Burden of liver cancer in the European region from 1990 to... : Annals of Medicine and Surgery (original) (raw)
Introduction
Liver cancer is one of the main causes of cancer-related mortality worldwide and thus significantly contributes to global cancer morbidity and mortality according to the Global Burden of Disease Study 2019[1]. This may in part be explained by the strong relationship liver cirrhosis has with viral hepatitis, alcohol consumption, and metabolic diseases[2,3]. Indeed, a meta-analysis on 1965 subjects suggested that metabolic risk factors-particularly type 2 diabetes-carry a risk ratio for liver cancer of up to 2.25 times more[4]. Other socio-economic factors also come into play, where the incidence of liver cancer is increasing in regions with a high socio-cultural index due mainly to lifestyle factors such as obesity and alcohol use[1,5]. The geographical inequalities in liver cancer incidence are underlined by epidemiological studies[6].
The epidemiology of liver cancer is important to be evaluated in Europe, as it is increasingly a public health and economic burden. Liver cancer is the sixth most common cause of cancer deaths in Europe, with 62,650 new cases and 54,624 deaths reported in 2022[7,8]. Projections indicate a 22% rise in burden by 2040 without improved prevention strategies. Geographical inequalities also point at the problem’s complexity from an incidence rate of 29.5 per 100,000 reported to be recorded by Romania and going as low, for instance, as just 10 per 100,000 in Poland driven by great differences in general prevalence regarding both hepatitis B, C infection, alcohol uptake, and healthcare access but also from the socio-economically vulnerable populations—migrants too[8,9]. Viral hepatitis is a leading risk factor, with 12% and 41% of liver cancer deaths due to hepatitis B and C virus, respectively. On the European front, initiatives are focused on vaccination and antiviral treatments, as highlighted by the “Europe’s Beating Cancer Plan.” The better the epidemiologic understanding, the better the assurance that interventions will be appropriately targeted and equitable[7,10].
Despite the enormous research regarding liver cancer, large gaps exist in understanding its complete epidemiological profile, particularly in Europe; hence, further research in addressing these disparities in global health outcomes will be imperative. The aim of this study is to evaluate the epidemiology of liver cancer in Europe from 1990 to 2021, using data from the Global Burden of Disease Study 2021, in order to identify trends, regional variations, and key risk factors that influence liver cancer outcomes.
Methods
The global burden of disease study
The study was conducted in line with the STROCSS criteria[11]. The Global Burden of Disease Study is an extensive multinational collaboration that assesses diseases and injuries and related risk factors comprehensively and then provides n-year estimates for 204 countries and territories between the years 1990 and 2021. Managed by the Institute for Health Metrics and Evaluation of the University of Washington, the study pulls standardized data from the Global Health Data Exchange tool regarding liver cancer burden. Sources include hospital records, population surveys, censuses, vital registration systems, systematic reviews, and disease-specific registries. To make sure the estimates are robust in cases of incomplete or missing data, the GBD study used the most advanced statistical modeling, including DisMod-MR 2.1, a Bayesian meta-regression tool that incorporates variables for age, sex, and geographic location to enhance the resolution of estimates. Further, it ensures consistency and reliability in many diverse datasets through very strict processes for cleaning of data, thus making findings comprehensive and comparable across many different geographic and demographic contexts[12,13].
Main outcomes and variables
These data include the national and regional incidence and mortality of liver cancer, as well as disability-adjusted life years (DALYs) due to liver cancer for all ages, sexes, and years from 1990 to 2021. Data were then analyzed at the aggregated levels of Europe and the EU member states. The measure of the total burden of disease-DALYs-is the sum of years lived with disability due to sickness (YLDs) and years of life lost due to early mortality (YLLs)[14,15]. Another tool utilized for this study is the SDI, or socio-demographic Index, which is a summary measure of national development ranging between 0 and 1[16]. The three components of SDI are income per capita, fertility rate among women under 25, and average educational attainment for those aged 15 and over. Mortality, DALYs, and incidence rate were the main metrics used to assess the burden of liver cancer in European nations.
Statistical analysis
In this study, estimates of rates per 100 000 people with 95% uncertainty intervals (UI) were estimated using methodology developed for GBD and presented along with estimates of age-standardized incidence rates (ASIR), age-standardized mortality rates (ASMR), and age-standardized disability-adjusted life year rates (ASDR). To assess trends over time, we have performed joinpoint regression analysis to evaluate the level of time at which statistically significant changes in the trend were observed. Annual Percent Change (APC) values and their 95% confidence intervals (CIs) were determined for each segment, while the Average Annual Percent Change (AAPC) was calculated by weighting APCs based on segment lengths to provide an overall trend summary. Grid Search Modeling Method with default settings was employed for up to five significant joinpoints, given the criteria of at least two data points between the joinpoints using the Monte Carlo Permutation method with _P_-value < 0.05. For plotting and displaying the data in various graphs, Python 3.8 was applied along with libraries such as Folium for displaying choropleths, Matplotlib for bar and other plots, Statsmodels, Numpy for mathematical use, and Pandas. Choropleth maps showing regional patterns were created. LOESS regression was done to investigate the associations of ASIR, ASMR, ASDR, and the socio-demographic Index, yielding a smoothed curve that describes the association of these measures.
Results
Regional burden of liver cancer in Europe
In Europe, the ASIR of liver cancer increased from 3.04 [2.93–3.14] in 1990 to 4.20 [3.93–4.40] in 2021, with an AAPC of 1.05 [1.01–1.08] (Fig. 1). The ASMR similarly increased from 3.08 [2.96–3.18] to 3.86 [3.59–4.05] over the same period, reflecting an AAPC of 0.70 [0.45–0.94] (Fig. 2). The ASDR also showed a rising trend from 78.48 [76.09–80.74] to 91.43 [86.48–95.79], showing an AAPC of 0.45 [0.27–0.62] (Fig. 3). Of the subregions in which the most pronounced trends were noted, Western Europe shows an AAPC of the ASIR as high as 1.26 [1.15–1.37], followed by its ASMR as 0.81 [0.40–1.22] and ASDR accordingly as 0.64 [0.25–1.03]. Correspondingly, the ASIR, ASMR, and ASDR continuously showed a minimal decline for Central Europe, with a respective AAPC of −0.12 [−0.16 to −0.08], − 0.19 [−0.57 to 0.18], and −0.39 [−0.78 to 0.01]. Europe thus also had more rapid growth both in terms of ASIR (Europe: 1.05 [1.01–1.08] vs. Global: 0.12 [0.06–0.18]) and ASDR compared to the global level, therefore indicating a growing regional burden (Table 1).
Age-standardized incidence rates of live cancer in Europe and European sub-regions and comparison with global level from 1990 to 2021.
Age-standardized mortality rates of live cancer in Europe and European sub-regions and comparison with global level from 1990 to 2021.
Age-standardized DALYs rates of live cancer in Europe and European sub-regions and comparison with global level from 1990 to 2021. DALYS: disability-adjusted life years.
Table 1 - Trends and average annual percentage change (AAPC) of age standardized incidence, mortality and DALYs rate of liver cancer in global, Europe, European sub-regions, and European Countries Level in 1990 and 2021
| Locations | 1990 | 2021 | 1990–2021 | ||||||
|---|---|---|---|---|---|---|---|---|---|
| ASIR [95% UI] | ASMR [95% UI] | ASDR [95% UI] | ASIR [95% UI] | ASMR [95% UI] | ASDR [95% UI] | Incidence AAPC [95% CI] | Mortality AAPC [95% CI] | DALYs AAPC [95% CI] | |
| Global | 5.90 [5.43, 6.48] | 5.86 [5.38, 6.46] | 172.86 [157.84, 190.16] | 6.15 [5.58, 6.90] | 5.65 [5.13, 6.30] | 149.29 [135.24, 167.48] | 0.12 [0.06, 0.18] | −0.11 [−0.23, 0.01] | −0.46 [−0.59, − 0.33] |
| Europe | 3.04 [2.93, 3.14] | 3.08 [2.96, 3.18] | 78.48 [76.09, 80.74] | 4.20 [3.93, 4.40] | 3.86 [3.59, 4.05] | 91.43 [86.48, 95.79] | 1.05 [1.01, 1.08] | 0.70 [0.45, 0.94] | 0.45 [0.27, 0.62] |
| Central Europe | 2.98 [2.74, 3.22] | 3.17 [2.92, 3.43] | 82.20 [75.67, 88.79] | 2.87 [2.58, 3.19] | 3.01 [2.71, 3.35] | 73.70 [65.97, 82.13] | −0.12 [−0.16, − 0.08] | −0.19 [−0.57, 0.18] | −0.39 [−0.78, 0.01] |
| Eastern Europe | 1.77 [1.69, 1.85] | 1.82 [1.73, 1.90] | 53.47 [51.33, 55.68] | 2.34 [2.17, 2.52] | 2.41 [2.24, 2.60] | 64.40 [59.67, 69.67] | 0.89 [0.73, 1.04] | 0.86 [0.35, 1.36] | 0.53 [−0.01, 1.07] |
| Western Europe | 3.57 [3.40, 3.72] | 3.53 [3.35, 3.68] | 86.18 [83.06, 89.37] | 5.33 [4.93, 5.61] | 4.58 [4.23, 4.84] | 106.07 [99.82, 111.42] | 1.26 [1.15, 1.37] | 0.81 [0.40, 1.22] | 0.64 [0.25, 1.03] |
| Albania | 11.91 [8.37, 15.24] | 12.99 [9.16, 16.69] | 317.74 [221.17, 406.29] | 7.60 [5.10, 11.02] | 8.18 [5.44, 11.85] | 191.35 [128.19, 283.14] | −1.44 [−1.54, − 1.33] | −1.40 [−1.77, − 1.03] | −1.59 [−1.96, − 1.22] |
| Andorra | 11.01 [7.80, 15.80] | 10.79 [7.68, 15.44] | 265.62 [189.92, 381.71] | 10.87 [7.61, 14.86] | 10.06 [7.10, 13.91] | 232.48 [158.29, 323.84] | −0.04 [−0.14, 0.06] | −0.24 [−0.39, − 0.09] | −0.41 [−0.61, − 0.22] |
| Austria | 2.88 [2.64, 3.14] | 2.78 [2.53, 3.03] | 69.42 [63.88, 75.51] | 5.84 [5.19, 6.47] | 4.92 [4.38, 5.46] | 112.79 [100.62, 125.14] | 2.32 [2.20, 2.43] | 1.77 [1.43, 2.11] | 1.52 [0.95, 2.10] |
| Belarus | 2.38 [2.08, 2.75] | 2.50 [2.18, 2.89] | 67.26 [58.82, 77.56] | 2.70 [2.14, 3.37] | 2.74 [2.17, 3.42] | 74.43 [58.05, 93.42] | 0.37 [0.20, 0.55] | 0.29 [−0.31, 0.88] | 0.32 [−0.31, 0.95] |
| Belgium | 2.84 [2.59, 3.08] | 2.94 [2.68, 3.21] | 66.56 [61.15, 72.40] | 4.16 [3.74, 4.65] | 3.96 [3.53, 4.42] | 90.52 [81.64, 100.53] | 1.21 [1.04, 1.37] | 1.10 [0.67, 1.52] | 1.11 [0.74, 1.49] |
| Bosnia and Herzegovina | 6.17 [5.18, 7.11] | 6.59 [5.55, 7.60] | 169.58 [143.14, 194.89] | 5.70 [4.25, 7.17] | 6.09 [4.54, 7.74] | 143.03 [106.15, 178.09] | −0.25 [−0.32, − 0.19] | −0.29 [−0.62, 0.04] | −0.61 [−0.89, − 0.33] |
| Bulgaria | 7.35 [5.96, 8.83] | 7.95 [6.44, 9.57] | 198.91 [161.50, 238.56] | 3.33 [2.48, 4.43] | 3.53 [2.62, 4.70] | 91.47 [68.36, 122.29] | −2.47 [−2.69, − 2.25] | −2.70 [−3.49, − 1.91] | −2.52 [−3.29, − 1.75] |
| Croatia | 2.55 [2.12, 3.08] | 2.66 [2.21, 3.22] | 65.91 [54.48, 79.93] | 3.05 [2.44, 3.84] | 2.92 [2.34, 3.69] | 68.40 [54.68, 86.23] | 0.59 [0.33, 0.85] | 0.22 [−0.81, 1.25] | 0.02 [−1.08, 1.12] |
| Cyprus | 3.31 [2.55, 4.29] | 3.68 [2.86, 4.76] | 77.21 [60.17, 100.40] | 3.33 [2.53, 4.48] | 3.32 [2.54, 4.40] | 68.60 [51.00, 92.39] | 0.03 [−0.01, 0.06] | −0.31 [−0.59, − 0.03] | −0.39 [−0.62, − 0.15] |
| Czechia | 4.51 [4.02, 5.06] | 4.80 [4.27, 5.39] | 121.94 [108.55, 136.87] | 2.47 [1.99, 2.99] | 2.55 [2.06, 3.09] | 59.28 [47.20, 72.02] | −1.92 [−2.04, − 1.81] | −1.87 [−2.64, − 1.09] | −2.14 [−2.97, − 1.30] |
| Denmark | 1.76 [1.62, 1.90] | 1.45 [1.34, 1.56] | 36.48 [33.69, 39.12] | 3.23 [2.86, 3.68] | 2.81 [2.50, 3.17] | 62.36 [55.67, 70.53] | 1.96 [1.79, 2.14] | 2.17 [1.08, 3.28] | 1.73 [0.61, 2.85] |
| Estonia | 3.02 [2.59, 3.46] | 3.16 [2.71, 3.61] | 86.06 [73.67, 98.77] | 3.73 [3.13, 4.42] | 3.82 [3.21, 4.50] | 94.89 [79.13, 113.54] | 0.69 [0.61, 0.78] | 0.91 [0.26, 1.56] | 0.60 [−0.05, 1.25] |
| Finland | 3.32 [3.02, 3.64] | 2.95 [2.68, 3.23] | 71.06 [64.82, 77.97] | 5.46 [4.83, 6.08] | 4.14 [3.69, 4.59] | 90.13 [80.78, 99.82] | 1.62 [1.53, 1.71] | 1.03 [0.55, 1.51] | 0.67 [0.11, 1.22] |
| France | 4.82 [4.34, 5.30] | 4.87 [4.40, 5.33] | 121.54 [109.13, 134.44] | 6.91 [6.02, 7.76] | 5.87 [5.16, 6.60] | 137.89 [120.41, 155.96] | 1.16 [1.06, 1.25] | 0.58 [0.30, 0.85] | 0.35 [0.09, 0.62] |
| Germany | 2.83 [2.56, 3.12] | 2.83 [2.56, 3.11] | 66.70 [60.30, 73.09] | 4.96 [4.46, 5.49] | 4.17 [3.75, 4.61] | 95.31 [87.36, 104.11] | 1.83 [1.67, 2.00] | 1.27 [1.06, 1.49] | 1.19 [0.95, 1.42] |
| Greece | 2.10 [1.97, 2.22] | 2.10 [1.97, 2.22] | 50.57 [47.93, 53.19] | 4.40 [4.08, 4.69] | 4.15 [3.82, 4.42] | 102.39 [95.41, 108.98] | 2.40 [2.27, 2.52] | 2.19 [1.57, 2.81] | 2.29 [1.47, 3.12] |
| Hungary | 2.75 [2.36, 3.22] | 2.94 [2.52, 3.44] | 76.12 [64.97, 89.65] | 1.69 [1.37, 2.06] | 1.76 [1.43, 2.14] | 43.72 [34.83, 53.89] | −1.51 [−1.79, − 1.24] | −1.66 [−2.34, − 0.98] | −1.80 [−2.63, − 0.97] |
| Iceland | 2.36 [2.14, 2.59] | 2.31 [2.10, 2.53] | 56.64 [50.92, 62.34] | 4.48 [3.93, 5.09] | 4.06 [3.58, 4.58] | 90.19 [78.99, 102.03] | 2.07 [1.94, 2.21] | 1.84 [1.35, 2.34] | 1.65 [1.31, 2.00] |
| Ireland | 1.82 [1.68, 2.00] | 1.89 [1.74, 2.08] | 44.06 [40.60, 48.18] | 3.47 [2.98, 3.92] | 3.25 [2.78, 3.66] | 71.47 [62.23, 79.73] | 2.12 [2.04, 2.19] | 1.68 [1.00, 2.35] | 1.52 [1.29, 1.75] |
| Israel | 2.11 [1.94, 2.29] | 2.24 [2.06, 2.42] | 50.91 [46.93, 55.36] | 2.40 [2.12, 2.66] | 2.35 [2.08, 2.60] | 53.24 [47.64, 59.13] | 0.41 [0.38, 0.43] | 0.01 [−0.22, 0.23] | 0.02 [−0.20, 0.24] |
| Italy | 6.69 [6.32, 6.96] | 6.47 [6.09, 6.72] | 157.24 [150.77, 163.24] | 5.15 [4.71, 5.53] | 4.30 [3.90, 4.60] | 97.71 [90.54, 104.14] | −0.85 [−0.95, − 0.74] | −1.45 [−2.97, 0.09] | −1.69 [−3.19, − 0.17] |
| Latvia | 2.51 [2.23, 2.83] | 2.61 [2.32, 2.95] | 72.26 [64.16, 82.39] | 3.10 [2.59, 3.64] | 3.21 [2.66, 3.77] | 82.72 [68.57, 98.18] | 0.73 [0.23, 1.23] | 0.59 [−0.85, 2.06] | 0.63 [−0.53, 1.81] |
| Lithuania | 2.15 [1.95, 2.41] | 2.19 [1.98, 2.46] | 58.10 [52.35, 65.07] | 3.48 [3.00, 4.02] | 3.37 [2.91, 3.86] | 88.57 [75.33, 103.59] | 1.56 [1.22, 1.91] | 1.47 [0.53, 2.41] | 1.43 [0.22, 2.64] |
| Luxembourg | 3.30 [3.10, 3.51] | 3.42 [3.21, 3.63] | 81.68 [76.99, 87.06] | 4.25 [3.79, 4.74] | 4.06 [3.63, 4.49] | 89.37 [80.01, 99.35] | 0.80 [0.69, 0.91] | 0.49 [−0.01, 0.99] | 0.28 [−0.50, 1.07] |
| Malta | 1.89 [1.72, 2.08] | 1.97 [1.80, 2.17] | 45.67 [41.54, 50.68] | 2.93 [2.51, 3.42] | 2.79 [2.38, 3.23] | 64.16 [54.76, 75.00] | 1.40 [1.27, 1.52] | 1.15 [0.88, 1.42] | 1.12 [0.84, 1.41] |
| Monaco | 3.78 [2.70, 5.19] | 3.70 [2.64, 5.04] | 90.11 [65.24, 122.52] | 8.27 [5.96, 11.36] | 7.68 [5.54, 10.63] | 181.44 [127.93, 247.20] | 2.56 [2.44, 2.69] | 2.40 [2.26, 2.54] | 2.30 [2.16, 2.44] |
| Montenegro | 5.32 [3.97, 6.98] | 5.61 [4.17, 7.38] | 143.12 [107.74, 186.16] | 6.27 [4.60, 8.38] | 6.67 [4.90, 8.87] | 154.80 [112.68, 208.48] | 0.52 [0.48, 0.57] | 0.59 [0.19, 1.00] | 0.28 [0.06, 0.51] |
| Netherlands | 1.19 [1.11, 1.28] | 1.26 [1.17, 1.36] | 31.20 [29.10, 33.43] | 2.42 [2.19, 2.66] | 2.56 [2.31, 2.81] | 58.79 [53.75, 64.34] | 2.30 [2.20, 2.40] | 2.31 [1.47, 3.16] | 2.05 [1.24, 2.87] |
| North Macedonia | 9.35 [7.71, 11.31] | 10.08 [8.28, 12.23] | 252.26 [209.69, 303.84] | 8.03 [6.17, 10.26] | 8.89 [6.86, 11.29] | 194.15 [147.98, 248.40] | −0.50 [−0.64, − 0.35] | −0.40 [−0.58, − 0.23] | −0.86 [−1.06, − 0.67] |
| Norway | 1.62 [1.54, 1.70] | 1.57 [1.49, 1.64] | 39.91 [38.28, 41.52] | 3.96 [3.64, 4.20] | 3.41 [3.12, 3.63] | 82.32 [76.92, 87.27] | 2.93 [2.63, 3.23] | 2.53 [1.44, 3.64] | 2.39 [1.39, 3.39] |
| Poland | 0.58 [0.54, 0.62] | 0.64 [0.59, 0.68] | 15.14 [14.19, 16.27] | 1.68 [1.52, 1.84] | 1.80 [1.62, 1.96] | 44.25 [40.13, 48.53] | 3.50 [3.11, 3.90] | 3.33 [2.29, 4.38] | 3.38 [2.34, 4.42] |
| Portugal | 2.00 [1.83, 2.17] | 2.13 [1.96, 2.30] | 53.61 [48.70, 58.79] | 4.82 [4.34, 5.32] | 4.79 [4.32, 5.26] | 119.35 [107.32, 133.76] | 2.89 [2.64, 3.14] | 2.71 [2.12, 3.30] | 2.68 [2.01, 3.35] |
| Republic of Moldova | 3.06 [2.85, 3.30] | 3.17 [2.95, 3.41] | 94.01 [87.98, 101.04] | 2.84 [2.49, 3.22] | 2.93 [2.59, 3.30] | 81.48 [70.94, 92.48] | −0.23 [−0.42, − 0.04] | 0.20 [−2.24, 2.70] | −0.02 [−2.40, 2.41] |
| Romania | 1.32 [1.13, 1.54] | 1.39 [1.19, 1.63] | 38.47 [32.51, 45.26] | 2.90 [2.42, 3.48] | 3.03 [2.54, 3.64] | 77.38 [64.43, 93.33] | 2.58 [2.45, 2.70] | 2.49 [1.91, 3.08] | 2.23 [1.61, 2.86] |
| Russian Federation | 1.66 [1.61, 1.71] | 1.71 [1.66, 1.77] | 51.04 [49.72, 52.53] | 2.57 [2.36, 2.78] | 2.67 [2.46, 2.89] | 70.20 [64.55, 76.09] | 1.40 [1.24, 1.56] | 1.29 [0.38, 2.21] | 0.93 [0.08, 1.78] |
| San Marino | 2.06 [1.64, 2.60] | 1.99 [1.58, 2.50] | 47.42 [37.91, 59.22] | 2.48 [1.56, 3.68] | 2.30 [1.46, 3.36] | 53.26 [33.17, 79.25] | 0.61 [0.57, 0.66] | 0.47 [0.39, 0.54] | 0.38 [0.31, 0.46] |
| Serbia | 5.11 [3.90, 6.50] | 5.51 [4.20, 7.04] | 136.63 [103.77, 172.79] | 4.94 [3.66, 6.44] | 5.20 [3.88, 6.72] | 123.60 [91.22, 162.52] | −0.13 [−0.22, − 0.04] | −0.17 [−0.32, − 0.03] | −0.34 [−0.61, − 0.07] |
| Slovakia | 5.26 [4.13, 6.56] | 5.56 [4.38, 6.91] | 144.91 [113.61, 181.20] | 3.70 [2.69, 5.09] | 3.84 [2.80, 5.29] | 94.57 [67.79, 130.90] | −1.14 [−1.20, − 1.08] | −1.17 [−1.61, − 0.73] | −1.35 [−1.81, − 0.90] |
| Slovenia | 4.14 [3.69, 4.64] | 4.32 [3.84, 4.86] | 113.78 [101.27, 127.20] | 4.50 [3.74, 5.51] | 4.59 [3.81, 5.60] | 103.53 [85.49, 126.66] | 0.28 [0.25, 0.31] | 0.10 [−0.27, 0.46] | −0.29 [−1.07, 0.48] |
| Spain | 3.98 [3.66, 4.31] | 4.06 [3.72, 4.39] | 99.91 [92.32, 107.94] | 5.94 [5.17, 6.69] | 5.24 [4.57, 5.87] | 123.72 [109.36, 138.61] | 1.28 [1.20, 1.37] | 0.77 [0.48, 1.05] | 0.63 [0.32, 0.93] |
| Sweden | 2.43 [2.24, 2.62] | 2.57 [2.37, 2.77] | 62.58 [58.23, 67.60] | 2.76 [2.38, 3.17] | 2.81 [2.43, 3.21] | 65.80 [57.01, 76.08] | 0.37 [0.18, 0.57] | 0.46 [−1.08, 2.03] | 0.34 [−1.22, 1.92] |
| Switzerland | 4.30 [3.87, 4.73] | 4.02 [3.62, 4.42] | 100.44 [90.40, 110.43] | 4.39 [3.90, 4.89] | 3.83 [3.38, 4.25] | 84.99 [76.26, 94.58] | 0.07 [0.03, 0.12] | −0.13 [−0.34, 0.08] | −0.54 [−0.75, − 0.33] |
| Ukraine | 1.74 [1.48, 2.00] | 1.76 [1.50, 2.03] | 51.94 [44.66, 59.26] | 1.37 [1.00, 1.75] | 1.37 [1.00, 1.75] | 39.41 [28.25, 51.27] | −0.91 [−1.24, − 0.58] | −0.85 [−2.08, 0.39] | −0.91 [−2.19, 0.38] |
| United Kingdom | 2.02 [1.95, 2.07] | 1.89 [1.81, 1.94] | 46.31 [45.03, 47.33] | 6.42 [6.03, 6.67] | 5.33 [4.98, 5.55] | 121.87 [116.39, 126.01] | 3.80 [3.61, 3.98] | 3.32 [3.07, 3.57] | 3.12 [2.88, 3.37] |
Abbreviations: AAPC, average annual percentage change; ASIR, age-standardized incidence rate; ASMR, age-standardized mortality rate; ASDR, age-standardized DALYs rate; DALYs, disability-adjusted life years.
Sex- and age-specific burden of liver cancer
In Europe, the age-standardized incidence, mortality, and DALYs rates of liver cancer were consistently higher among males compared to females in both 1990 and 2021. In 2021, the ASIR for males was 6.58 [6.18–6.94] (Fig. 4), far higher than that of females at 2.30 [2.09–2.43]. The ASMR for males reached 6.27 [5.56–6.93] compared to 2.38 [2.02–2.43] for females (Fig. 5). It was further shown in the inequality between males and females in terms of DALYs wherein male had 147.93 [132.65–139.99], while for females it has obtained 53.47 [47.17–50.84] (Fig. 6). In the general combined incidence, mortality, and DALYs rates notably rise by aging. Among men, the peak DALYs and deaths shifted from the age group 85–89 years in 1990 to 95 + years in 2021, indicating that liver cancer is an emerging burden among the elderly. These findings underscore the effect of sex and aging on the burden of liver cancer in Europe (Supplementary Figures 1; https://links.lww.com/MS9/A839, 2. https://links.lww.com/MS9/A840 and 3. https://links.lww.com/MS9/A841).
Age-standardized incidence rates for mesothelioma, 1990–2021 in Europe in both genders.
Age-standardized mortality rates for mesothelioma, 1990–2021 in Europe in both genders.
Age-standardized DALYs rates for mesothelioma, 1990–2021 in Europe in both genders. DALYS: disability-adjusted life years.
National burden of liver cancer in Europe
In 2021, the highest ASIR values were observed for Andorra with an ASIR of 10.87, Monaco with an ASIR of 8.27, and North Macedonia with an ASIR of 8.03. The lowest ASIR values were recorded in Ukraine with an ASIR of 1.37, Poland with an ASIR of 1.68, and Hungary with an ASIR of 1.69 (Supplementary Figure 4. https://links.lww.com/MS9/A842). During the period of 1990–2021, United Kingdom (AAPC = 3.8), Poland (AAPC = 3.5), and Norway (AAPC = 2.93) have shown the highest increasing rates of ASIR. Correspondingly, the significant drops of ASIR were registered in Bulgaria (AAPC = −2.47), Czechia (AAPC = −1.92), and Hungary (AAPC = −1.51) (Fig. 7).
Average annual percent change (AAPC) of Incidence rate of liver cancer across different countries of Europe, from 1990 to 2021.
Among them, ASMR was the highest for Andorra-10.06, North Macedonia-8.89, and Albania-8.18 in 2021. The countries having the smallest ASMR include the following: Ukraine, whose ASMR is 1.37; Hungary is 1.76; Poland is 1.8 (Supplementary Figure 5. https://links.lww.com/MS9/A843). The most significant increases in ASMR in the same period were observed for United Kingdom, with an AAPC of 3.32, Poland, with an AAPC of 3.33, and Portugal, with an AAPC of 2.71. On the other hand, the most significant decreases were seen in Bulgaria, with an AAPC of −2.7, Czechia, with an AAPC of −1.87, and Hungary, with an AAPC of −1.66 (Supplementary Figure 6. https://links.lww.com/MS9/A844).
Regarding ASDR in 2021, the highest burdens were observed in Andorra (ASDR = 232.48), North Macedonia (ASDR = 194.15), and Albania (ASDR = 191.35). Countries with the lowest ASDR included Ukraine (ASDR = 39.41), Hungary (ASDR = 43.72), and Poland (ASDR = 44.25) (Supplementary Figure 7, https://links.lww.com/MS9/A845). The largest increases in ASDR over the study period were noted in United Kingdom (AAPC = 3.12), Poland (AAPC = 3.38), and Norway (AAPC = 2.39). In contrast, notable reductions in ASDR were reported in Bulgaria (AAPC = −2.52), Czechia (AAPC = −2.14), and Hungary (AAPC = −1.8) (Supplementary Figure 8, https://links.lww.com/MS9/A846).
Burden of different types of liver cancer
In 2021, among the different types of liver cancer, the highest age-standardized incidence rate (ASIR) was attributed to liver cancer due to hepatitis C (ASIR = 1.50 [1.23–1.79]), followed closely by liver cancer due to alcohol use (ASIR = 1.49 [1.23–1.75]). In contrast, the lowest ASIR was observed for hepatoblastoma (ASIR = 0.05 [0.04–0.05]). Regarding the AAPC from 1990 to 2021, the largest increase in ASIR was noted for liver cancer due to non-alcoholic steatohepatitis (NASH) (AAPC = 1.56 [1.51–1.61]), whereas hepatoblastoma experienced the largest decline (AAPC = −0.69 [−1.02 to −0.36]) (Table 2).
Table 2 - Trends and average annual percentage change (AAPC) of age standardized incidence, mortality and DALYs rate of liver cancer and risk-attributable liver cancer in European region in 1990 and 2021
| Causes | 1990 | 2021 | 1990–2021 | ||||||
|---|---|---|---|---|---|---|---|---|---|
| ASIR [95% UI] | ASMR [95% UI] | ASDR [95% UI] | ASIR [95% UI] | ASMR [95% UI] | ASDR [95% UI] | Incidence AAPC [95% CI] | Mortality AAPC [95% CI] | DALYs AAPC [95% CI] | |
| Liver cancer | 3.04 [2.93, 3.14] | 3.08 [2.96, 3.18] | 78.48 [76.09, 80.74] | 4.20 [3.93, 4.40] | 3.86 [3.59, 4.05] | 91.43 [86.48, 95.79] | 1.05 [1.01, 1.08] | 0.70 [0.45, 0.94] | 0.45 [0.27, 0.62] |
| Liver cancer due to hepatitis C | 1.06 [0.90, 1.25] | 1.12 [0.95, 1.31] | 24.22 [20.58, 28.88] | 1.50 [1.23, 1.79] | 1.43 [1.18, 1.71] | 29.43 [24.31, 35.24] | 1.11 [1.07, 1.15] | 0.78 [0.45, 1.10] | 0.58 [0.17, 0.99] |
| Liver cancer due to other causes | 0.11 [0.09, 0.14] | 0.11 [0.09, 0.14] | 3.19 [2.57, 3.95] | 0.16 [0.12, 0.20] | 0.14 [0.11, 0.18] | 3.83 [3.01, 4.82] | 1.15 [1.11, 1.19] | 0.77 [0.58, 0.95] | 0.58 [0.36, 0.80] |
| Liver cancer due to alcohol use | 1.05 [0.88, 1.22] | 1.06 [0.89, 1.23] | 26.26 [21.88, 30.60] | 1.49 [1.23, 1.75] | 1.35 [1.11, 1.58] | 31.93 [26.38, 37.31] | 1.13 [1.08, 1.17] | 0.77 [0.55, 0.99] | 0.61 [0.43, 0.78] |
| Liver cancer due to hepatitis B | 0.56 [0.45, 0.71] | 0.55 [0.44, 0.69] | 17.01 [13.68, 21.06] | 0.69 [0.53, 0.88] | 0.62 [0.47, 0.79] | 18.17 [14.01, 22.75] | 0.67 [0.62, 0.72] | 0.33 [0.15, 0.52] | 0.15 [−0.04, 0.35] |
| Hepatoblastoma | 0.06 [0.06, 0.07] | 0.03 [0.03, 0.04] | 3.08 [2.87, 3.32] | 0.05 [0.04, 0.05] | 0.02 [0.01, 0.02] | 1.34 [1.20, 1.49] | −0.69 [−1.02, − 0.36] | −2.75 [−2.92, − 2.57] | −2.71 [−2.89, − 2.54] |
| Liver cancer due to NASH | 0.19 [0.15, 0.25] | 0.20 [0.16, 0.26] | 4.72 [3.71, 6.05] | 0.31 [0.24, 0.40] | 0.30 [0.23, 0.39] | 6.73 [5.25, 8.68] | 1.56 [1.51, 1.61] | 1.28 [1.12, 1.45] | 1.13 [0.91, 1.35] |
Abbreviations: AAPC, average annual percentage change; ASIR, age-standardized incidence rate; ASMR, age-standardized mortality rate; ASDR, age-standardized DALYs rate; DALYs, disability-adjusted life years.
The ASIR of liver cancer in Europe has risen from 3.04 in 1990 to 4.20 in 2021, with Western Europe showing the greatest increase. Males have a larger incidence of liver cancer than females, and elderly people (95 and up) are the most affected, with peak DALYs and deaths shifting from 85 to 89 years in 1990. In 2021, Andorra, Monaco, and North Macedonia had the highest liver cancer rates, while Ukraine, Hungary, and Poland had the lowest. Hepatitis C and alcohol use were the leading causes of liver cancer, with NASH having the fastest-growing burden. Regions with higher socio-demographic index (SDI) values had higher liver cancer burdens, indicating inequities in healthcare access and diagnosis.
For ASMR in 2021, the highest burden was associated with liver cancer due to hepatitis C (ASMR = 1.43 [1.18–1.71]) and alcohol use (ASMR = 1.35 [1.11–1.58]), while the lowest was for hepatoblastoma (ASMR = 0.02 [0.01–0.02]). The greatest increase in ASMR over time was observed in liver cancer due to NASH (AAPC = 1.28 [1.12–1.45]), while hepatoblastoma exhibited the largest reduction (AAPC = −2.75 [−2.92 to −2.57]).
In terms of age-standardized DALYs rates (ASDR) in 2021, the highest burden was linked to liver cancer due to alcohol use (ASDR = 31.93 [26.38–37.31]) and hepatitis C (ASDR = 29.43 [24.31–35.24]), while the lowest was again for hepatoblastoma (ASDR = 1.34 [1.20–1.49]). The highest increase in ASDR over time was observed for liver cancer due to NASH (AAPC = 1.13 [0.91–1.35]), and the steepest decline was in hepatoblastoma (AAPC = − 2.71 [−2.89 to −2.54]).
SDI burden of liver cancer
Liver cancer burden substantially varied across the different levels of the Socio-demographic Index. Generally, the high-income regions like Western Europe have higher age-standardized incidence, mortality, and DALYs compared with the low-income regions like Eastern Europe. For example, Western Europe exhibited a linear increase in both ASIR and ASDR, probably a reflection of increased awareness and diagnosis due to better health infrastructure. In contrast, Eastern Europe, with relatively lower levels of SDI, showed lower ASIR and ASDR rates, although it did not strictly follow the pattern for mortality (ASMR) (Fig. 8 and Supplementary Figures 9, https://links.lww.com/MS9/A847, 10. https://links.lww.com/MS9/A848). The values for Central Europe were intermediate, reflecting its intermediate position. This trend indicates that, though higher levels of SDI are related to better health access and increased detection, the burden of liver cancer remains an important challenge across all regions, irrespective of the SDI level.
Socio-demographic index (SDI) trends of age-standardized incidence rate for liver cancer, 1990–2021 in Europe and European sub-regions.
Discussion
The study highlights the increasing burden of liver cancer across Europe, with significant variations by region, sex, age, and cancer subtype. From 1990 to 2021, Europe experienced a notable rise in ASIR, ASMR, and ASDR rates, particularly in Western Europe, which showed the highest growth rates compared to Central and Eastern Europe. Males consistently had higher rates than females, and older age groups bore the greatest burden, with a shift in peak DALYs and deaths from 85 to 89 years in 1990 to 95 + years in 2021. At the national level, Andorra, Monaco, and North Macedonia recorded the highest ASIR, ASMR, and ASDR values in 2021, while Ukraine, Hungary, and Poland showed the lowest. Liver cancer types attributed to hepatitis C and alcohol use demonstrated the highest ASIR, ASMR, and ASDR, with NASH showing the fastest growth. Higher SDI regions had greater liver cancer burdens, emphasizing the role of healthcare access and diagnosis.
The burden of liver cancer varies across Europe compared to the global level and other regions. Worldwide, liver cancer accounted for an estimated 905 677 new cases and 782 000 deaths in 2020, and is expected to increase to 1.39 million cases by 2040[17,18]. In comparison, the ASIR in Europe was 4.20 in 2021, which is lower compared with the global rate seen in highly burdened regions such as East Asia[19]. About 75% of the global cases occur in the Asia-Pacific region, with more than 50% occurring in China alone. In comparison, Europe exhibits slower growth, though its rates are increasing, particularly in Western Europe. Globally, the ASMR was 5.9 per 100 000 in 2019, whereas Europe’s ASMR was slightly lower at 3.86 in 2021. Regional comparisons also reveal some inequalities: East Asia represents the highest burden worldwide, while the ASIR is much higher than that of Europe[19,20]. Meanwhile, North America, which generally shows lower ASIR and ASMR than Europe, is displaying rapid increases in liver cancer burden[21]. In 2021, the ASDR in Europe stood at 91.43, still below the average for the globe of 151.1 reported in 2019. These contrasts put into relief Europe’s intermediate position, facing rising rates of liver cancer but not the global peaks seen in Asia-Pacific.
Liver cancer has striking variation in incidence and mortality by gender and age, which reflects biological, behavioral, and environmental factors. There is a much higher burden of this disease among males compared with females worldwide[22,23]. The male-to-female ratio for ASIR ranges from 2.5 to 2.9, while mortality rates, ASMR, also reflect about 521,826 male deaths versus 236,899 female deaths in 2022[17]. This may be explained by a number of factors that include higher consumption of alcohol and smoking among males, increasing the risk of liver cancer. Besides, the infection rates for both HBV and HCV are higher in males[24]. In this case, HBV accounts for much higher numbers of infections among males compared to females, standing at 203,000 for men and 70,000 in 2015. This disparity is increased further due to biological issues, which include the metabolism of alcohol and different responses of males’ immunity against certain infectious diseases[22,25]. The burden of liver cancer also increases with age, while the highest incidence was found to be in individuals aged 75 and older, notably among males. In 2019, men aged 65–74 have an incidence rate of 72 per 100,000 as against 25 per 100,000 among their women counterparts. This may be because of the cumulative effect of chronic exposure to risk factors such as infections by HBV/HCV, consumption of alcohol, and liver damage over time. Other chronic liver diseases, such as cirrhosis and non-alcoholic fatty liver disease (NAFLD), have higher prevalence in older age groups, which increases the risk for liver cancer. Regional differences affect the age-specific burden: East Asia has a higher incidence among older age groups due to historical HBV prevalence and dietary factors[22,24].
Liver cancer burden in Europe stands at a national level with important heterogeneity due to a differential distribution of various risk factors, healthcare conditions, socioeconomic status, and demography. The viral determination is dominated mainly by viral hepatitis; especially HBV and HCV, in fact, as a rule of the high prevalence rate in Southern and Eastern parts compared to Northern parts[7,8]. Already in 2012, HCV-I alone accounted for 41% of all deaths on account of liver cancer. Alcohol consumption is another major cause of liver cancer in countries like France and Germany that have higher rates of heavy drinking. Growing obesity and metabolic disorders, such as diabetes, are adding to the geographic divide, with obesity more common in certain regions[26]. These differences are taken one step further by access to healthcare: countries with expansive screening programs and heavy vaccination against hepatitis have lower burdens of liver cancer due to early detection and treatment. Socio-economic inequalities widen the gap, as the most vulnerable populations face barriers in accessing health care and prevention. Moreover, liver cancer is more common among elderly people and males, with the incidence peaking in the age group of 65-plus years, and the male-to-female incidence ratio is 2.5:3[27]. These disparities in the burden of liver cancer emphasize the need for targeted interventions, focusing on reducing risk factors, improving access to screening and treatment, and addressing socio-economic inequalities as a way of mitigating the burden of liver cancer in Europe.
The increasing burden of liver cancer due to NASH in Europe reflects the convergence of lifestyle changes, obesity trends, and demographic factors. One of the most important drivers of NASH, namely obesity, has gained momentum in Europe and is closely related to metabolic syndrome, which also encompasses insulin resistance and hypertension[28]. NAFLD and its progression to NASH are rising in association with increasing obesity rates in the population, strongly promoting increases in liver cancer incidence[29]. The apparent burden of many cancers is also being impacted by better awareness and detection as a result of diagnostic advancements in medical imaging and changing nomenclature and criteria on diagnosis. Improved detection leads, in turn, to both more diagnoses and, hopefully, the ability to monitor improvements in the disease condition-that is, NAFLD and NASH’s long-term potential to advance, in some cases, ultimately to liver cancer[30]. Furthermore, dietary habits, like the Western diet with high intakes of sugars and fats, along with sedentary lifestyles, increase the incidence of obesity and NASH. There is also an aging population in Europe, which is more susceptible to metabolic syndrome and its complications. Healthcare disparities across the region further influence this burden: countries with less robust public health initiatives face higher rates of untreated obesity and NASH[31]. It is complex to address the issues of obesity prevention, lifestyle modification, early detection of the disease, and equal access to healthcare in finding a solution for NASH-related liver cancer.
Several limitations of this study exist. First, the estimates of the liver cancer burden depend on the availability and quality of data, and may therefore vary across regions. Potential underreporting and misclassification are more probable in low-income settings. Second, modeled estimates, such as those emanating from the Global Burden of Disease methodology, could introduce biases with assumptions in the modeling. Furthermore, since specific information on many potential individual risk factors, including alcohol consumption or prevalence of viral hepatitis, is often missing, it will not allow the identification of clear causation. Finally, healthcare inequalities and diagnostic criteria may contribute to discrepancies between findings among countries.
Conclusion
This study underlines that liver cancer burden in Europe is determined by increasingly higher rates of obesity, changing lifestyles, aging of the population, aside from sustained differences in access to care and prevalence of the risk factors. The incidence and mortality rates have continuously grown more in Western as compared to Central Europe, which in turn showed the least decline. To this end, addressing the public health challenge requires comprehensive strategies: prevention, early detection, and access to care equitably, with the focus on key risk factors like NASH, hepatitis infections, and alcohol consumption.
Ethical approval
This paper relies on aggregated secondary data from web sources rather than individual data points. This study only published aggregated epidemiological data, not individual data. So we the authors are aware that there is no need for ethical statements.
Consent
No individuals are involved in the current study. This paper relies on aggregated secondary data from web sources rather than individual data points. This study only published aggregated epidemiological data, not individual data. So we the authors believe that there is no need for patient consent forms.
Sources of funding
This study had no funding support and received no grants.
Author contributions
M.A.K participated in conceptualization, data curation, formal analysis, methodology, supervision and writing – review and editing. O.K participated in writing – original draft and visualization. S.H participated in investigation and review and editing. B.E.Z participated in using software and visualization. A.K participated in formal analysis. S.S.M participated in and writing – original draft and data curation. H.K participated in writing – original draft.
Conflicts of interest disclosure
The authors declare no conflict of interests.
Research registration unique identifying number (UIN)
We registered our study at: https://researchregistry.knack.com/. Registration number is: researchregistry10992.
Guarantor
Mohammad Amin Khadembashiri.
Provenance and peer review
Not commissioned, externally peer-reviewed.
Data availability statement
This study used publicly available datasets. The data are available here: Global Burden of Disease (GBD) Compare Viz Hub, https:vizhub.healthdata.org.gbd-compare.
Acknowledgements
The authors would like to thank the Institute for Health Metrics and Evaluation for supplying GBD data.
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Keywords:
DALYs; europe; incidence; liver cancer; mortality
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