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Turati et al. Hepatoma Res 2022;8:19 https://dx.doi.org/10.20517/2394-5079.2021.130 Page 3 of 15

Various studies indicated that the incidence of ICC has increased over the last decades in most
countries [14-17] . By contrast, reported trends for ECC have been inconsistent, with some studies showing a
[14]
decrease or stabilization [15,16] and others an increase , possibly at a slower rate compared to ICC [17,18] .

As for mortality, a study based on official death certification data showed a global increase in ICC mortality
and a decrease or stabilization in ECC mortality over the 1995-2016 period, with wide variations in rates
[19]
across geographic regions . Recently, a mortality trends study based on American data from 2009 to 2018
showed an increase in ICC mortality over the whole period, but a stable trend for ECC mortality until 2013,
[16]
followed by an increase thereafter .
In the present study, we updated temporal trends in mortality from ICC and ECC in countries worldwide
with reliable data from the World Health Organization (WHO) database.

METHODS
We extracted official death certification data from ICC and ECC, separately, from the WHO mortality
database , from 1995 to 2018 or the last available year when the Tenth Revision of the International
[20]
Classification of Diseases (ICD-10) was used (ICD-10 code C22.1 for ICC and C24.0 for ECC).

We selected countries according to population size and data coverage, i.e., all countries considered had over
two million inhabitants and more than 85% death certification coverage . Thus, we analyzed data from 29
[21]
countries worldwide, including 17 countries from Europe [13 of which belonging to the European Union
(EU)], 8 countries from the Americas, and 4 from Australasia. We also analyzed data from Hong Kong as a
Special Administrative Region of the People’s Republic of China (SAR).

We extracted estimates of the resident populations, based on official censuses, from the same WHO
database . For American countries, since data were unavailable in the WHO database for several years, we
[20]
extracted the populations from the Pan American Health Organization database .
[22]

From the matrices of certified deaths and resident populations, we computed age-specific rates for each
five-year age group (from 0-4 to ≥ 85 years and from 0-4 to ≥ 80 years for American countries), country, sex,
and calendar year. We then computed age-standardized mortality rates per 100,000 person-years at all ages
and for the age group 45-64 years, using the direct method based on the 1960 world standard population .
[23]
For nine major countries with a population greater than 40 million (plus Australia), we performed a
joinpoint regression analysis of ICC and ECC mortality trends over the period 1995-2018 . We thus
[24]
identified the years when a significant change in the linear slope of the temporal trend (on a log scale)
[25]
occurred by testing from zero up to a maximum of three inflection points (called “joinpoints”) . The
estimated annual percentage change (APC) was then computed for each of the identified trends by fitting a
regression line to the natural logarithm of the rates using the calendar year as a covariate. We also estimated
the average APC over the entire study period.

RESULTS
Table 1 gives the age-standardized mortality rates from ICC and ECC per 100,000 person-years, in 2010-
2014 (around 2012) and 2015-2018 (around 2016), the annual average deaths in the last period, and the
percent change in rates, according to country and sex.