Our results show that there are significant differences in the overall and local distribution of liver cancer risk factors. The disease burden of liver cancer in Hubei Province was increasing against the backdrop of a declining overall liver cancer disease burden in China. Although the number of liver cancer cases in China remained at a high level, both ASIR and ASMR for liver cancer arising from each specific cause showed a significant downward trend[7, 30]. It was closely related to China's aggressive liver cancer prevention and control policy in recent decades. In particular, liver cancer due to hepatitis B had a faster decline in ASIR and ASMR than liver cancer due to other etiologies, a phenomenon consistent with the vaccination policy of the hepatitis B vaccination schedule that had been in place in China since 1992[15]. It is surprised that a clear trend of increasing of the cases and ASIR of liver cancer for each cause in Hubei Province was found, which hinted a limited effect of certain broad-level prevention policies for liver cancer. The ASMR of liver cancer due to four etiologies in Hubei Province showed a trend of dropping steadily after 2010, the ASMR of the female LCAU group was observed an increase instead. Women's more frequent participation in workplace alcohol culture could be a possible reason with the rapid economic development over recent years. And the CIR and CMR of liver cancer were increasing rapidly and exceed ASR of liver cancer in Hubei Province after 2015. It was obvious that the rapid increase in CIR and CMR was blame to the aging of Chinese population.
Hepatitis B remained the most important risk factor for the development of liver cancer in Hubei Province, both in the male and female population. From 1990 to 2019, the ASIR for LCHB had been showing an increasing trend in the male population, and higher than the average level of LCHB in the Chinese female population. It has been suggested that there may be a super additive and super multiplicative interaction between family history of liver cancer and HBV infection on the development of liver cancer[31]. In Chinese population, a family history of liver cancer is associated with an increased risk of liver cancer. This risk is particularly high for those whose mothers have the disease[32]. The hepatitis B vaccine has a protection period of at least 12 years, with antibody levels decreasing over time, and there are problems with incomplete vaccination against hepatitis B[33, 34]. However, it is not a mandatory policy to chase booster shots for hepatitis B in most areas of China, and the habit of regular medical check-ups is common among the elderly, so the likelihood of finding a negative HBsAb in the younger age group is substantially lower [35]. In the analysis of age effects, the age profile demonstrated that the risk of liver cancer caused by hepatitis B increases with age. In the cohort effect, the risk of liver cancer due to hepatitis B was consistently reduced in the birth cohort after the 1990–1994 group. This illustrated that the risk of LCHB was remarkably reduced in younger age groups and in the birth cohort following the implementation of the hepatitis B vaccine policy. It was reasonable to assume that the limited effective protection period of the hepatitis B vaccine had contributed to the continued increase in ASIR for hepatitis B-induced liver cancer in Hubei Province.
Although LCHC was apparently lower than LCHB at ASIR levels, LCHC remained a serious public health problem in developing countries[2, 36, 37]. Treatment of hepatitis C with direct-acting antiviral drugs (DAAs) based therapy for HCV can have a cure rate of over 90%[38]. In this study, the trend in the incidence of LCHC was generally consistent with that of hepatitis B. Even with effective treatment measures in place, LCHC was still elevated in the ASIR in Hubei Province because acute hepatitis C is generally asymptomatic and more difficult for patients to detect, thus making it more likely to turn into chronic hepatitis C and eventually lead to LCHC[39]. Considering that the transmission route of hepatitis C is similar to that of hepatitis B, but there is no effective vaccine for HCV, it is recommended to combine screening for hepatitis B to reduce the financial cost while increasing the detection rate of acute and chronic hepatitis C for early detection, diagnosis and treatment[16].
Alcohol consumption is strongly associated with the development of liver cancer, a phenomenon that is more common in males[40]. The incidence and mortality rates of LCAU in Hubei Province exhibited notable differences from those of LCAU in China as a whole between male and female groups. The LCAU had an ASIR of 7.35 (4.85–9.35) for the 2015–2019 female population in Hubei Province, which was approximately four times higher than the ASIR for males. According to the analysis of alcohol consumption in Chinese patients with liver disease, males are usually the main consumers of alcohol and both ASIR and ASMR are higher in males than in females at the overall level in China[41]. Possible reasons for this particular trend in Hubei Province are: relatively lower tolerance of alcohol in the female population in Hubei Province; consumption of specific varieties of alcohol; and the presence of certain mutagens that enhance the sensitivity of females to alcohol [42].And further research is needed to elucidate this remarkable trend in Hubei Province.
LCOC is the second most common type of liver cancer cause in males in Hubei Province, with other causes including non-alcoholic diet, aflatoxins, tobacco and obesity [43, 44]. The ASIR for liver cancer due to other factors remained largely unchanged in the Hubei Province female population, which may be related to the acquisition of risk factors. The gender specificity of hepatocarcinogenesis was revealed in a study on the association of metabolic syndrome (MetS) and its components with liver cancer[45]. In a prospective cohort study, the results indicate that the significant risk factors associated with an increased incidence of liver cancer in men are central obesity and hyperglycemia[10, 45]. In studies of sex hormones, higher androgen receptor density is associated with increased visceral fat, which is more important than total obesity in the carcinogenic role of the liver[46, 47]. There was another study reporting on the role of sex hormone signaling in the mechanism between type 2 diabetes and hepatocarcinogenesis[48]. These facts provides strong evidence for differences in metabolism-related factors between gender groups. And the higher availability of these risk factors in males than in females accounts for the long-standing higher overall incidence of liver cancer in males than in females.
4.1 Age Effect
A uniform pattern of age effects in the incidence and mortality of liver cancer increases with age up to the age of 80 years. This is in general agreement with the M. Sayiner’s study and the pattern can be observed in the vast majority of the world[49]. According to the results of the seventh population census, the proportion of people aged 60 and over in the resident population in Hubei Province was 20.42%, up 6.49 percentage points from 2010. Among the population aged 60 and above in Hubei Province, 6.6380 million people aged 60–69 are in the lower age group, accounting for 56.28% of the total elderly population, 0.45 percentage points higher than the national average, and the degree of ageing has deepened[50]. The changes in the age structure of the population lead to changes in the burden of disease [51]. The age profile of incidence and mortality of LCAU in females in Hubei Province showed significant specificity. Both incidence and mortality rates of LCAU increase at a significantly higher rate with age than other types of liver cancer, and surpass LCHB as the type of liver cancer with the most serious disease burden in the region in the age groups of 65–69 and 70–74 years. These evidences should be considered when making adjustments to liver cancer prevention and control policies in Hubei Province.
4.2 Period Effect
The period covered by this study was one in which China's economic and social development had achieved remarkable results after more than 10 years of Reform and Openness, and where people's living standards and medical facilities and services had continued to improve. In our research, the incidence of liver cancer in males in Hubei Province showed a continuous upward trend with the change of period, and the risk of liver cancer from various causes did not decrease with the improvement of economic conditions and medical technology compared with the reference period. Studies in recent years have shown that economic and social development is positively correlated with the prevalence of chronic diseases and negatively correlated with acute infectious diseases[52]. Therefore, we believe that the economic and social development in Hubei Province has limited the progression of liver cancer due to viral hepatitis to a certain extent, but the significant increase in material conditions, the high energy diet leading to obesity and diabetes are generally high in the male population, and these diseases are associated with the development of liver cancer [44]. In addition, alcohol consumption and high energy diet are not uncommon in the group of patients with viral hepatitis, and the presence of the former is detrimental to prognosis of acute viral hepatitis and increases the likelihood of acute viral hepatitis turning into chronic viral hepatitis [53], leading to an increased incidence of LCHB and LCHC. In Wang’s study, it was suggested that improvements in medical conditions have increased the screening rate of liver cancer[7]. Not only improvements in medical technology, but also social development, have led to an increase in people's concern for their own health [54, 55], which increased the screening rate of liver cancer. A general decrease in mortality rates for all types of liver cancer was shown after 2010, suggesting that improved medical technology has reduced the risk of death from liver cancer.
4.3 Cohort Effect
In China, the period before 1949 was one of instability and extreme lack of living, material and medical conditions, which leading to the slow development of public health in China [56]. After the founding of the People's Republic of China, there was lack of solid industrial foundation, coupled with natural disasters that further caused famine, and it was only after the reform and opening up that the economy entered a phase of steady and rapid growth. To set the reference cohorts for LCHB, LCHC and LCOC in 1955 and for LCAU in 1950 is a reasonable choice, taking into account the facts of the above historical process. And we assumed that medical investment and development will also be hampered and the risk of liver cancer incidence and mortality will rise when the general economic and social development of China encounters setbacks. In this study, the birth cohort before the reference cohort demonstrated a gradual increase in their risk of liver cancer incidence and death. In the male group, the turning point in the downward trend in the risk of death for the birth cohort occurs after the reference cohort, when the risk of death from liver cancer declines rapidly after a short rise in the birth cohort. In the female cohort, the risk of death from liver cancer has been declining since the birth cohort after 1915, and plateaued after 2000. The effect of the cohort on liver cancer incidence and mortality is largely consistent with previous study [7]. For example, after the introduction of hepatitis B vaccination in newborns in China in 1992, the risk of LCHB incidence and mortality declined dramatically in men and women in Hubei Province, but we also note that in recent years this downward trend has not only slowed in the female population in Hubei Province, but has even increased in incidence. Further prevention and control measures need to be considered.
4.4 Net Drift with Local Drifts [27]
In net drift analysis, the disease burden in the female LCHB group, LCHC group and LCOC group demonstrated a decreasing trend across all ages, while there was no significant decreasing trend in the total disease burden in the female LCAU group and the male liver cancer group from all causes, indicating that the disease burden of liver cancer is higher in males than females in Hubei Province. For local drift, the difference was not statistically significant in the female LCAU group only, suggesting that the change in disease burden in LCAU was not significant and robust across the age groups of females in Hubei Province. It could be assumed that the age effect is less influential on LCAU than the risk factor (alcohol) itself. In the male population, the age of increased disease burden in the LCHB and LCOC groups was after 45 years of age, with the LCHC group advancing to 40 years of age, and the LCAU group exhibiting an increased disease burden after 50 years of age. The results suggested that the priority population for liver cancer prevention and control in Hubei Province is males aged after 40 years for and females aged after 85 years.
Some strengths of this study need to be claimed. First, Age-Period-Cohort model is a classic model for studying the burden of disease and can provide a valuable insight into long-term trends in disease. Secondly, the source of the data is mainly retrieved from the cancer registries, birth and death registration systems in the following parts of Hubei Province. Finally, we reveal differences in the pattern of liver cancer disease due to different etiologies
There were some limitations to the current study. Firstly, the data on the disease burden of liver cancer in Hubei Province are all five-year averages, which leads to a reduction in the precision of our study. Secondly, risk factors for liver cancer have a mutually reinforcing effect on each other, but this information was not refined during data collection and we were unable to analyze these factors further in this study. Finally, this research is a descriptive study with relatively insufficient ability to reveal the causes of trends.