Over the past decades, liver cancer has been known as one of the primary lethal neoplasms which has a widespread distribution across the globe with a serious threat to the public health . The present paper provided strong evidence that the patterns of LC [1-MIR] rates and its components were extremely diverse among world super-regions for both genders from 1990 through 2019. One reason that may explain this disparity would be differences in distributions of risk factors in various populations. In particular, SAEAO was the only super-region with the largest ASIRs and ASMRs related to LC versus other regions over the last 30 years. Similar findings were noted in Lin et al. announced that East Asia and Southeast Asia had the highest liver cancer burden among geographic regions, accounting for about 85% of the global incidents and deaths from 1990 to 2017 . These results highlight that LC in these countries was likely to be remained as a major public health problem, albeit with a change in the distribution of cases around the world.
With respect to the time period, a generally declining pattern was observed for ASIR and ASMR in SAEAO and LAC with the steepest slope, which benefited from primary and secondary prevention, new treatments development, and improvement of antiviral therapy. In line with what we observed for the trends in these regions, a comparative analysis of temporal trends in LC incidence rates among Eastern and Southeastern Asian countries reported that the rates decreased between 1983 and 2007 . Also, the study of Jemal et al. found that since the early 1960s to 2008, the incidence rates in most of the Asia populations (including China and Korea) fell which is thought to reflect reduction in transmission of hepatitis B virus (HBV). Conversely, they approved that LC incidence and mortality rates increased in Oceania due to widespread hepatitis C virus (HCV) infection . The ongoing decrements in mortality of LC in these continents can be partially attributed to the expansion in access to healthcare services namely primary care, health promotion actions, and improvements in socioeconomic aspects.
Another striking finding was that the largest increasing time trends in ASIR and ASMR was observed in HI and SSA till 2000, followed by a monotone slight decline during 2000–2019. This result reminds us that liver cancer should not be placed at a lower priority in disease prevention and treatment in those regions. Although the reasons behind the growing patterns in the LC incidence and mortality in these countries are absolutely unclear, a part of the trend, especially in the initial years of the study, may be attributed to economic development, increased exposure to environmental risk factors, lifestyle habits, and a rise in the number of patients registered. Similar findings have been reported in other recently published paper showing that the incidence and mortality have increased substantially from 1982 to 2014/2015 . Population aging and growth, high alcohol consumption, and low intake of vegetables and fruit likely play a small, or minimal role in upward trend of LC among these populations.
Looking at the temporal patters of ASIR and ASMR in SA, changes were not as pronounced as those observed in other regions over the entire reporting period. Furthermore, there was a gentle decline of ASIR and ASMR in these populations from 2002 to 2019. LGCMs also showed that the initial values of ASIR and ASMR at the start of this study differed across the continents, probably because of unequal healthcare coverage and variations in compliance to regular screening and necessary treatments. Moreover, countries of CEEECA had the highest average rates of change in incidence and mortality compared to other regions, though this may be due—at least in part- a different proportion and variable time trends of LC. Such findings can be justified by a report in Europe where there was between country variability in mortality patterns and trends since 1970s continued over the 1990s but levelled off during the 2000s .
In terms of gender, concordant with those published by previous epidemiological studies [33, 34], the ASIR and ASMR attributed to LC in males were higher than that of females across different super-regions. However, the reasons for this gender time-dependent changes are complex and may stem from differences in genetic risk factors, hormonal changes, metabolic factors, treatments received, compliance with antiviral therapies, and tumor biology . Based on the LGCMs, it was seen that the overall mean levels of initial ASIR and ASMR in males were substantially greater in comparison to females of all super-regions in 1990. Nevertheless, the slopes of ASIRs and ASMRs in these regions illustrated that the growth trajectories for both males and females were almost similar over the period 1990–2019 which is broadly in accordance with some reports .
Among both sexes, the average rates of change of ASIR and ASMR were highest and lowest in CEEECA and NAME, respectively over time. Although to our knowledge, there were no published articles covering the period of our study, our findings regarding gender differences in LC incidence and mortality rates are confirmed by a number of available literature. On the basis of GLOBOCAN 2018 estimates, some papers suggested that Eastern Asia, South Eastern Asia and Northern and Western Africa suffered from the highest incidence among both sexes and highest mortality in females. Likewise, the highest mortality was found in Eastern Asia and Western Africa in males. Accordingly, the lowest incidence and mortality tended to predominate in South Central Asia, Western Asia, Central Europe, and Eastern Europe for either gender [1, 41]. Based on a report in China, the unfavorable trends of LC in men and women was more likely to be exposed to risk factors such as tobacco use, alcohol abuse, and income inequality that interactions between them may have led to an increment in risk of LC . In a recent incidence and mortality descriptive analysis from GLOBOCAN 2018, the author observed that few regions, like East Asia and South East Asia had higher disparities in men and women, whilst Central America and South America had lesser male-female disparities in terms of ASIR and ASMR as well as counts . Another research performed a comprehensive analysis based on the GBD study 2017 assessed the global temporal trends in liver cancer incidence and mortality during 1990–2017. They observed that East Asia had the highest ASIR and ASMR for both genders and the latter was as high as 40.4/100,000 among males. The biggest difference in the ASMR of men and women was revealed in High-income Asia Pacific. Contrary to our results, in their research, the incidence and mortality have grown in males but reduced in females, suggesting that this gap might broaden in the future. Further, they found that the incidence and mortality rates were greater in females compared to males in the Latin American countries over the last 28 years. Nonetheless, more researches are required to confirm these conjectures . In a recent study by Li et al., the authors provided evidence that hepatocellular carcinoma (HCC) predominantly may affect males with incidence twofold to fourfold more common in males than females . Petrick et al. using the joinpoint analysis demonstrated the incidence rates of LC in males were two to three times greater than in females among countries of Africa and the Americans. Compatibly, European countries had the highest variability in incidence between sexes. In their opinion, the higher rates in men is most likely due to higher prevalence of known LC risk factors such as alcohol consumption, smoking, differences in sex steroid hormones, immune responses and/or epigenetic differences between females and males . Nevertheless, we wondered that whether the underlying causes might contribute to this gender disparity. Hence, further examinations are warranted to falsify such these hypotheses. Furthermore, with respect to time trends, it is apparent that there were considerable gaps between males and females in ASIR and ASMR within super-regions; notably, the gaps remained constant until the ending year of this study. Although we could find no regional studies that examined the gap between genders for temporal trends of liver cancer burden, it is probable that differences in some factors such as education, income, and employment are conducive to the gender gaps. Nonetheless, future studies require to find further factors related to the differences and explore ways to narrow the gender gap over time. Globally, it was observed about 27.5 and 33.3% reductions in incidence and mortality rates were occurred in total populations, respectively during a 30-year follow-up. This might be due in part to preventive measures including self-examination, public education, and development of new multiple treatment options and better control in past decades.
Particularly, the rates at the global level showed that the LC incidence and mortality rates among males declined by almost 25.7 and 32.3%, respectively from 1990 to 2019. Whilst, the drop among females in incidence and mortality rates were 30.4 and 35.1%, respectively in this 30-year period. Clearly, these results imply that although the males had higher rates, the females have experienced a further reduction in both incidence and mortality throughout the observation period which is encouraging. The reason of the more decrement was not completely investigated. Nonetheless, various explanations could be proposed for this phenomenon. First, steeper overall improvement in LC in women than men is potentially associated with the success of public health effects and growing the awareness of LC risk. Second, females were significantly more possibly to undergo liver transplant. Ultimately, females with LC were also more likely to undergo screening than males with the disease.
Based upon the data from the GBD study 2019, the patterns for age-specific trends differed across regions. It was illustrated that much more similar rates of change in LC incidence and mortality in the respective continents occurred among persons aged 0–14 and 15–49 so that the growth trajectories for these age groups remained fixed in all regions over the whole study time 1990–2019. In accordance with a previously reported study, we have seen that the LC incidence and mortality rates in the group aged 50–69 and = > 70 years were higher than that of the 15–49 and 0–14 age groups throughout the study period .
The results obtained from LGC analysis demonstrated that the highest initial values of incidence and mortality by the year 1990 were belonged to SAEAO among individuals aged 70 years or older and the lowest were recorded in NAME and HI in individuals aged below 14 years, respectively, demonstrating older people experienced a heavier disease burden due to LC. Subsequently, individuals aged 70+ years had the most average rates of change in incidence and mortality among CEEECA countries, while the lowest were occurred in SSA for the same age group. The evidence indicates that LC has a strong relationship with age such that the aging could contribute to the increasing disease burden of LC. Furthermore, both age-specific incidence and mortality trends showed the most rapid increases among HI (from 1990 to 2006) and CEEECA (from 1999 to 2010) countries compared to the others in those aged 70 and over; therefore calling for better preventive measures in these countries. Regarding the patterns of incidence and mortality for patients aged 50–69 years, with exception of SAEAO, the trends were relatively steady during the interval 1990–2019. In parallel, Zhai et al. using GBD data 2017 observed that the incidence of primary liver cancer was higher in middle-aged people among high and middle income countries . As well, Lee et al. in Korea as a high-income country concluded that age-specific incidence of LC incremented gradually with age and those aged over 80 years possess the highest incidence, and follows a similar trends in some Asia countries including China, Japan. Philippines, Singapore, and Thailand . In another study, researchers found that trends of mortality from LC in the United States and Australia were similar to those observed in Central and Northern European countries, indicating upward trends in individuals aged 45–64 years . A study by Liu and colleagues assessed temporal patterns in LC incidence and death by sex, age, and etiology in China from 1990 to 2017. They reported the most pronounced increase in ASIR and ASMR were among older people aged ≥ 70 years, whereas it remained stable in the other two age groups (15–49 and 50–69 years) during 2004–2014, which is consistent with our results. The rises were partly due to the increase in healthcare availability in recent years . On the contrary, a Chinese study with a follow-up period of 30 years documented that people between ages of 15 and 49 years had a greater reduction in incidence and deaths from 1990 to 2019 compared with people at 50–69 years of age . Overall, temporal trends in LC incidence and mortality rates among all age groups have been decreasing in the world throughout the study period which is reflective of improved therapeutic strategies. Interestingly, the 15–49 years old group had the highest percentage decrease in incidence and mortality accounted for about 38.7 and 46.7% respectively compared to other age groups. According to some publications, age is a firm prognosis in many malignant cancers; nevertheless, the association between aging and cancer is still not clear [47, 48]. It was confirmed that genome alternations including DNA mutations accumulate with age. A recent study delineate the liver greatly affected by aging in terms of its function and structure and contains regulation of the tumorigenicity and development of HCC through liver microenvironment modulation which might facilitate tumor formation and progression .
In the current article, [1-MIR] has been utilized as an approximation of the five-year relative survival clarified by a number of evidence-based studies [3, 4, 50] that can be reliably applied. In general, the geographic continent analysis provided that the super-regions were different in time patterns of [1-MIR] representing regional varieties in health care systems, screening cancer, effective treatment, and prognosis for LC. Of the 7 super-regions compared, we discovered that HI had the highest [1-MIR] rates for both genders, males, and the 0–14 years old population from 1990 to 2019. The values of [1-MIRs] in both genders and males suggest the five-year relative survival rates were moderately poor in these countries which might be due to high recurrence rates and a more advanced tumor stage at diagnosis. In contrast, subjects of 0–14 years have experienced almost superior five-year relative survival rates in comparison to other three age categories such that the rate was about 61% at the end of the follow-up years. A possible explanation includes that, children 0–14 years of age had the most favorable prognosis; plus, poorer biological behavior among younger people might be compensated by better liver function, more aggressive therapy, and faster recovery contributing to longer survival . An alternative elucidation could be that, tumors from age groups with favorable survival are biologically less aggressive compared with those tumors from age groups with lower survival. Our findings are in agreement with some previous reports in the United States  and Taiwan . There is yet a descriptive study to be undertaken using GLOBOCAN 2012 database that implicated high rates of MIRs in less developed regions regardless of age and gender. That study also reported North America had the lowest MIR (0.82), while Latin America and Caribbean had the highest MIRs (1.04). These different results may thus contribute to the treatment familiarity, surgical, and invasive procedure techniques . Globally, the overall picture of the observed findings of [1-MIR] rates indicated the rates were not considerable and almost all of them were around 0 for either sex or different age categories, implying a poor five-year relative survival rate and worsening cancer care. Constant development of systemic therapies especially in patients with an advanced stage, improving the early detection of LC, enhancing surgical techniques, postoperative care, and timely surgical treatment are key factors in improving the survival rate for patients with LC. However, since the [1-MIR] is an indirect measure and also an overestimation of LC five-year relative survival with at least 10% in some countries, the results should be interpreted with caution . Notably, due to the limited information in this context, further follow-up studies of the [1-MIR] from liver cancer would be warranted in various parts of the world.
Concomitantly, joinpoint regression analysis demonstrated that liver cancer incidence and mortality have declined significantly in both males and females over the past two decades. Likewise, similar trends in incidence and mortality were observed across age groups. [1-MIR], however, exhibited significant upward trends in age and sex groups during the study period. This means that the mortality rate was declining over time more quickly compared to the incidence rate. Few studies have examined the trend of liver cancer in the world as a whole in terms of incidence, mortality and [1-MIR]. A study by Lin et al. on GBD 2017 data showed that the mortality rate and incidence rate increased between 1990 and 2017 . That is completely in contrast to our study. One reason could be that the trend incidence and mortality assessments in their study were only based on the APC and not the AAPC. Therefore, the overall trend of mortality and incidence rate in their study was incorrectly reported. To examine the incidence and mortality of a cancer over the years, it is necessary to report AAPCs to determine whether the trend has changed significantly. APC may decrease in one period and increase in another, but AAPC may not show any significant change. In another paper conducted by Huang et al., an upward in incidence rates was revealed in many countries between 1980 and 2017. However, a global analysis of trends in incidence was not conducted in this study . In general, when examining the trends of incidence and mortality worldwide, the correct statistical methodology should be considered. Whereas in the above studies, AAPC was reported for different regions but not specifically for global. One of the advantages of the AAPC criteria is that it can provide information about how incidence and mortality have changed over time. This may help explain global differences in the liver cancer trends.
The ICC estimates in unconditional multilevel models (without any independent variable) declared a high degree of clustering in the GBD data so that the majority of the variation lies at the country level. Indeed, 88% of total variations in repeated measures of incidence and mortality are due to differences between countries. The differences might be attributed to some factors such as income inequality, access to the health care facilities, and clinical and behavioral characteristics. The current study employed 4-level random intercept multilevel hierarchical models to explore whether there are significant differences between more developed and less-developed countries in terms of mean incidence and mortality during the specified time interval. By using these models, the data hierarchical structure can be specified by varying the random effects at each level of the hierarchy. In these hierarchies, there is vital information to identify better and targeted policy formulation. The results obtained from fitting multilevel model exhibited that the development status had a statistically significant negative effect on both LC incidence and mortality rates such that the means of these metrics in more developed countries were significantly lower than those in less-developed ones. This observation demonstrates the importance of socio-economic factors in declining trends of LC burden over the long-term. In 2012, it was reported approximately 95% of total incidence and 96% of all deaths from LC occurred in less developed areas. These countries are often in the process of industrialization which can affect all aspects of lives like health . On the other hand, HBV causes 2/3 cases of LC in less-developed countries, while only 1/4 cases in more developed ones. Moreover, HCV in less-developed countries (such as Egypt and Liberia) is a fairly less important cause of LC so that it causes 1/8 cases, whilst almost 1/2 cases in more developed countries. Thus, HBV and HCV can be strong risk factors for LC in less-developed countries . Our findings are in keeping with recently published cross-sectional studies that found a negative correlation between LC incidence and mortality and HDI levels. The authors confirmed that the countries with higher levels of HDI were related with lower LC incidence and mortality rates [12, 56,57,58]. The correlation is more likely caused by promotion of aggressive clinical guidelines, the development of sophisticated technology, the improvement of socioeconomic status, and increase in average academic years. On the other hand, health care disparities and availability of essential technology and resources for prevention, may result in the substantial gap between the more developed and less-developed populations in terms of incidence and mortality. This is a worrying message for health policy makers. Consequently, to close the gap, both wealthier and poorer parts of the world should be focused on promoting heightened awareness, preventive measures, earlier detection, better patient care, screening, and effective treatment.
The strengths of the present study are worthy of mention. First, this work benefitted from its longitudinal design, with a notable number of repeated measurements, and a lengthy follow-up which can provide more evidence of a causal association. The novelty of this study beyond previous researches on the relationship of HDI and burden of LC is its use of multilevel modelling approach to attribute the variability of random effects across various levels of hierarchical structure. Of note, the consideration of random effects at each level makes it possible reliable estimates by reflecting hierarchy, thereby correcting the underestimation of standard errors. However, such variations cannot be captured in traditional repeated measures analysis such as analysis of variance (ANOVA). Furthermore, since liver cancer tumors have high lethality, the [1-MIR] appears to be as an alternative fairly accurate simple measure for five-year relative survival rate. Despite these strengths, a number of limitations of this research should be recognized. First of all, this report was based on the most recently updated data from the GBD 2019 in which ascertainment bias in cancer registries may lead to a problem in data accuracy. Second, although we tried to consider nearly 204 countries and territories, missing data of liver cancer incidence and mortality reduced our cases to approximately 184 countries due to limited information sources. Finally, owing to the lack of longitudinal information of important risk factors such as HBV and HCV infections, occupational exposures, chemical, and pollution exposures, alcohol drinking, and tobacco use, the effects of them on liver cancer outcomes were not examined. These factors may play important roles in explaining and detecting trend of LC incidence and mortality rates. Consequently, we suggest further future longitudinal studies to determine the impact of the underlying factors on the liver cancer outcomes in different regions and countries using random slope coefficient multilevel model.