotypes of HBV (A through H) have been identified on the basis of greater than 8% nucleotide divergence over the whole genome (Devesa et al., 2004). Genotype A is prevalent in Europe, Africa, and North America. Genotype B is prevalent in Taiwan (China), China, Thailand, South-east Asia, and genotype C is prevalent in China, Japan, the Republic of Korea, and South-east Asia. Genotype D is predominant in India, Mediterranean areas, and the Middle East region. Genotype E is limited to West Africa. Genotypes F and G are mostly found in Central and South America. Genotype H has been observed in Mexico and Central America (see Table 1.1).

Table 1.1

Global distribution of HBV genotypes.

Compared with patients infected with the HBV genotype B, those infected with genotype C have a significantly lower rate of spontaneous HBeAg seroconversion (Furusyo et al., 2002; Kao et al., 2004), a higher histological activity index of necroinflammation or fibrosis score (Lindh et al., 1999; Chan et al., 2002; Kobayashi et al., 2002; Lee et al., 2003a), and a higher risk of developing acute exacerbations (Chu et al., 2002; Kao et al., 2004), reactivation of HBV (Chu & Liaw, 2005, 2007), end-stage liver disease (Kao et al., 2000; Chan et al., 2003; Chu & Liaw, 2005), and HCC (Yu et al., 2005; Yang et al., 2008).

1.2.2. Transmission and risk factors for infection

HBV is highly contagious and is transmitted by percutaneous and permucosal exposure to infected blood and other body fluids (i.e. semen and vaginal fluid). The highest concentrations of the virus occur in blood and wound secretions (WHO, 2001). Moderate concentrations of HBV are found in semen and vaginal fluid, and lower concentrations occur in saliva. HBV is not spread by air, food, or water. Common modes of transmission include mother-to-infant, child-to-child, unsafe injection practices and blood transfusions, and sexual contact. HBV may be detected in serum 30–60 days following infection, and may persist for widely variable periods of time.

Perinatal transmission from HBsAg-positive mothers to their newborn infants (vertical) or transmission from one child to another (horizontal) is a major source of HBV infections in many countries where chronic HBV infection is highly endemic (WHO, 2001). Perinatal transmission usually happens at the time of birth; in-utero transmission is relatively rare, accounting for less than 2% of perinatal infections in most studies. There is no evidence that HBV can be spread by breastfeeding (Beasley et al., 1975). The risk of perinatal transmission depends on the HBeAg serostatus of the mother. The risk of HBV infection approximately ranges from 70–90% for HBeAg-positive mothers to 5–20% for HBeAg-negative mothers (Okada et al., 1976; Beasley et al., 1977). The spread of HBV from child to child usually happens in household settings but may also occur in child daycare centres and schools (WHO, 2001). The most probable pathways of child-to-child spread involve contact of skin sores, small breaks in the skin, or mucous membranes with blood or skin sore secretions (Margolis et al., 1997). HBV may also spread because of contact with saliva through bites or other breaks in the skin, and as a consequence of the premastication of food (MacQuarrie et al., 1974; Scott et al., 1980; Beasley & Hwang, 1983; Williams et al., 1997). The virus may spread from inanimate objects such as shared towels or toothbrushes, because it can survive for at least 7 days outside the body, and can be found in high titres on objects, even in the absence of visible blood (Petersen et al., 1976; Bond et al., 1981; Martinson et al., 1998). Among Gambian children aged 6 months to 5 years, a significant association was observed between HBV infection and the presence of bedbugs in each child’s bed (Vall Mayans et al., 1990). But controlling bedbugs by insecticide spraying of the child’s dwelling did not have any effect on HBV infection (Vall Mayans et al., 1994).

Unsafe injection practices such as the re-use of a syringe or needle from patient to patient without sterilization are a common source of transmission of HBV in many developing countries (Kane et al., 1999; Simonsen et al., 1999). In addition, unsatisfactory infection control practices, including the re-use of contaminated equipment for medical, cosmetic or dental procedures, failure to use appropriate disinfection and sterilization practices for equipment and environmental surfaces, and improper use of multidose medication vials, can also result in the transmission of HBV. Blood transfusion is also a common source of HBV transmission in countries where the blood supply is not screened for HBsAg. In addition, the injection of illicit drugs using shared needles is a common mode of HBV transmission in many developed countries.

HBV is efficiently transmitted by sexual contact, which accounts for a high proportion of new infections among adolescents and adults in countries with low and intermediate endemicity of chronic HBV infection (Alter & Margolis, 1990). Risk factors for sexual transmission include multiple sexual partners, prostitution, and lack of protection in sexual activity (e.g. the use of condoms). In countries where HBV infection is highly endemic, sexual transmission does not account for a high percentage of cases because most persons have been infected since childhood.

1.2.3 Persistence, latency, and natural history of infection

Persons infected with HBV have both short-term and long-term outcomes. On becoming infected, a person can have either a symptomatic disease (i.e. acute hepatitis B), or an asymptomatic infection with no signs or symptoms of disease. In persons with acute hepatitis B, the incubation period after becoming infected is usually 3–4 months, with a range of 6 weeks to 6 months. Symptoms and signs of disease usually last for several weeks. About 1–2% of persons with acute hepatitis B die from fulminant hepatitis. Both symptomatically and asymptomatically infected persons may either recover from the infection and develop lifelong immunity, or develop a chronic infection that usually lasts throughout life. Persons affected with chronic infection often do not become sick from their infection for decades after becoming infected. However, about 25% of those who become chronically infected during childhood and 15% of those who acquire chronic infection at older ages develop either HCC or cirrhosis.

The age at which a person becomes infected with HBV is the main factor determining the risk of developing chronic infection. Among children who are under 5 years of age when they become infected, fewer than 10% are symptomatic. However, 80–90% of those infected infants and 30–50% of children infected between 1–4 years of age develop a chronic infection. In contrast, 30–50% of adults are symptomatic when first infected but only 2–5% of adults develop a chronic infection. Most of the disease burden associated with HBV infection is in persons who develop the chronic condition.

Thus, the natural course of chronic HBV infection is highly variable at an individual level but also varies with age of infection. The classical description of the natural history of chronic HBV infection is shown in Fig. 1.4 (Chen et al., 2007a; Dienstag, 2008). Early life/perinatal infection is characterized by a period of ‘immune tolerance’ where the host co-exists with the virus without apparent injury to the host. This period of immune tolerance is characterized by detectable circulating HBsAg, HBeAg, the absence of anti-HBe antibody, high levels of circulating HBV DNA and normal serum alanine aminotransferase (ALT). This immune tolerance may last for years generally without evidence of liver injury.

Fig. 1.4

Natural history of chronic hepatitis B virus infection

Following the immune tolerance phase, infected patients progress through a phase of immune detection/clearance where the host immune system tries to clear infected hepatocytes resulting in hepatic inflammation, elevation of serum ALT, and reduction of the circulating HBV DNA level. The immune clearance phase is highly variable in duration and frequency but a prolonged phase or recurrent episodes of acute liver inflammation may result in repeated cycles of injury and regeneration, resulting in necroinflammation/fibrosis and an increased risk of progression to cirrhosis and HCC. In some cases, conversion to anti-HBe-seropositive status follows the immune clearance phase. The progression of chronic hepatitis B to a state of detectable liver injury represents the start of the disease state, which is characterized by the presence of HBsAg and HBeAg in serum (HBeAg-positive chronic hepatitis B), moderate-to-high levels of circulating HBV DNA, elevation of serum ALT, and the absence of anti-HBe antibody. In some cases, where seroconversion to anti-HBe-seropositive status is associated with ongoing viral replication, there is detectable anti-HBe antibody (HBeAg-negative chronic hepatitis B). In these HBeAg-negative–anti-HBe-positive hepatitis B cases, the HBV DNA level in serum is usually lower than in HBeAg-positive chronic hepatitis B (Chen et al., 2007a).

Finally, a proportion of infected persons will be able to inactivate the infection and go into the ‘non-replicative phase’ of chronic HBV infection or what is sometimes referred to as the ‘inactive carrier state’. This phase is characterized by the continued presence of HBsAg in serum, the absence of HbeAg, and the presence of anti-HBe antibody, low levels of serum HBV DNA, and normal serum ALT. The patients in the inactive carrier state do not usually progress to liver injury. This may in part be dependent on the events that occurred during the immune clearance phase and the presence or absence of pre-existing liver fibrosis. Most of adult infections resolve spontaneously, and the few patients (approximately 5%) who do not clear the infection progress directly to the chronic infection phase, and do not experience an immune tolerance phase (Chen et al., 2007a).

A specific group of patients who are seronegative on HBsAg but seropositive on HBV DNA has been identified, and their infection defined as occult hepatitis B (Hu, 2002; Torbenson & Thomas, 2002; Chen, 2005). Although occult hepatitis B has long been documented (Hoofnagle et al., 1978), it was difficult to investigate it before the availability of HBV polymerase chain reaction (PCR). The molecular and immunological mechanisms underlying occult hepatitis B still remain incompletely elucidated. Several hypotheses have been proposed for the occurrence of occult HBV infection. They include the mutation of HBV surface, core and X genes, the integration of HBV DNA into host genomes, the HBV infection of peripheral blood mononuclear cells, the formation of the circulating immune complex containing HBV, the altered host’s immune response to HBV, and the superinfection and interference of HBV by other viruses. Persons with occult HBV infection may transmit HBV through transfusion, haemodialysis, and organ transplantation. Occult HBV infection may contribute to the acute exacerbation of co-existing chronic hepatitis B and even fulminant hepatitis, and to the development of HCC. It also affects disease progression and treatment response of chronic hepatitis C (Hu, 2002; Torbenson & Thomas, 2002).

There is a wide variation in the prevalence of occult hepatitis B among various patient groups, blood and organ donors, and healthy controls. The prevalence of seropositivity of HBV DNA in HBsAg-seronegative subjects is in the range of 0–10% among those without liver disease, 11–19% in patients affected with chronic hepatitis, and 12–61% in HCC patients (Bréchot et al., 2001; Chen, 2005).

1.2.4 Vaccination and viral treatment

Both vaccine and antiviral treatments are available for the control of HBV infection. The HBV vaccination programme has reduced the perinatal and horizontal transmission of HBVs and the prevalence of HBsAg in many countries including Taiwan (China) (Tsen et al., 1991; Hsu et al., 1999; Ni et al., 2001, 2007; Lin et al., 2002, 2003; Chien et al., 2006; Lu et al., 2006; Su et al., 2007, 2008), Saudi Arabia (Al-Faleh et al., 1999; Madani, 2007), southern Italy (Da Villa et al., 1998), and Senegal and The Gambia (Vildósola, 2000). HBV vaccination has been shown to result in a dramatic decrease in the number of HBV infections among health care workers (Mahoney et al., 1997). It has been well documented that national HBV vaccination programmes have reduced the mortality in childhood fulminant hepatitis (Kao et al., 2001; Chien et al., 2006), and HCC incidence (Chang et al., 1997, 2000, 2005; Chien et al., 2006).

Alpha-interferon and nucleotide/nucleoside analogues have been used to treat patients affected by chronic hepatitis B. Randomized controlled trials have shown the efficacy of antiviral treatment to improve the histological grade and to reduce the risk of liver cirrhosis and HCC (Dienstag, 2008).

2. Cancer in Humans

This section reviews the epidemiological data published since the previous IARC Monograph (IARC, 1994). The current review only focuses on cohort and case–control studies with the exception of those descriptive studies which may reflect the effect of hepatitis B vaccination. Many of these studies have not focused primarily on hepatitis B, but on other factors that potentially interact with hepatitis B in causing HCC.

3. Cancer in Experimental Animals

In this Volume, the Working Group decided not to include a separate section on “Cancer in Experimental Animals” in the Monographs on viruses but rather to include description of such studies under Section 4 (below). The reasoning for this decision is explained in the General Remarks.

4. Other Relevant Data

4.2. Chronic necro-inflammatory hepatic disease in hepatocarcinogenesis

HBV-induced chronic necro-inflammatory hepatic disease (cirrhosis and chronic hepatitis) is characterized by continuous or intermittent necrosis of hepatocytes, followed by regenerative proliferation. Its central role in hepatocarcinogenesis is supported by the observation that the lifetime risk for developing HCC in chronic HBV carriers with cirrhosis is higher than that in carriers without cirrhosis (Arbuthnot & Kew, 2001).

Hepatocytes are normally in a quiescent state with an extremely low turnover rate, but they react to the loss of liver cells with an extraordinarily vigorous proliferative response. This response is tightly controlled and lasts only until the initial number of hepatocytes is restored; it does not normally lead to cancer (Fausto, 1997, 1999; Overturf et al., 1997). Existing quiescent hepatocytes are responsible for this regenerative cell proliferation, and only uncommonly do hepatic progenitor (oval) cells directly give rise to tumour cells, although it is possible that hepatocytes originating from these cells are at higher risk for oncogenesis than other hepatocytes (Fausto, 1997, 1999).

The proliferation of hepatocytes is regulated by several factors, including nuclear factor-κ-B (NF-ĸB), transforming growth factor-α (TGF-α), insulin-like growth factor-2 (IGF-2), and hepatocyte growth factor (HGF) (Grisham, 2001). Transcriptional activation of these factors by mediators, such as tumour necrosis factor-α (TNF-α), chemokines, and interleukins released during the inflammatory process regulates proliferation, and has an anti-apoptotic effect through the upregulation of the anti-apoptotic target gene BCL2 (Grisham, 2001).

With sustained proliferation, at some point and for reasons as yet poorly understood, the regulation of proliferation may become unrestrained, which is an essential step in hepatocarcinogenesis, complicating chronic necro-inflammatory hepatic disease. Unrestrained hepatocyte proliferation, in association with the accumulation over time of several genetic and epigenetic changes, results in the formation of hyperplastic nodules that may progress to dysplastic nodules, and finally to HCC (Fausto, 1999).

By increasing the hepatocyte turnover rate, chronic necro-inflammatory hepatic disease:

• enhances the risk of a cell acquiring critical mutations,
• leads to reactivation of telomerase, and
• may also provides an opportunity for other selective growth advantage of cells to become manifest.

Concurrently with these oncogenic mechanisms, distortion of the lobular architecture of the liver by fibrosis, and nodular regeneration of hepatocytes in cirrhosis modify normal cell-to-cell and cell-to-extracellular matrix interactions, which may contribute to the loss of cell-growth control, senescence, and apoptosis (Davis & Kresina, 1996).

4.2.1. Virus-induced chronic necro-inflammatory hepatic disease

One way in which mutations can arise is by the generation of reactive oxygen species and/or reactive nitrogen species that induce oxidative/nitrosative stress and DNA damage (Trush & Kensler, 1991; Bartsch & Nair, 2006). Putative mechanisms of free-radical-induced hepatocyte damage and malignant transformation are the mutagenic properties of the free radicals and their effect on lipid peroxidation (Cheeseman, 1993; Bartsch & Nair, 2006). In addition to DNA modifications caused directly by reactive oxygen species and reactive nitrogen species, DNA bases can be modified by lipid peroxidation products such as trans-4-hydroxy-2-nonenal (HNE), 4-hydroperoxy-2-nonenal (HPNE), and malondialdehyde (MDA) to form various exocyclic adducts, including malondialdehyde-deoxyguanine (M₁dG), and etheno- and propano-DNA adducts (Bartsch & Nair, 2006).

Oxidative stress and upregulation of inducible nitric oxide synthase (iNOS) has been demonstrated in chronic viral hepatitis (Loguercio & Federico, 2003). A massive increase (up to 90-fold) in the 1,N⁶-ethenodeoxyadenosine (εdA) concentration in urine was detected in HBV-infected patients with chronic hepatitis and liver cirrhosis (Bartsch & Nair, 2006). εdA could arise from HBV-induced chronic inflammation, overproducing reactive oxygen species, reactive nitrogen species, and DNA-reactive lipid-peroxidation-derived aldehydes such as HNE (see Fig. 4.1).

Fig. 4.1

Illustration explaining how chronic infection and inflammatory processes can lead to deregulation of cellular homeostasis and carcinogenesis

4.2.2. Reactivation of telomerase

During the progression of chronic hepatitis to cirrhosis, progressive shortening of telomeres occurs as a consequence of multiple cycles of cell injury, death, and regeneration, and results in the premature senescence of hepatocytes. Telomere-shortening beyond a critical length causes a proliferative block, which becomes manifest as chromosomal instability, end-to-end fusion, and cell death. Hepatocarcinogenesis is characterized by the evolution of clones of hepatocytes with increased telomerase expression and an immortalized phenotype (Farazi et al., 2003).

4.3. Direct mechanisms of hepatocarcinogenesis

HBV may also play a direct role in HCC via two major mechanisms. The first mechanism is the integration and mutation of the viral genome into the host cellular DNA, which may result in the altered expression of important cellular genes. The second one is the expression of HBV proteins, which may have a direct effect on cellular functions and in the promotion of malignant transformation (Brechot et al., 2010).

4.3.1 Role of the integration of HBV DNA into the host genome

Although insertion of hepadnaviral DNA into host DNA is not a requirement for viral replication, HBV genome integrations have been reported in over 85–90% of HBV-related HCCs (Bonilla Guerrero & Roberts, 2005). Integration occurs as a result of a recombination event and takes place at one or, far more often, multiple sites (Matsubara & Tokino, 1990; Rogler & Chisari, 1992; Robinson, 1994). Integration is an early event and selective clonal amplification of hepatocytes with unique integration patterns is thought to occur during progression to malignancy (Minami et al., 2005). The integrant may be a single linear sequence of the viral genome (almost always with nucleotides missing from one or both ends), but more often comprises rearranged fragments of viral DNA. Complete and intact viral genomic DNA has been found only rarely in integrants. No two insertions are alike. Linear viral DNA is the preferential form used as an integration substrate (Yang & Summers, 1999).

The exact mechanisms of hepadnaviral DNA integration into cellular DNA are not known, but the evidence available suggests that integration preferentially occurs at sites of double-strand DNA breaks in the cellular DNA (Bill & Summers, 2004). The frequent cell divisions and DNA strand breaks that occur in chronic hepatitis and cirrhosis create opportunities for HBV DNA to be integrated into chromosomal DNA (Dandri et al., 2002). In addition, the existence of preferred topoisomerase-1 cleavage motifs in the vicinity of the DR1 and DR2 sites, may predispose the insertion of HBV DNA into cellular DNA (Wang & Rogler, 1991).

There are several ways in which integrated hepadnaviral DNA may contribute to hepatocarcinogenesis. The insertion of HBV DNA into cellular DNA in human HCC does not occur at specific sites; however, several reports have found integration events near cellular oncogenes or other genes involved in cellular growth (Paterlini-Bréchot et al., 2003; Bonilla Guerrero & Roberts, 2005; Minami et al., 2005). Among the cellular genes with HBV integration events are retinoic acid receptor β, cyclin A2, mevalonate kinase, mcm8, neurotropic tyrosin receptor kinase 2 (NTRK2), IL1R-associated kinase 2 (IRAK2), p42 mitogen-activated protein kinase 1 (p42 MAPK1), telomerase, and others (Dejean et al., 1986; Wang et al., 1990; Paterlini-Bréchot et al., 2003; Bonilla Guerrero & Roberts, 2005; Minami et al., 2005). These studies suggest that the presence of an integrated HBV genome could lead to the inappropriate activation of targeted cellular genes, and in these cases, provide a mechanism for HBV-mediated carcinogenesis.

In the case of woodchuck hepatitis virus (WHV), the integration of the viral genome in or near c-MYC or N-MYC proto-oncogenes in 50% of infected animals considerably enhances the transcriptional activity of the corresponding cellular promoters (Fourel et al., 1990; Tennant et al., 2004). This observation provides strong evidence for a direct role of WHV in hepatocarcinogenesis. However, given that no human cellular gene appears to be targeted with a similar frequency by HBV, it is currently unclear to what extent this mechanism applies to human liver cancer.

Integration of HBV DNA into cellular DNA may also induce structural changes in the flanking DNA sequences. These are highly varied, include small and large deletions, translocations, duplications, or amplification of chromosomal sequences (Matsubara & Tokino, 1990; Takada et al., 1990; Buendia, 2000; Laurent-Puig et al., 2001). Such changes occur more frequently in HBV-related HCC than in HCC attributable to other causes (Laurent-Puig et al., 2001).

4.3.2. Role of HBV proteins

Transcriptional activation by HBV proteins of cellular genes distant from the site of integration (transactivation) that influence cellular proliferation and differentiation or apoptosis is a more frequent, and probably more important, mechanism of inherent hepatocarcinogenesis (Buendia, 2000). This effect is mediated through signal transduction pathways. Two HBV proteins, HBx and PreS/S (when 3′ truncated during or after integration), have been shown to have indirect transactivating capability, and have been implicated in the development of HCC by this means (Murakami, 1999; Feitelson, 2006).

(a) Hepatitis B virus x protein (HBx)

The smallest HBV protein (16.5 kDa), HBx, expressed both in the cytoplasm and the nucleus, is essential for viral replication (Murakami, 1999; Feitelson, 2006).

Because the gene is close to the preferred integration sites of HBV, it is the region of the genome most often included in integrants (Paterlini et al., 1995), and a selective accumulation of HBx gene transcripts has been reported in HBV-related HCC. Antibodies against HBx have been demonstrated in the sera of chronic carriers, which confirms the expression of the viral protein (Pál et al., 2006).

Integrated HBx, even when truncated and mutated, may still retain some of its functions. Alternatively, mutation and/or truncation may activate specific functions of HBx (Schlüter et al., 1994). Evidence that HBx is contributing to HCC comes in part from knockdown experiments in which reduction in the levels of HBx leads to growth suppression (Chan & Ng, 2006; Cheng et al., 2007). In addition, no HCC related to avian hepadnaviruses, which are devoid of the X ORF, have been reported (Murakami, 1999).

HBx does not contain any structural motifs that indicate a capacity to bind DNA directly, and functions through protein-to-protein interaction. HBx activates transcription from various HBV promoters, other viral promoters, and from the promoters of a large number of cellular genes including oncogenes, cytokines, growth factors, and several genes involved in cell-cycle control and progression, DNA repair, apoptotic cell death, cellular adhesion, and angiogenesis (Murakami, 1999; Feitelson, 2006; Table 4.1).

Table 4.1

Some targets of transactivation by HBx.

A wide variety of cis-elements have been shown to be responsive to HBx which includes binding sites for AP-1, AP-2, NF-κB, SRF, c/EBP, Ets, ATF1, and CREB (Table 4.1).

Transcriptional regulation by HBx may occur through direct interaction with transcription factors in the nucleus, like shown for ATF-2, CREB, Oct-1, p53, bZIP, and other components of the basal transcription machinery (Table 4.2).

Table 4.2

Some HBx-interacting cellular proteins.

HBx transactivation may also occur by modulating cell-signalling pathways within the cytoplasm (Table 4.3). NF-κB-signalling that mediates cellular stress responses that control the expression of several acute-phase response proteins, cytokines, and adhesion molecules is among the pathways modulated by HBx though the activation of “Mitogen Activated Protein Kinase” (MAPK) pathways (Benhenda et al., 2009).

Table 4.3

Some reported interactions of the HBx viral protein with major cellular signal-transduction pathways.

HBx has also been shown to inhibit the activity of some serine protease inhibitors and components of the proteasome complex, specifically PSMA7 (Zhang et al., 2000), and might thus modulate the turnover of certain cellular proteins involved in transcription or regulation of cell-cycle progression, or both.

Among the cellular proteins whose functions are known to be perturbed by HBx protein is the tumour-suppressor p53. The p53 protein maintains chromosomal integrity by arresting the cell cycle in G₁, regulating the DNA damage control responses, and regulating the induction of apoptosis and/or senescence (Shimamura & Fisher, 1996). In vitro HBx expression studies have shown that HBx protein binds to specific sequences in the C-terminal end of p53, preventing its entry into the nucleus, and abrogating its sequence-specific DNA-binding and transcriptional activity (Elmore et al., 1997; Takada et al., 1997).

“Phosphatase and Tensin homology deleted on chromosome 10” (PTEN) is another important tumour-suppressor which has been shown to be a transcriptional target of p53 (Stambolic et al., 2001). Inactivation of both p53 and PTEN proteins by HBx protein results in increased levels of hypoxia-induced factor-1α (HF1-α) and vascular endothelial growth factor (VEGF), both of which are important for the survival and neovascularization of early-stage tumours (Huang & Kontos, 2002).

HBx protein may impair DNA-repair mechanisms by several means. Besides its potential inhibition of p53-dependent DNA repair, HBx can repress the transcription of two components of the repair factor TFIIH – XPB and XPD (Jaitovich-Groisman et al., 2001). The protein also directly interferes with DNA repair by forming a complex with the DNA-repair protein, HBx-associated protein (XAP-1), which normally binds to damaged DNA in the first step of nucleotide excision repair (Becker et al., 1998). Recent evidence shows that HBx binds the UV-damaged DNA binding protein 1 (DDB1), a protein involved in DNA repair and cell-cycle regulation. This interaction leads to interference with S-phase progression and induces lagging chromosomes during mitosis. Consequently, HBx may exert deleterious activities in dividing, but not quiescent, hepatoma cells (Martin-Lluesma et al., 2008).

In addition to its inhibitory effects on p53-induced apoptosis, HBx protein inhibits caspase-3-dependent apoptosis (Gottlob et al., 1998). Conversely, HBx may also sensitize cells to programmed cell death induced by TNF-α, an effect mediated by prolonged stimulation by N-MYC transcription and the stress-mediated MAPK pathway (Su & Schneider, 1997).

(b) Hepatitis B virus 3′ truncated PreS/S proteins

Like the HBx gene, the PreS/S gene is frequently included in HBV DNA integrants in patients with HCC. When 3′ truncated during or after integration, the gene has transactivating properties and might contribute to oncogenesis (Schlüter et al., 1994). The truncated medium surface protein is exclusively cytoplasmic in location and has pleotropic effects on gene transcription. Its transactivating effects are mediated by modulating protein kinase C (PKC) signal transduction and interaction with several transcription factors such as NF-ĸB and AP-1 (Lauer et al., 1994; Hildt et al., 1996). Potentially oncogenic transcriptional effects include the stimulation of promoter sequences of c-MYC, c-FOS, and c-HA-RAS oncogenes, and the inflammation-associated cytokine, IL-6 (Kekulé et al., 1990; Meyer et al., 1992; Lauer et al., 1994). Mutated PreS protein may induce endoplasmic reticulum stress (Wang et al., 2003b), which in turn stimulates the expression of cyclooxygenase-2 through activation of NF-ĸB and P38-MAPK (Hung et al., 2004). In transgenic mice that overproduce in hepatocytes the large envelope protein of HBV, this protein accumulated in the endoplasmic reticulum. This led to cytopathic effects that contributed to a progressive disease culminating in liver cancer (Chisari et al., 1989). The relevance of this animal model to HBV-associated HCC in human remains unclear.

5. Evaluation

There is sufficient evidence in humans for the carcinogenicity of chronic infection with HBV. Chronic infection with HBV causes hepatocellular carcinoma. Also, positive associations have been observed between chronic infection with HBV and cholangiocarcinoma and non-Hodgkin lymphoma.

Chronic infection with HBV is carcinogenic to humans (Group 1).

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