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Journal of Clinical and Experimental Hepatology logoLink to Journal of Clinical and Experimental Hepatology
. 2023 Dec 14;14(2):101320. doi: 10.1016/j.jceh.2023.101320

The Global Burden of Early-Onset Biliary Tract Cancer: Insight From the Global Burden of Disease Study 2019

Pojsakorn Danpanichkul ∗,∗, Cheng H Ng †, Darren JH Tan ‡, Mark D Muthiah †,‡, Siwanart Kongarin §, Karan Srisurapanont §, Yatawee Kanjanakot ‖, Kwanjit Duangsonk , Daniel Q Huang †,‡,#, Hiroyuki Suzuki ∗∗, Denise M Harnois ††, Ju D Yang ‡‡, Mazen Noureddin §§, Karn Wijarnpreecha ‖‖,¶¶,∗∗
PMCID: PMC10796968  PMID: 38261906

Abstract

Backgrounds/objectives

The escalating incidence of early-onset gastrointestinal cancers is becoming a primary global health concern. Biliary tract cancer (BTC) has been relatively understudied in this regard. We conducted an epidemiological study regarding the burden of this condition.

Methods

We utilized data from the Global Burden of Disease Study 2019 to investigate the temporal trends in early-onset BTC (EOBTC), encompassing the estimation of frequencies and age-standardized rates (ASRs) of EOBTC incidence, mortality, and disability-adjusted life-years (DALYs), from 2010 to 2019.

Results

EOBTC constituted nearly 7%of all BTC cases worldwide. The incidence rates of EOBTC decreased significantly in most regions, except in the Eastern Mediterranean (annual percentage change +1.04 %), where the incidence is rising. Stratified by the sociodemographic index (SDI), countries with low middle SDI (annual percentage change +0.5 %) show increasing incidence of EOBTC. The ASR of death and DALYs decreased in most regions. The ASR of EOBTC-related death and disability attributable to high body mass index increased in most regions, with the highest increase in Southeast Asia and low, middle SDI strata.

Conclusions

There was a reduction in the burden of EOBTC globally, except for Eastern Mediterranean countries and low-middle SDI countries.

Keywords: biliary tract cancer, cholangiocarcinoma, gallbladder cancer, early-onset cancer

Biliary tract cancer (BTC) is a highly aggressive invasive tumor that arises from the gallbladder, cystic duct, or biliary tree.1,2 The deadly nature of BTC, with high mortality rates, poses a significant challenge to the healthcare community.3 The mortality rate for BTC is alarmingly high, with only 20 % of patients surviving beyond 5 years after diagnosis.4 Moreover, up to 20 % of cancers with an unknown primary site can be attributed to a biliary tract origin, underscoring the significance of this condition.5,6

Historically, cancer, including BTC, has been considered a disease of the elderly. However, growing research indicates an upward trend in younger individuals affected by malignancies.7,8 The increasing incidence of various cancers, including gastrointestinal cancers, among younger individuals, may be due to the interaction between genetics, behavioral, and environmental factors.9,10 Although numerous studies have explored the incidence of other cancers among younger populations, only a few studies have investigated BTC in this context.11, 12, 13 Therefore, this study aims to fill the gap by investigating the temporal trend of early-onset BTC (EOBTC) incidence, mortality, and disability-adjusted life years (DALYs) in young adults from 2010 to 2019.

METHODS

Ethic Approval Statements

The current study is exempt from IRB review as secondary data analysis with no confidential patient information was involved.

Data Source

The present research draws data from the Global Burden of Disease Study 2019 (GBD 2019). This global initiative aims to evaluate the effects of diseases and risk factors across 204 countries and territories worldwide. By utilizing information from the online data catalog Global Health Data Exchange (GHDx) query tool, which is managed by the Institute for Health Metrics and Evaluation, this study examines the incidence, mortality, and DALYs associated with BTC in the overall population and young adults on a global scale. The comprehensive nature of the GBD 2019 ensures a robust assessment of the impact of this condition across geographical regions and populations.

Definitions and Measures

BTC refers to C23 and C24 as per the International Classification of Diseases, Tenth Revision (ICD-10)–was used to map the presence of the disease. EOBTC (early-onset biliary tract cancer) referred to BTC diagnosed in patients aged 15–49 years using the same ICD 10 code. The primary objective of this investigation is to quantify the disease burden of EOBTC worldwide, specifically stratified by the World Health Organization (WHO) 6 regions, including Africa, the Eastern Mediterranean, Europe, the Americas, Southeast Asia, and the Western Pacific. However, for the Americas, the WHO classification combined North, Central, and South America, exhibiting different epidemiological variations regarding BTC. Additionally, we also stratified countries by sociodemographic index (SDI).

Sociodemographic Index (SDI) is a composite measure that combines rankings of countries and territories per capita incomes, educational attainment, and fertility rates (Supplemental Table 1). The index is on a scale of 0–1, where 0 represents the minimum level of development relevant to health, and 1 represents the maximum level. Based on the SDI values, countries are categorized into high, high-middle, middle, low-middle, and low SDI categories. The comprehensive methodology adopted to ascertain the disease burden of BTC from the GBD 2019 has been described previously.14 Succinctly, the data harnessed for this study were derived from population-based health registries, vital registration systems, or verbal autopsy studies. To ensure data accuracy, the GBD 2019 study evaluated the data quality from each country or territory on a scale from 0 (lowest quality) to 5 (highest quality). Data quality ratings for the causes of death data from each country are available in Supplemental Table 2. Various statistical methodologies, such as misclassification correction, garbage code redistribution, and noise reduction algorithms, were employed to manage data heterogeneity. The researchers employed the Cause of Death Ensemble model, a Bayesian geospatial regression analysis, to estimate the mortality linked to BTC by age, sex, country/territory, and year.

For the thorough analysis of risk factors, GBD 2019 groups 82 individual risk factors into three distinct groups: (1) environmental and occupational, (2) behavioral, and (3) metabolic, and the estimation methods for individual risk factors have been detailed in the GBD 2019 risk factors summary article. To assess the level of exposure to each risk factor, the GBD 2019 study utilizes Bayesian meta-regression modeling, known as DisMod-MR 2.1, which considers factors such as age, sex, and spatiotemporal location. For risk factors with stable exposure, spatiotemporal Gaussian process regression was employed. The population-attributable fraction for each risk factor was calculated by considering the risk function, exposure level, and theoretical minimum risk exposure level across age, sex, location, and year. The burden of biliary tract cancer attributed to risk factors was then calculated by multiplying the deaths and DALYs by the corresponding population-attributable fraction. In GBD 2019, the burden of high body mass index (BMI) was defined as a BMI greater than 20–25 kg/m2.15

Data and Statistical Analysis

Estimates for the frequency of incident cases and deaths were reported with 95 % uncertainty intervals (UIs) as 2.5th and 97.5th ranked values across all 1000 draws from a posterior distribution. Age-standardized rates were derived using the direct method to the GBD 2019 population estimate.16

Age-standardized incidence rate (ASIR) is calculated by dividing the number of new disease cases in a particular age group by the total population in that age group, multiplied by 100,000, expressing the incidence as a population unit. Age-standardized death rate (ASDR) is obtained by dividing the number of deaths in a particular age group by the corresponding population of that age group and multiplying it by 100,000. Similarly, Age-standardized disability-adjusted life years (ASDALYs) are obtained by dividing the number of disabilities in a particular age group by the population of a specific age group and multiplying it by 100,000. The DALYs measure the disease burden by combining years of life lost and years lived with disability. The proportion of EOBTC to BTC is calculated by dividing the number of incidences in 2019 of EOBTC by that of EOBTC at the same time.

For changes in age-standardized rates over time, we calculated annual percentage change (APC) and 95 % confidence interval (CI) in age-standardized rates using the Joinpoint regression program, version 4.6.1.0 (Statistical Research and Applications Branch, National Cancer Institute, Bethesda, MD). When the annualized rate of change and the lower boundary of its 95 % CI were both positive, this was considered an increasing trend. By contrast, when the annualized rate of change and the upper limit were negative, this was considered a decreasing trend.

RESULTS

The Global Burden of Biliary Tract Cancer in all Ages

Globally in 2019, the estimated number of cases, deaths, and DALYs attributed to BTC were 199,211 (95 % UI 166,769 to 219,615) cases, 172,441 (95 % UI 144,899 to 188,615) deaths, and 3.62 million (95 % UI 3.1 million to 4 million) DALYs. The ASIR, ASDR, and ASDALYs for BTC in 2019 were 2.49 (95 % UI: 2.09 to 2.75), 2.17 (95 % UI: 1.81 to 2.38), and 43.99 (95 % UI: 37.59 to 48.24) per 100,000, respectively (Table 1). Between 2010 and 2019, there was a decline in ASIR, ASDR, and ASDALYs with an APC of −0.87 % (95 % CI: −0.97 to −0.76 %), −0.92 % (95 % CI: −1.01 to −0.82 %), and −0.99 % (95 % CI: −1.06 to −0.91 %), respectively.

Table 1.

Frequencies and Age-Standardized Rates of Incidence, Deaths, and DALYs of Patients With Biliary Tract Cancer in 2010 and 2019, and the Temporal Changes of Age-Standardized Rates From 2010 to 2019, Stratified by Sex.

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Abbreviation: ASR: age-standardized rate, APC: annual percentage change, DALYs: disability-adjusted life years, SDI: sociodemographic index.

Stratified by sex, the ASIR for females experienced a decrease with an APC of −0.9 % (95 % CI: −1.02 to −0.77 %), while males had a reduction with an APC of −0.81 % (95 % CI: −0.87 to −0.75 %). The ASDR also declined in females with an APC of −0.95 % (95 % CI: −1.05 to −0.85 %) and males with an APC of −0.83 % (95 % CI: −0.92 to −0.73 %). Similarly, the ASDALYs showed a decrease in females aged 15–49 years with an APC of −0.96 % (95 % CI: −1.05 to −0.86 %), while males experienced a descending trend with an APC of −1% (95 % CI: −1.09 to −0.91 %) (Table 1).

By WHO region, the Western Pacific region had the highest number of BTC-related incidences (n = 75,891), deaths (n = 65,405), and DALYs (1.25 million). Between 2010 and 2019, all regions experienced a decline in ASIR, ASDR, and ASDALYs of BTC, with the most significant changes observed in the Western Pacific region with an APC of −1.62 % (95 % CI: −1.88 to −1.36 %) for ASIR, −1.78 % (95 % CI: −2.04 to −1.52 %) for ASDR, and −1.88 % (95 % CI: −2.1 to −1.65 %) for ASDALYs (Table 1). In terms of the America subregion, Latin America and the Caribbean exhibited the highest number of incidences (n = 45,810), deaths (n = 42,299), and DALYs (976,536). Stratified by SDI, all strata experienced a decline in ASIR and ASDR of BTC, with the most significant changes observed in low SDI countries, with an annual percent change (APC) of −1.25 % (95 % CI: −1.34 to −1.15 %) for ASIR and −1.47 % (95 % CI: −1.56 to −1.38 %) for ASDR. ASDALYs exhibited the highest decline in low middle SDI countries with an APC of −1.5 % (95 % CI: −1.63 to −1.37 %) (Table 1). The ASIRs of BTC in 2019 by country are demonstrated in Figure 1A and Supplemental Table 3.

Figure 1.

Figure 1

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(A) Age-standardized incidence rates of biliary tract cancer in patients across all ages in 2019 by country/territory. (B) Age-standardized incidence rates of biliary tract cancer in patients aged 15–49 in 2019 by country/territory.

The Global Burden of Early-Onset Biliary Tract Cancer

For EOBTC, the estimated number of cases, deaths, and DALYs in 2019 were 13,723 (95 % UI: 11,736 to 15,194) cases, 9761 (95 % UI: 8321 to 10,715) deaths, and 456,165 (95 % UI: 388,506 to 500,980) DALYs (Figure 2A, C and E). The ASIR, ASDR, and ASDALYs for EOBTC among young adults in 2019 were 0.35 (95 % UI: 0.3 to 0.39), 0.25 (95 % UI: 0.21 to 0.27), and 11.59 (95 % UI: 9.87 to 12.73) per 100,000, respectively (Table 2, Figures 2B, D and F). Like the older population, between 2010 and 2019, there was a decrease in ASIR, ASDR, and ASDALYs for EOBTC, with an APC of −0.44 % (95 % CI: −0.59 to −0.29 %), −0.57 % (95 % CI: −0.75 to −0.4 %), and −0.57 % (95 % CI: −0.73 to −0.4 %), respectively (Table 2).

Figure 2.

Figure 2

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(A) The number of biliary tract cancer cases in patients aged 15–49 in 2010 and 2019; stratified by World Health Organization region. (B) Age-standardized incidence rates attributable to biliary tract cancer in patients aged 15–49 in 2010 and 2019 by the World Health Organization region. (C) The number of biliary tract cancer-related deaths in patients aged 15–49 in 2010 and 2019; stratified by World Health Organization region. (D) Age-standardized death rates attributable to biliary tract cancer in patients aged 15–49 in 2010 and 2019, by the World Health Organization region. (E) The number of biliary tract cancer-related disabilities in patients aged 15–49 in 2010 and 2019; stratified by World Health Organization region. (F) Age-standardized disability-adjusted life years attributable to biliary tract cancer in patients aged 15–49 in 2010 and 2019, by the World Health Organization region.

Table 2.

Frequencies and Age-Standardized Rates of Incidence, Deaths, and DALYs of Patients With Biliary Tract Cancer Aged 15–49 years in 2010 and 2019, and the Temporal Changes of Age-Standardized Rates From 2010 to 2019, Stratified by Sex.

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Abbreviation: ASR: age-standardized rate, APC: annual percentage change, DALYs: disability-adjusted life years, SDI: sociodemographic index.

The Global Burden of Early-Onset Biliary Tract Cancer, Stratified by Sex

In 2019, the estimated number of new cases in females was 7178 (95 % UI: 5856 to 8326), with 5277 (95 % UI: 4191 to 6060) deaths and 246,328 (95 % UI: 195,085 to 283,481) DALYs. Among males aged 15–49 years, there were 6544 (95 % UI: 5304 to 7446) cases, 4485 (95 % UI: 3753 to 5084) deaths, and 209,837 (95 % UI: 176,353 to 237,759) DALYs (Table 2, Figure 3G–I). The ASIR for females decreased with an APC of −0.37 % (95 % CI: −0.59 to −0.15 %), and males decreased with an APC of −0.52 % (95 % CI: −0.66 to −0.38 %). The ASDR decreased in females with an APC of −0.41 % (95 % CI: −0.64 to −0.18 %) and males with an APC of −0.76 % (95 % CI: −0.99 to −0.53 %). Similarly, the ASDALYs decreased in females aged 15–49 years with an APC of −0.43 % (95 % CI: −0.66 to −0.2 %), while males experienced a descending trend with an APC of −0.72 % (95 % CI: −0.9 to −0.54 %) (Table 2).

Figure 3.

Figure 3

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(A) The number of biliary tract cancer cases in patients aged 15–49 in 2010 and 2019; stratified by Sociodemographic Index. (B) The number of biliary tract cancer-related deaths in patients aged 15–49 in 2010 and 2019, stratified by Sociodemographic Index. (C) The number of biliary tract cancer-related disabilities in patients aged 15–49 in 2010 and 2019, stratified by Sociodemographic Index. (D) Age-standardized incidence rates attributable to biliary tract cancer in patients aged 15–49 in 2010 and 2019, by Sociodemographic Index. (E) Age-standardized death rates attributable to biliary tract cancer in patients aged 15–49 in 2010 and 2019, by Sociodemographic Index. (F) Age-standardized disability-adjusted life years attributable to biliary tract cancer in patients aged 15–49 in 2010 and 2019, by Sociodemographic Index. (G) Age-standardized incidence rates attributable to biliary tract cancer in patients aged 15–49 in 2010 and 2019 by gender. (H) Age-standardized death rates attributable to biliary tract cancer in patients aged 15–49 in 2010 and 2019 by gender. (I) Age-standardized disability-adjusted life year’s attributable to biliary tract cancer in patients aged 15–49 in 2010 and 2019 by gender.

The Global Burden of Early-Onset Biliary Tract Cancer, Stratified by the World Health Organization Region and the America Subregion

For EOBTC, the Southeast Asia region had the highest number of EOBTC-related incidences (n = 4265), deaths (n = 3308), and DALYs (n = 154,665) (Table 2, Figure 2A and C, and 2E). Similar to the pattern observed for older age groups with BTC, Africa had the lowest number of EOBTC-related incidents (n = 673), deaths (n = 542), and DALYs (25,658). In the America subregion, Latin America and the Caribbean exhibited the highest number of incidences (n = 1295), deaths (n = 963), and DALYs (44,815). Between 2000 and 2019, Africa, Europe, the Americas, and the Western Pacific region experienced a decline in ASIR, ASDR, and ASDALYs of EOBTC. The Southeast Asia region showed stable rates, while the Eastern Mediterranean region witnessed an increase with an APC of 1.04 % (95 % CI: 0.97–1.11 %) for ASIR, 0.71 % (95 % CI: 0.54–0.88 %) for ASDR, and 0.65 % (95 % CI: 0.48–0.81 %) for ASDALYs (Table 2).

The Burden of Early Onset Biliary Tract Cancer by Country

Figure 1B and Supplemental Table 4 display the ASIRs and ASDRs of EOBTC by country in 2019. The ASIRs ranged from 0.06 (95 % UI 0.04 to 0.09) per 100,000 in Nigeria to 1.7 (95 % UI 1.19 to 2.37) in Chile. Among the countries with the highest ASIRs are Thailand (ASIR: 1.35, 95 % UI 0.71 to 1.98), Taiwan (ASIR: 0.88, 95 % UI 0.58 to 1.27), and the Republic of Korea (ASIR: 0.82, 95 % UI 0.6 to 1.24). The ASDRs ranged from 0.05 per 100,000 (95 % UI 0.04 to 0.07) in Nigeria to 1.12 per 100,000 (95 % UI 0.94 to 1.4) in Chile. Besides Chile, countries such as Thailand (ASDR: 0.82, 95 % UI 0.43 to 1.19), Mongolia (ASDR: 0.57, 95 % UI 0.22 to 0.9), and Bolivia (ASDR: 0.55, 95 % UI 0.35 to 0.82) also had notable high ASDRs.

The Burden of Early Onset Biliary Tract Cancer, Stratified by the Sociodemographic Index

In terms of EOBTC, the middle SDI countries had the highest number of EOBTC-related incidences (n = 4172) and deaths (n = 3030), and DALYs (141,466) (Table 2, Figure 3A and B, and 3C). The ASIR, ASDR, and ASDALYs of EOBTC stratified by SDI can be found in Figures 3D, 3E, and 3F).

Aligned with BTC in older age groups, EOBTC showed the lowest number of incidences (n = 1173), deaths (n = 970), and DALYs (45,750) in low SDI countries. Between 2010 and 2019, all SDI strata experienced a decline in ASIR, with the most significant change observed in high SDI countries (APC: −1.44 %, 95 % CI -1.64 to −1.24 %) (Table 2). ASDR and ASDALYs of EOBTC also declined in all SDI strata but remained stable in low-middle SDI countries (Table 2). The most pronounced decline was observed in high SDI countries for both ASDR (APC -1.54 %, 95 % CI: −1.7 to −1.38 %) and ASDALYs (APC -1.51 %, 95 % CI: −1.67 to −1.35 %).

The Burden of Early Onset Biliary Tract Cancer Attributable to High Body Mass Index

The number of deaths, DALYs, ASDRs, and ASDALYs of EOBTC attributable to high BMI in people aged 15 to 49 by region, country, SDI, and gender are summarized in Supplemental Table 5 and Figure 4. From 2010 to 2019, the ASDRs (APC:0.99 %, 95 % CI 0.83 to 1.14) and ASDALYS (APC: 1.01 %, 95 % CI 0.85–1.17 %) of EOBTC attributable to high BMI increased. ASDRs (APC: 0.86 %, 95 % CI 0.66–1.06 %) and ASDALYs (APC: 0.87 %, 95 % CI 0.67–1.08 %) increased in females and to a high extent in males (ASDR APC: 1.4 %, 95 % CI 1.31–1.5 %; ASDALYs APC: 1.43 %, 95 % CI 1.34–1.51 %). By WHO region, the Southeast Asia region had the highest number of EOBTC-related deaths (n = 397) and DALYs (18,290) attributable to high BMI (Figures 4A and 4C). By SDI, the middle–high SDI exhibited the highest EOBTC-related deaths (n = 507) and DALYs (23,416) (Figure 4B and 4D). The age-adjusted rates of EOBTC attributable to high BMI were most elevated in America in both ASDR (0.07, 95 % UI 0.04 to 0.1) and ASDALYs (3.13, 95 % UI 1.82 to 4.7) (Figure 4E and 4G). Stratified by SDI, this burden was highest in middle high SDI in both ASDR (0.05, 95 % UI 0.03 to 0.08) and ASDALYs (2.17, 95 % UI 1.19 to 3.68) (Figure 4F and 4H). In addition, the most pronounced increase in deaths (APC: 2.21 %, 95 % CI 1.97–2.45 %) and DALYs (APC: 2.17 %, 95 % CI 1.91–2.42 %) from EOBTC attributable to high BMI was also observed in Southeast Asia. In terms of the America subregion, Latin America and Caribbean exhibited the highest burden, with mortality of 237 (95 % UI 138 to 364) and disabilities of 10,915 (95 % UI 6365 to 16,808) regarding EOBTC attributable to high BMI. The decline of ASDR and ASDALYs was observed in High-income North America and South Latin America. In contrast, the burden was increased in Latin America and Caribbean in both deaths (APC: 0.66 %, 95 % CI 0.5–0.82 %) and DALYs (APC: 0.67 %, 95 % CI 0.51–0.83 %). Stratified by SDI, both ASDRs and ASDALYs increased in all regions except for the high SDI region. The greatest increases in ASDR (APC: 2.86 %, 95 % CI 2.75–2.97 %) and ASDALYs (APC: 2.82 %, 95 % CI 2.71–2.93 %) were observed in low-middle SDI countries. Similar parameters across all aged populations were designated in Supplemental Table 6.

Figure 4.

Figure 4

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(A) The number of biliary tract cancer-related deaths attributable to high body mass index in patients aged 15–49 in 2010 and 2019; stratified by World Health Organization region. (B) The number of biliary tract cancer-related deaths attributable to high body mass index in patients aged 15–49 in 2010 and 2019; stratified by Sociodemographic index. (C) The number of biliary tract cancer-related disabilities attributable to high body mass index in patients aged 15–49 in 2010 and 2019; stratified by World Health Organization region. (D) The number of biliary tract cancer-related disabilities attributable to high body mass index in patients aged 15–49 in 2010 and 2019; stratified by Sociodemographic index. (E) Age-standardized death rates of biliary tract cancer attributable to high body mass index in patients aged 15–49 in 2010 and 2019; stratified by World Health Organization region. (F) Age-standardized death rates of biliary tract cancer attributable to high body mass index in patients aged 15–49 in 2010 and 2019; stratified by Sociodemographic index. (G) Age-standardized disability-adjusted life years of biliary tract cancer-related disabilities attributable to high body mass index in patients aged 15–49 in 2010 and 2019; stratified by the World Health Organization region. (H) Age-standardized disability-adjusted life years of biliary tract cancer-related disabilities attributable to high body mass index in patients aged 15–49 in 2010 and 2019; stratified by Sociodemographic index.

DISCUSSION

Historically, cancer, including BTC, has been predominantly observed in older individuals. However, emerging evidence indicates an increasing incidence of cancer occurrence among younger people.17,18 However, there is a lack of comprehensive epidemiological trends of EOBTC, which limits our understanding of its global, regional, and national variation. To address this gap, our study utilizes data from GBD 2019 to investigate the burden of EOBTC in the younger population. Aligned with the BTC in older counterparts, the EOBTC burden is also highest in the very same regions as BTC, particularly in Southeast Asia, Latin America, and the Caribbean. The global variation is noticeable, and the incidence ranges from 0.06 cases per 100,000 in Nigeria to 20-fold higher in endemic areas such as Chile and Thailand.19, 20, 21

The Asia–Pacific region, characterized in GBD 2019 as Southeast Asia and the Western Pacific region, exhibited the highest burden of BTC. This could be explained by the high prevalence of parasitic infection, namely Opisthorchiasis, which is the leading risk factor of BTC in Southeast Asia.22, 23, 24, 25 However, the risk factors vary by each country. For example, the high burden of this condition among the Thai population could be explained by eating fermented food and Praziquantel use.21 Nevertheless, it needs to be mentioned that the GBD 2019 did not separate BTC into gallbladder and cholangiocarcinoma.16 For example, India contributes 10 % of the global burden of gallbladder cancer. The risk factors could overlap with BTC in other areas but also include exposure to heavy metals, drinking unsafe water, and pollutants in patients with gallstones that have been identified, which promote carcinogenesis.26, 27, 28 Regarding the Pacific Island, obesity seemed to be the prominent risk factor compared to risk factors for Asians.29 Our study aligned with previous studies regarding the downtrend of BTC in the Asia–Pacific region.30 However, our study contrasts with the study by Kang et al. from Korea, which pointed out the rising trend of extrahepatic cholangiocarcinoma.31 This could result from the differences in pathogenesis, risk factors, and age group among different types of BTC. However, it should be mentioned that the studies regarding BTC in this region focused mainly on the BTC in the overall population.26,27,32 Only one study from Japan has been conducted regarding EOBTC.33 Further study needs to be conducted to understand the epidemiology of EOBTC in this region comprehensively.

In terms of Latin America and the Caribbean, the high burden of BTC, possibly including EOBTC, could be mainly driven by the high burden of gallstones, chronic salmonellosis, and high BMI.34 In terms of sex, the burden of BTC, along with its older counterparts, was higher in females compared to males.35,36 While the underlying processes remain unclear, multiple studies have reported the heightened exposure to hormones, such as estrogen and progesterone, possibly stimulating the genesis of biliary stones.37 Furthermore, a correlation has been observed between high parity and a heightened risk of gallstones.34,35 In terms of mortality and disabilities, the declining burden could be attributed to the increasing rate of cholecystectomy and other advancements in the healthcare system.38,39

Despite the highest burden of EOBTC and BTC observed in Southeast Asia and Latin America, the highest proportion of EOBTC to overall BTC was observed in Eastern Mediterranean, accounting for 15% of overall BTC cases, compared to 7% on a global scale. Additionally, even though most regions have experienced a decline in incidence, the Eastern Mediterranean has witnessed an increasing trend of burden. The underlying causes behind the rising burden of BTC in the region are unclear. Generally, risk factors associated with BTC include primary sclerosing cholangitis, gallstone, chronic viral infection, and abnormal pancreaticobiliary duct junction.40, 41, 42 Nevertheless, it should be noted that the carcinogenesis of BTC is the result of complex interactions between host and environmental factors.43,44 Therefore, studies focused on this condition in the Eastern Mediterranean region and low-middle SDI countries are crucial for understanding this rising burden.

The incidence and burden of gastrointestinal cancer in the young, including colorectal, pancreatic, and liver cancer, are witnessing an upward trend.9,13,18,45,46 However, the exact causes behind this trend are not fully understood. Still, it could be due to alterations in exposure to risk factors during early life or young adulthood, including a Westernized diet, coupled with the increasing wave of metabolic syndrome and other elements, which could all have played a role in these changes in exposure.47,48 In contrast to other early-onset gastrointestinal cancers, our study found a declining burden of EOBTC. It would be possible that the BTC in the young could be affected by different risk factors compared to other types of risk factors, resulting in a difference in the decadal trend of the burden.49,50 Regarding clinical implication, clinicians and young adults often mistakenly dismiss early cancer symptoms as benign, leading to delayed diagnosis. While no research specifically examines this issue in BTC, a study by Sandhu et al. found that young patients with early-onset colorectal cancer typically wait an over 6 months after symptom onset to receiving treatment, which likely contributes to more advanced disease stages. Currently, no current guideline has been mentioned for the screening of EOBTC. The best method for reducing the burden of this condition could be reducing the risk factors, including obesity. Additionally, current research focusing on BTC, the relatively rare but high mortality condition, has not kept pace with advancements in other fields of early-onset cancer, such as colorectal cancer.51 Therefore, further study needs to be conducted to understand this relatively rare yet high-burden condition.

While our analysis provides valuable insights, it is crucial to acknowledge certain limitations, many of which are tied to our reliance on GBD estimates. The precision of these estimates is largely determined by the quality and comprehensiveness of each country's vital registration system. In countries where such data sources are lacking, the GBD estimates primarily rely on modeling techniques, predictive covariates, historical trends, or extrapolated trends from neighboring countries.16 Additionally, GBD does not provide separate data for each type of BTC, such as gallbladder cancer and extrahepatic- and intrahepatic cholangiocarcinoma, which multiple studies reported the increasing incidence and mortality.52,53 Regardless of these limitations, our study offers a comprehensive update on the declining burden of BTC in the young population, which has increased in the Eastern Mediterranean region and low-middle SDI countries. From bench to bedside, the comprehensive understanding of this condition is still basic compared to other early-onset cancers; there is an ongoing need for further studies basic science, clinical, and epidemiological studies of malignant neoplasm in the biliary tree to be conducted.

The highest burden of EOBTC followed the same pattern as BTC in the older population, which was highest in Southeast Asia and Latin America. The global burden of EOBTC decreased in most regions but increased in incidence in the Eastern Mediterranean region. Given the poor prognosis and under-studied nature of BTC, it is imperative to conduct further studies to better understand EOBTC, particularly in regions where the burden of this disease is high or rising.

Credit authorship contribution statement

Guarantor of the article – Pojsakorn Danpanichkul, Karn Wijarnpreecha.

Conceptualization – Pojsakorn Danpanichkul, Karn Wijarnpreecha, Mazen Noureddin.

Data curation – Pojsakorn Danpanichkul, Siwanart Kongarin, Hiroyuki Suzuki.

Formal analysis – Pojsakorn Danpanichkul, Siwanart Kongarin, Daniel Huang, Mark D. Muthia.

Funding acquisition - No funding required.

Investigation – Pojsakorn Danpanichkul, Darren Jun Hao Tan, Daniel Huang.

Methodology – Pojsakorn Danpanichkul, Karan Srisurapanont.

Project Administration – Pojsakorn Danpanichkul, Cheng Han Ng, Darren Jun Hao Tan.

Supervision –Karn Wijarnpreecha, Daniel Huang, Hiroyuki Suzuki.

Validation – Pojsakorn Danpanichkul, Siwanart Kongarin, Darren Jun Hao Tan.

Visualization – Pojsakorn Danpanichkul, Karan Srisurapanont.

Writing, original draft –Pojsakorn Danpanichkul, Darren Jun Hao Tan, Cheng Han Ng, Mark D. Muthiah.

Writing, review, and editing – Pojsakorn Danpanichkul, Karn Wijarnpreecha, Cheng Han Ng, Denise M Harnois, Ju Dong Yang, Mazen Noureddin, Daniel Huang.

All authors have read and approved the final version of the manuscript for submission.

Funding statement

No external funding was received for this study.

Data availability statement

Data from the Global Burden of Disease (GBD) study 2019 can be accessed utilizing the GlobalHealth Data Exchange (GHDx) query tool (http://ghdx.healthdata.org/gbd-results-tool), which the Institute for Health Metrics and Evaluation maintains.

Conflict of interest

Cheng Han Ng has served as a consultant for Boxer Capital. Daniel Q. Huang has served as an advisory board member for Eisai and receives funding support from the Singapore Ministry of Health’s National Medical Research Council under its NMRC Research Training Fellowship (MOH-000595-01). Mazen Noureddin has been on the advisory board for 89BIO, Gilead, Intercept, Pfizer, Novo Nordisk, Blade, EchoSens, Fractyl, Terns, Siemens, and Roche diagnostic; has received research support from Allergan, BMS, Gilead, Galmed, Galectin, Genfit, Conatus, Enanta, Madrigal, Novartis, Pfizer, Shire, Viking and Zydus; and is a minor shareholder or has stocks in Anaetos, Rivus Pharma and Viking.

Acknowledgments

The figures of world maps were created by using mapchart.net.

Footnotes

Appendix A

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jceh.2023.101320.

Contributor Information

Pojsakorn Danpanichkul, Email: pojsakorndan@gmail.com.

Karn Wijarnpreecha, Email: dr.karn.wi@gmail.com.

Appendix A. Supplementary data

The following is the Supplementary data to this article:

Multimedia component 1
mmc1.docx (234.3KB, docx)

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Multimedia component 1
mmc1.docx (234.3KB, docx)

Data Availability Statement

Data from the Global Burden of Disease (GBD) study 2019 can be accessed utilizing the GlobalHealth Data Exchange (GHDx) query tool (http://ghdx.healthdata.org/gbd-results-tool), which the Institute for Health Metrics and Evaluation maintains.

Articles from Journal of Clinical and Experimental Hepatology are provided here courtesy of Elsevier

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