Risk factors
High risk/low risk
References
Viral factors
1. HBsAg
Positive/negative = 66/1
Beasley et al. (1981)
2. HBeAg in HBsAg-positive persons
Positive/negative = 60/10
Yang et al. (2002)
3. HBV DNA level
High {[>106]/105 ~ 106/[104 ~ <105]}/low [<104]copies/ml = 11/9/3/1
Chen et al. (2006)
4. HBV genotype
[C or D]/[A or B]
Tseng et al. (2012)
Host factors
1. Age
>40/<40 years = 2–12/1
2. Age at HBeAg seroconversion
Older (>40 Years)/younger (<30 Years) = 5/1
Chen et al. (2010)
3. Ethnic group
Asian or African/others
Ferlay et al. (2010)
4. Gender
Male/female = 2–4/1
5. Family HCC history
Positive/negative = 2–3/1
Turati et al. (2012)
6. Liver cirrhosis
Yes/no = 12/1
Yu et al. (1997)
7. Maternal HBsAg
Positive/negative = 30/1
Chang et al. (2009)
Other factors
Smoking
Yes/no = 1–2/1
Habitual alcohol
Yes/no = 1–2/1
4.1 Viral (HBV) Risk Factors for HCC
4.1.1 Seropositive HBsAg
Chronic HBV infection with persistent positive serum HBsAg is the most important determinant for HCC. A prospective general population study of 22,707 men in Taiwan showed that the incidence of HCC among subjects with chronic HBV infection is much higher than among non-HBsAg carriers during long-term follow-up. The relative risk is 66. These findings support the hypothesis that HBV has a primary role in the etiology of HCC (Beasley et al. 1981).
4.1.2 Active Viral Replication
HBeAg is a marker of active HBV replication. Chronic HBV-infected subjects with prolonged high HBV replication levels or positive HBeAg after 30 years of age have a higher risk of developing HCC during follow-up. Those HBsAg carriers with persistent seropositive HBeAg have 3–6 times higher risk of developing HCC than those with negative serum HBeAg (Yang et al. 2002) (Table 1). Higher HBV DNA levels predict higher rates of HCC in those with chronic HBV infection. In comparison with those with serum HBV DNA level < 104 copies/ml, those with greater serum HBV DNA levels [104 ~ <105], [105 ~ 106], or [>106] copies/ml have a higher risk of HCC [2.7, 8.9, or 10.7] during long-term follow-up (Chen et al. 2006).
4.1.3 HBV Genotype
There are at least ten genotypes of HBV identified with geographic variation.
4.1.4 HBV Mutants
The presence of pre-S mutants carries a high risk of HCC in HBV carriers and was proposed to play a potential role in HBV-related hepatocarcinogenesis (Wang et al. 2006). Subjects infected with HBV core promoter mutants were reported to have a higher risk of developing HCC.
4.2 Host Factors for HCC (Table 1)
4.2.1 Age Effect
Older age (>40 years) is a risk factor for HCC development (Tseng et al. 2012; Chen et al. 2008). It is very likely due to the accumulation of genetic alterations with gain or loss of genes and liver injury with time during chronic HBV infection. HCC patients are mostly (around 80 %) anti-HBe seropositive at diagnosis (Chien et al. 1981). This implies that HCC occurs after long-term HBV infection and liver injury, and that the patients have seroconverted to anti-HBe. Chronic HBV-infected patients with delayed HBeAg seroconversion after age 40 have significantly higher risk of developing HCC (hazard ratio 5.22), in comparison with patients with HBeAg seroconversion before the age of 30 (Chen et al. 2010).
4.2.2 Male Predominance
There is a strong male predominance in HBV-related HCC, with a male to female ratio of 2–4:1, even in children (Ferlay et al. 2010; Ni et al. 1991; Schafer and Sorrell 1999). Male gender is a risk factor for the development of HCC, but the mechanisms are not fully understood. The higher activity of androgen pathway functions as a tumor-promoting factor in male hepatocarcinogenesis, and the higher activity of the estrogen pathway functions as a tumor-suppressing factor in female hepatocarcinogenesis. As both mechanisms function in a ligand-dependent manner, both the ligand and the receptor of these sex hormones are suggested to be included in assessing the relative risk of HCC patients of each gender (Yeh and Chen 2012). Additionally, the RNA-binding motif (RRM) gene on Y chromosome (RBMY), which encodes a male germ cell-specific RNA-binding protein associated with spermatogenesis, is considered as a candidate oncogene specific for male liver cancer (Tsuei et al. 2004).
4.2.3 Other Host Factors
Chronic severe liver injury caused by hepatitis virus or other agents, leading to hepatocyte transformation and finally HCC. Liver cirrhosis is a precancerous lesion for HCC (Yu et al. 1997). Cirrhotic HBV carriers have a 3–8 % annual rate of developing HCC. The risk of HCC also varies in different ethnic groups. In North America as an example, Asian, Hispanic, and African American have higher rates of HCC than non-Hispanic White people (Ferlay et al. 2010).
Those with positive HCC family history have a higher risk of HCC in comparison with those without a positive history of HCC. Familial clustering of HCC suggests the role of genetic predisposing factors in addition to the intrafamilial transmission of HBV infection (Chang et al. 1984). In a meta-analysis, based on nine case–control and four cohort studies, for a total of approximately 3,600 liver cancer cases, the pooled relative risk for family history of liver cancer was 2.50 (95 % CI, 2.06–3.03) (Turati et al. 2012) (Table 1).
4.3 Maternal Effect
Those with positive maternal serum HBsAg have a higher risk of 30 times in developing HCC than those with negative maternal HBsAg (Chang et al. 2009). HBeAg is a soluble antigen produced by HBV. It can cross the placenta barrier from the mother to the infant. Transplacental HBeAg from the mother induces a specific loss of responsiveness of helper T cells to HBeAg and HBcAg in neonates born to HBeAg-positive HBsAg carrier mothers (Hsu et al. 1992). This may help to explain why 85–90 % of the infants of HBeAg-positive carrier mothers became persistently infected (Beasley et al. 1977), while only approximately 5 % of the infants of HBeAg-negative HBsAg carrier mothers became persistently infected. The immune tolerance state persists for years to decades after neonatal HBV infection.
4.4 Environmental/Life Style Factors
5 Prevention of Liver Cancer
The prognosis of HCC is grave, unless it is detected early and complete resection or ablation is performed. Even in such cases, de novo recurrence of HCC is always a problem. Prevention is thus the best way toward the control of HCC. There are three levels of liver cancer prevention, i.e., primary, secondary, and tertiary prevention of liver cancer (Fig. 1). Universal vaccination to block both mother-to-infant and horizontal transmission routes, starting from neonates to interrupt HBV infection, is the most effective and safe way to prevent HCC.
Fig. 1
Strategies for primary, secondary, and tertiary prevention of liver cancer. HBV immunization is the most effective way. For persons who have been infected by hepatitis virus, antiviral therapy may delay or reduce the risk of developing HCC in a minor degree. The effect of other strategies such as chemoprevention and avoidance of risky behavior is still not confirmed and is under investigation. HBV hepatitis B virus; IFN interferon; NA nucleos(t)ide analog
Antiviral therapy for hepatitis B is aimed at the normalization of the liver enzymes, HBeAg clearance, reduction in HBV DNA levels as well as inflammation and fibrosis in the liver. Studies have shown that a finite course of conventional interferon-α (IFN) therapy may provide long-term benefit for achieving a cumulative response as well as reducing the progression of fibrosis and the development of cirrhosis and/or HCC. Long-term therapy with nucleos(t)ide analogs may also improve fibrosis or reverse advanced fibrosis as well as reduce disease progression and possibly the development of HCC. However, current antiviral therapies and immune modulating agents do not reach a high sustained response rate. Even in those with sustained response, HBV cannot be eradicated from the hosts in the majority of treated cases because it is difficult to eliminate cccDNA by this treatment. Drug resistance after prolonged use of NUC is another problem. Antiviral therapy, therefore, may have some but limited beneficial effect in preventing HBV-related complications including HCC.
A prospective randomized controlled trial of antiviral therapy was conducted in patients with HBV-related cirrhosis. HCC was diagnosed in 3.9 % of lamivudine-treated patients and in 7.4 % of placebo controls after a median follow-up of 32 months (p = 0.047) (Liaw et al. 2004). Another retrospective study revealed that the cumulative incidence of HCC at the end of 15 years (median 6.8 years) follow-up in the 233 interferon (IFN)-treated patients and 233 controls was 2.7 versus 12.5 % (p = 0.011). Yet, significant reduction in HCC was only observed in patients with preexisting cirrhosis and HBeAg seroconverters (Lin et al. 2007). The outcome with pegylated IFN (PEG-IFN) and newer nucleoside/nucleotide may be better because of more effective viral suppression effect, and/or a low risk of resistance. However, the treatment outcomes still need to be improved, and more effective, safe, and affordable anti-HBV agents/strategies are needed (Liaw 2011).
For HCC patients who have been treated successfully by surgery, liver transplantation, or local therapy, tertiary prevention of HCC using antiviral therapy against HBV or HCV may potentially prevent late tumor recurrence (Braitenstein et al. 2009). Yet, further study is needed to confirm its efficacy.
Other strategies to prevent HCC such as chemoprevention of high-risk subjects (Jacobson et al. 1997; Egner et al. 2001), prevention of high-risk behavior, changes in environment and/or diet, and liver transplantation for precancerous lesion (e.g., liver cirrhosis) may also be helpful to prevent liver cancer. Yet, more evidence is needed to support their efficacy.
5.1 Primary Prevention of Hepatitis B Virus Infection by Immunization
5.1.1 Universal Hepatitis B Vaccination in Infancy
Currently, there are mainly three strategies of universal immunization programs in the world, depending on the resources and prevalence of HBV infection (Table 2). In countries with adequate resources, such as the USA, pregnant women are screened for HBsAg but not HBeAg. It is recommended that every infant receive three doses of HBV vaccine. In addition, infants of all HBsAg-positive mothers, regardless of HBeAg status, also receive HBIG within 24 h after birth (Shepard et al. 2006). This strategy saves the cost and the procedure of maternal HBeAg screening but increases the cost of HBIG, which is very expensive.
Table 2
Current pregnant women screening and universal infant hepatitis B virus (HBV) immunoprophylaxis strategies in different countries and proposed surveillance program for high-risk children with breakthrough infection linked to the specific strategies
Strategy type | Pregnant women screening | Neonatal immunization# | |||
|---|---|---|---|---|---|
HBsAg | HBeAg | HBV vaccine | HBIG to children of HBsAg (+)/HBeAg(−) mothers | HBIG to children of HBsAg (+)/HBeAg (+) mothers | |
I | Yes | No | Yes | Yes | Yes |
II* | Yes | Yes | Yes | No | Yes |
III | No | No | Yes | No | No |
The first universal hepatitis B vaccination program in the world was launched in Taiwan since July 1984 (Chen et al. 1987). Pregnant women were screened for both serum HBsAg and HBeAg (Strategy II).
To save the cost of screening and HBIG, some countries with intermediate/low prevalence of chronic HBV infection or inadequate resources do not screen pregnant women, and all infants receive three doses of HBV vaccines without HBIG. Using this strategy, the cost of maternal screening and HBIG can be saved. The efficacy of preventing the infants from chronic infection seems satisfactory (Poovorawan et al. 1989).
5.2 Effect of HBV Vaccination on the Reduction in HBV Infection and Related Complications
HBV vaccine has been part of the WHO global immunization, resulting in major declines in acute and chronic HBV infection. Approximately 90 % of the incidence of chronic HBV infection in children has been reduced remarkably in areas where universal HBV vaccination in infancy has been successfully introduced. After the universal vaccination program of HBV, the rate of chronic HBV infection was reduced to one-tenth of that before the vaccination program in the vaccinated infants worldwide. Fulminant or acute hepatitis also has been reduced.
Serial epidemiologic surveys of serum HBV markers were conducted in Taiwan (Hsu et al. 1986; Chen et al. 1996; Ni et al. 2001, 2007). The HBsAg carrier rate decreased significantly from around 10 % before the vaccination program to 0.6–0.7 % afterward in vaccinated children younger than 20 years of age. A similar effect has also been observed in many other countries (Whittle et al. 2002; Jang et al. 2001), where universal vaccination programs have been successfully conducted. Universal HBV vaccination in infancy is more effective than selective immunization for high-risk groups.
The HBV vaccination program has indeed reduced both the perinatal and horizontal transmission of HBV worldwide (Da Villa et al. 1995; Whittle et al. 2002). In the reports from many countries, such as Gambia and Korea, universal vaccination programs have been equally successful. The hepatitis B carrier rate has fallen from 5 to 10 % to less than 1 %, demonstrating that universal vaccination is more effective than selective immunization for high-risk groups (Montesano 2011).
6 Effect of Liver Cancer Prevention by Immunization against Hepatitis B Virus Infection (Table 3)
Current therapies for HCC are not satisfactory. Even with early detection and therapy for HCC, recurrence or newly developed HCC is often a troublesome problem during long-term follow-up. Therefore, vaccination is the best way to prevent HBV infection and HCC. Since it usually takes 40 years or longer for HCC to develop after HBV infection in most occasions, we may expect to see the reduction in HCC in adults 40 years after the implementation of the universal HBV vaccination program. Studies on the changes of the incidence of HCC in children born before and after universal HBV vaccination program in a hyperendemic area may facilitate our understanding of the effect of HCC prevention by HBV immunization, if the HCC in children is similar to the HCC in adults.
Table 3
Incidence rates of HCC among children 6–19 years old and born before or after universal HBV vaccination program
Age at diagnosis, year | HBV vaccination | Years | Hepatocellular carcinoma | ||
|---|---|---|---|---|---|
No. of HCCs | Incidence rate (per 105 person-years) | Rate ratio (95 % CI) | |||
Taiwan | Birth year | ||||
6–19 | No | 1963–1984 | 444 | 0.57 | 1 (referent) |
Yes | 1984–1998 | 64 | 0.17 | 0.30 (0.18–0.42) | |
Khon Kaen | (Thailand) | Birth year | |||
>5–18 | No | Before 1990 | 15 | 0.097 | 1 (referent) |
Yes | After 1990 | 3 | 0.024 | 0.25 | |
Alaska | (USA) | Diagnostic year | |||
<20 | No | 1969–1984 | 0.7–2.6 | ||
Yes | 1984–1988 | 2.9 | |||
Yes | 1989–2008 | 0.0–1.4 | |||
References
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