Mortality from liver diseases attributable to hepatitis B and C in the EU/EEA – descriptive analysis and estimation of 2015 baseline

Abstract

Background: WHO has set target to reduce mortality attributable to hepatitis B (HBV) and hepatitis C (HCV) by 65% by 2030, with 2015 as baseline. We aimed to describe the European Union/European Economic Area (EU/EEA) baseline mortality from liver diseases, as defined by WHO Core-10 indicator through ICD-10 codes, and estimate mortality attributable to HBV and HCV.

Methods: Age-standardised mortality rates per 100,000 for hepatocellular carcinoma (HCC, ICD-10 C22.0), chronic liver disease (CLD, ICD-10 K72-K75) and chronic viral hepatitis B and C (CHB/CHC, ICD-10 B18.1-B18.3) were calculated by gender, age-group and country using 2015 Eurostat data. Because aetiology fraction (AF) estimates were lacking for HCC and CLD as defined by C10, number of deaths in EU/EEA countries in 2015 from liver cancer (ICD-10 C22) and ‘cirrhosis and other chronic liver diseases’ (ICD-10 B18–B18.9, I85–I85.9, I98.2, K70–K70.3, K71.7, K74–K74.9, K75.2, K75.4–K76.2, K76.4–K76.9 and K77.8) were adjusted by corresponding AF estimates from Global Burden of Disease publications.

Results: In 2015, there were wide variations across countries in mortality rates from HCC, CLD and CHB/CHC. A 2015 mortality baseline of 63,927 deaths attributable to HBV and HCV is proposed, that includes 55% of liver cancer and 45% of ‘cirrhosis and other chronic liver diseases’ deaths.

Conclusions: The HBV and HCV attributable mortality in the EU/EEA is high. Greater efforts are needed to identify HBV and HCV infections at an early stage and link cases to care to reduce mortality from liver diseases. Country-specific AF estimates are needed to accurately estimate HBV, HCV associated mortality.

Keywords:

• Mortality
• hepatitis B
• hepatitis C
• Attributable fraction
• EU/EEA
• Baseline

Background

The World Health Organisation (WHO) estimated that viral hepatitis accounted for 1.34 million deaths worldwide in 2015 [1]. The majority of these deaths were due to the long term complications of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections, with cirrhosis accounting for 720,000 of these deaths and hepatocellular carcinoma resulting in 470,000 deaths. The WHO estimates indicate that mortality from viral hepatitis has risen by 22% since 2000 and the number of deaths from viral hepatitis now exceeds those from HIV [1]. Mortality due to hepatitis B and C infections is expected to increase further unless efforts to scale up testing and treatment are increased. The scaling up of testing is a huge challenge due to the largely asymptomatic nature of the infections with up to 80% of those infected unaware of their infection and many not getting diagnosed or treated until after liver damage has occurred [2,3].

In 2016, WHO launched the Global Health Sector Strategy (GHSS) on viral hepatitis that aims to eliminate viral hepatitis (HBV and HCV as the main infections of interest) as public health threats [4]. Aside a reduction in transmission, with a target to reduce new infections by 90%, the strategy aims at a 65% reduction in mortality due to HBV and HCV by 2030, with 2015 as the baseline year.

To support the implementation and monitoring of the global strategy for hepatitis, WHO proposed a monitoring and evaluation framework which includes a set of ten core indicators and 27 additional indicators [3]. One of the core indicators, Core 10: ‘Deaths from hepatocellular carcinoma, cirrhosis and chronic liver diseases attributable to HBV and HCV infections’ (C10) is for monitoring the progress towards the mortality target at global and national level. The indicator requires data on the number of deaths from specific International Classification of Diseases and Related Health Problems 10th Revision (ICD-10) codes that define HCC, liver cirrhosis and chronic liver disease (CLD) (Box 1). Mortality data need further adjustment by the proportion of patients with these conditions that died with chronic HBV and/or HCV infection, to calculate the burden of mortality attributable to HBV and HCV [5]. This approach assumes that the relative risk of death from HCC or from cirrhosis in persons infected with HBV or HCV is high (close to 1), thus the prevalence of infections among the deceased become a proxy for the HBV, HCV attributable fraction [6]. A meeting of experts in 2016 advised WHO on inclusion of deaths directly associated with viral hepatitis B and C and slightly enlarged the definition of cirrhosis to cover ICD-10 K74.0–K74.69 [7]. The structure of C10 in the WHO monitoring framework has not been, however changed.

This study aims to define a baseline value (2015) for the European Union (EU) and the European Economic Area (EEA) of mortality from liver diseases for supporting the monitoring process and, an estimation of the fraction of mortality attributable to HBV and HCV. In addition, a descriptive analysis of the 2015 mortality as defined by C10 by gender and age-group and by country was undertaken to identify variations across the EU/EEA and a trend analysis to identify any significant changes during the period 2011–2015.

Box 1. WHO Indicator Core 10: Deaths attributable to HBV and HCV infection

Definition: Deaths from hepatocellular carcinoma, cirrhosis and chronic liver diseases attributable to HBV and HCV infections

Numerator: Number of deaths from hepatocellular carcinoma, cirrhosis and CLDs attributable to HBV and HCV infection:

• Number of hepatocellular carcinoma (ICD-10 code C22.0) deaths multiplied by the proportion of HCC with chronic HBV and HCV infections.

• Number of cirrhosis deaths (ICD-10 codes K74.3, K74.4, K74.5, K74.6) multiplied by the proportion of cirrhosis with chronic HBV and HCV infections.

• Number of CLD deaths (ICD-10 codes K72–K75) with chronic HBV and HCV infections.

Denominator Not applicable

Source: adapted after WHO Monitoring and evaluation for viral hepatitis B and C: recommended indicators and framework. Geneva: WHO, 2016 [3]

Methods

Mortality data analysis

Number of deaths from HCC, ICD-10 code C22.0; CLD, ICD-10 codes K72–K75; cirrhosis, ICD-10 codes K74.3, K74.4, K74.5, K74.6 and chronic viral hepatitis B and C (CHB/CHC), ICD-10 codes B18.0–B18.2 by gender, age-group and EU/EEA Member State were obtained by request from Eurostat for the years 2011 to 2015 [8]. For each year, overall EU/EEA mortality rates from HCC, CLD, cirrhosis and CHB/CHC per 100,000 population were calculated using Eurostat population data in the denominator. Although the ICD-10 codes that define cirrhosis (K74.3–K74.6) are included in the CLD ICD-10 codes (K72–K75), cirrhosis was described separately in order to check for differences in mortality burden and its distribution.

For 2015, for the EU/EEA overall and for each country, the distribution of deaths from HCC, CLD, cirrhosis and CHB/CHC by gender and age group (≤24 years, 25–44 years, 45–64 years and ≥65 years) was investigated and expressed as proportions. For each Member State, age-standardised mortality rates for all the reported deaths and by gender were calculated for HCC, CLD, cirrhosis and CHB/CHC relative to the EU/EEA standard population (the average population of the 31 Member States in 2015; source Eurostat) [9]. National male-to-female ratio was calculated as a ratio of the age-standardised rates per 100,000 population among males and females.

The strength of correlation between national mortality rates for HCC, CLD, cirrhosis and mortality rates for CHB/CHC and alcoholic liver disease (ICD-10 K70, data from Eurostat) was assessed using Pearson correlation (r). Strong, medium and small correlation were defined when the value of r was ≥0.5, between <0.5 and ≤0.3, and between <0.3 and ≥0.1, respectively [10].

As a sensitivity analysis, the impact on the number of deaths of using a broader definition of liver cancer ICD-10 C22 (‘Malignant neoplasm of liver and intrahepatic bile duct’ including C22.0, C22.1, C22.2, C22.3, C22.4, C22.7 and C22.9) used in recent mortality studies [11,12] in contrast with using the WHO specific definition of HCC (ICD-10 C22.0) was assessed.

Regression models were used to examine the trend in mortality rates for HCC, CLD, cirrhosis and CHB/CHC for the period 2011-2015 in countries that consistently reported in a three-digit ICD-10 code format (e.g. C22.0 vs. C22).

Excel and STATA 13 were used for data analysis and the ECDC Map Maker tool (EMMa) was used for creating maps [13].

Estimating mortality attributable to HBV and HCV in 2015

As indicated by WHO, for estimating the fraction of mortality from liver diseases attributable to HBV and HCV, the number of deaths from HCC and CLD should be multiplied by the proportion of cases with chronic HBV and HCV infections. These proportions, also called aetiology fractions (AFs), are lacking for HCC, CLD and cirrhosis as defined by WHO’s C10. Instead, AF estimates have been published for mortality from liver cancer (ICD-10 C22 instead of C22.0) by The Global Burden of Disease (GBD), Liver Cancer Collaboration [14] and from ‘cirrhosis and other chronic liver diseases’ (ICD-10 B18–B18.9, I85–I85.9, I98.2, K70–K70.3, K71.7, K74–K74.9, K75.2, K75.4–K76.2, K76.4–K76.9, K77.8 instead of K72–K75) by The GBD, Causes of Deaths Collaborators [15,16]. The GBD AFs estimates are derived through literature review and modelling and express proportions of deaths from liver cancer or ‘cirrhosis and other chronic liver diseases’ that can be attributed to HBV and HCV but also to alcohol use and ‘other causes’ [16,17].

Considering the availability of AF estimates for liver cancer (ICD-10 C22) and for ‘cirrhosis and other chronic liver diseases’ (ICD-10 codes B18–B18.9, I85–I85.9, I98.2, K70–K70.3, K71.7, K74–K74.9, K75.2, K75.4–K76.2, K76.4–K76.9 and K77.8) for each EU/EEA country (except Liechtenstein) we have used these broader definitions of liver diseases instead of HCC and CLD to calculate the 2015 mortality attributable to HBV and HCV. The number of deaths from respective ICD-10 codes defining liver cancer and ‘cirrhosis and other chronic liver diseases’ obtained from Eurostat for each country, were adjusted by the GBD country specific aetiology estimates for HBV and HCV (Table 2).

Results

EU/EEA demographic picture

Hepatocellular carcinoma

In 2015, 23,883 persons were reported to have died of HCC in the EU/EEA, representing a rate of 4.6 per 100,000 population (Table 1).

Table 1. Number of deaths and age-standardised rates per 100,000 population from hepatocellular carcinoma, liver cirrhosis and chronic liver disease as defined by WHO core 10 indicator and chronic viral hepatitis B and C and alcoholic liver disease, by gender, 2015, the EU/EEA countries.

Country	HCC						Cirrhosis						Chronic liver disease						Chronic viral hepatitis						Alcoholic liver disease
	(ICD-10 codes C22.0)						(ICD-10 codes K74.3-K74.6)						(ICD-10 codes K72-K75)						(ICD-10 codes B18.0, B18.1, B18.2)						(ICD-10 codes K70)
	Total		Females		Males		Total		Females		Males		Total		Females		Males		Total		Females		Males		Total		Females		Males
	deaths	rate	deaths	rate	deaths	rate	deaths	rate	deaths	rate	deaths	rate	deaths	rate	deaths	rate	deaths	rate	deaths	rate	deaths	rate	deaths	rate	deaths	rate	deaths	rate	deaths	rate
Austria	487	5.8	109	2.5	378	9.2	779	9.2	238	5.5	541	13.0	826	9.7	264	6.1	562	13.5	262	3.1	149	3.5	113	2.7	669	7.8	159	3.6	510	12.2
Belgium	400	3.7	88	1.6	312	5.8	611	5.6	226	4.1	385	7.1	770	7.1	296	5.4	474	8.8	34	0.3	14	0.3	20	0.4	735	6.7	238	4.3	497	9.2
Bulgaria	224	2.9	83	2.1	141	3.9	1356	18.0	288	7.3	1068	29.7	1748	23.2	381	9.7	1367	38.0	8	0.1	1	0.0	7	0.2	131	1.8	12	0.3	119	3.3
Croatia	188	4.4	42	1.8	146	7.2	435	10.0	126	5.5	309	15.1	464	10.7	138	6.0	326	16.0	60	1.4	14	0.6	46	2.3	498	11.5	94	4.2	404	19.7
Cyprus	9	1.3	3	0.9	6	1.7	30	4.3	5	1.5	25	7.1	36	5.2	7	2.1	29	8.2	4	0.6	1	0.3	3	0.8	13	1.8	4	1.0	9	2.5
Czech Republic	274	2.7	66	1.3	208	4.3	466	4.5	200	3.8	266	5.3	643	6.2	281	5.3	362	7.3	26	0.3	10	0.2	16	0.3	1398	13.5	378	7.1	1020	20.2
Denmark	206	3.7	49	1.8	157	5.5	53	10.0	23	0.8	30	1.0	123	2.2	51	1.9	72	2.5	15	0.3	5	0.2	10	0.4	567	10.3	159	5.8	408	14.7
Estonia	32	2.5	7	0.9	25	4.7	71	5.5	44	6.1	27	4.6	85	6.5	47	6.5	38	6.5	5	0.4	2	0.3	3	0.5	230	17.8	61	8.6	169	29.6
Finland	264	4.6	64	2.2	200	7.0	127	2.2	74	2.6	53	1.9	152	2.7	87	3.0	65	2.3	6	0.1	2	0.1	4	0.1	951	17.1	242	8.6	709	25.8
France	4342	6.7	681	2.0	3661	11.7	2721	4.2	883	2.7	1838	5.9	3460	5.4	1249	3.8	2211	7.1	502	0.8	233	0.7	269	0.9	4344	6.8	1080	3.3	3264	10.5
Germany	4438	4.9	1095	2.4	3343	7.5	5942	6.6	2348	5.2	3594	8.1	6719	7.5	2786	6.1	3933	8.9	855	1.0	374	0.8	481	1.1	7958	9.0	2233	5.0	5725	13.1
Greece	320	2.8	71	1.2	249	4.3	560	4.9	170	2.9	390	6.9	670	5.8	222	3.8	448	8.0	56	0.5	18	0.3	38	0.7	177	1.6	23	0.4	154	2.8
Hungary	163	1.7	36	0.7	127	3.0	349	3.6	174	3.3	175	4.0	418	4.3	206	3.9	212	4.8	185	1.8	99	1.8	86	1.9	2731	27.6	670	12.5	2061	45.9
Iceland	11	4.4	4	3.1	7	5.4	4	1.4	1	0.9	3	2.1	6	2.3	2	1.8	4	2.9	3	1.2	1	0.9	2	1.4	8	2.8	5	3.6	3	2.0
Ireland	112	3.3	25	1.5	87	4.9	89	2.6	39	2.3	50	2.8	119	3.4	56	3.3	63	3.5	21	0.5	5	0.3	16	0.7	178	4.6	58	2.9	120	6.1
Italy	4871	7.1	1373	3.9	3498	10.5	4752	7.0	2002	5.7	2750	8.3	5386	7.9	2331	6.6	3055	9.3	2637	3.8	1412	4.0	1225	3.7	961	1.5	176	0.5	785	2.5
Latvia	35	1.7	11	0.9	24	3.0	194	9.7	72	6.4	122	14.2	202	10.1	75	6.7	127	14.8	54	2.7	18	1.6	36	4.1	163	8.2	60	5.5	103	11.6
Liechtenstein	0	0.0	0	0.0	0	0.0	1	3.2	1	6.5		0.0	1	3.2	1	6.5		0.0		0.0		0.0	0	0.0		0.0		0.0		0.0
Lithuania	80	2.7	23	1.3	57	4.7	429	14.7	183	11.2	246	19.2	459	15.7	196	12.0	263	20.5	28	1.0	11	7.0	17	1.3	314	10.7	90	5.6	224	17.2
Luxembourg	17	3.9	4	1.8	13	5.8	27	5.8	9	3.8	18	7.8	33	7.1	13	5.6	20	8.5	3	0.5		0.0	3	1.0	30	6.2	12	5.1	18	7.2
Malta	15	3.5	4	1.9	11	5.1	6	1.4	2	1.0	4	1.8	7	1.6	2	1.0	5	2.2		0.0		0.0		0.0	13	3.0	3	1.4	10	4.5
Netherlands	279	1.7	55	0.7	224	2.7	393	2.4	163	2.0	230	2.7	566	3.5	253	3.2	313	3.7	34	0.2	8	0.1	26	0.3	442	2.7	139	1.7	303	3.6
Norway	85	1.9	22	1.0	63	2.7	55	1.2	27	1.2	28	1.2	102	2.3	55	2.5	47	2.0	12	0.3	4	0.2	8	0.3	138	3.0	37	1.6	101	4.3
Poland	477	1.4	168	0.9	309	2.0	1544	4.3	640	3.4	904	5.4	2116	6.0	890	4.8	1226	7.3	293	0.8	120	0.6	173	1.0	4311	11.6	1050	5.4	3261	18.6
Portugal	536	4.9	75	1.3	461	9.0	396	3.6	123	2.2	273	5.3	551	5.1	186	3.2	365	7.1	128	1.2	33	0.6	95	1.9	643	6.0	107	1.9	536	10.5
Romania	682	3.6	245	2.5	437	4.9	7482	39.2	2881	28.9	4601	50.6	8222	43.1	3161	31.8	5061	55.7	55	0.3	34	0.3	21	0.2	700	3.6	160	1.6	540	5.9
Slovakia	143	3.2	38	1.6	105	5.1	294	6.2	118	4.8	176	8.0	374	8.0	155	6.2	219	10.1	20	0.4	9	0.4	11	0.5	1162	22.6	270	10.2	892	36.8
Slovenia	133	6.6	31	3.0	102	10.5	15	0.8	12	1.2	3	0.3	17	0.9	14	0.1	3	0.3	1	0.0	1	0.0		0.0	414	19.8	100	9.4	314	30.9
Spain	2727	6.0	599	2.6	2128	9.5	3169	7.0	1021	4.4	2148	9.6	3726	8.2	1255	5.4	2471	11.0	790	1.7	356	1.5	434	1.9	1238	2.7	188	0.8	1050	4.7
Sweden	221	2.3	54	1.1	166	3.3	234	2.4	90	1.9	144	2.9	362	3.7	154	3.2	206	4.1	78	0.8	27	0.6	49	1.1	405	4.3	115	2.5	288	5.9
United Kingdom	2112	3.5	458	1.5	1654	5.4	1983	3.3	865	2.9	1118	3.7	2783	4.6	1286	4.3	1497	4.9	300	0.5	95	0.3	205	0.7	5575	9.2	1936	6.3	3639	12.1
EU/EEA	23,883	4.6	5583	2.1	18299	7.3	34,567	6.7	13,048	5.0	21,519	8.6	41146.0	8.0	16,100	6.1	25,044	10.0	6475	1.3	3056	1.2	3417	1.4	37,097	7.2	9859	3.7	27,236	10.9

Source: Eurostat.

France, Germany, Italy, Spain and the UK reported more than 2000 deaths each and accounted for 77% (18,490) of the total number of EU/EEA cases. National mortality rates ranged between 1.3 in Cyprus to 7.1 in Italy (Table 1; Figure 1). Countries with rates higher than the EU/EEA rate of 4.6 per 100,000 included (in an increasing order) Germany, Portugal, Austria, Spain, Slovenia, France and Italy.

Figure 1. Age-standardised mortality rates per 100,000 population from hepatocellular carcinoma (ICD-10 code C22.0) in the EU/EEA countries in 2015.

In 2015, 76.6% (18,299) of deaths from HCC were among men. The EU/EAA mortality rate was 7.3 per 100,000 among men and 2.1 per 100,000 among women, giving an EU/EEA male-to-female ratio of 3.5. The male-to-female ratio ranged between less than 2.0 in Iceland, Bulgaria and Cyprus to more than 4.0 in Hungary, Estonia, France and Portugal (Supplementary File 2).

Overall in EU/EEA, the majority of HCC deaths were among people 65 years of age or older (73.4%, 17,543) (Supplementary File 3(A)). There were only 283 deaths (1.2%) among those below the age of 45 years.

In 2015, the deaths from HCC, ICD-10 C22.0, represented almost half (44.9%) of the 53,250 deaths recorded as ICD-10 C22, ‘malignant neoplasm of liver and intrahepatic bile duct’. The remainder of the deaths were 15,090 (28.3%) due to C22.9 ‘malignant neoplasm of liver, not specified as primary or secondary’, 13,882 (26.1%) C22.1 ‘Intrahepatic bile duct carcinoma’ and 395 (0.8%) other codes such as C22.2, C22.3, C22.4 and C22.7. No deaths were classified as C22.8 ‘malignant neoplasm of liver, primary, unspecified as to type’.

There was no correlation between country specific standardised mortality rates of HCC and ALD (p = .74), between HCC and cirrhosis (p = .97) and between HCC and CHB/CHC (p = .07) (Supplementary File 4).

Chronic liver disease

There were 41,146 deaths from CLDs reported from 31 EU/EEA countries in 2015, a rate of 8.0 per 100,000 population.

Just under half (49.4%) of the deaths were reported by three countries: Romania (8222, 20.0%), Germany (6719, 16.3%) and Italy (5386, 13.1%). National rates ranged between 0.9 in Slovenia and 43.1 per 100000 in Romania (Table 1). Seven countries reported rates above the EU/EEA average rate value: Spain, Austria, Latvia, Croatia, Lithuania, Bulgaria and Romania (Figure 2).

Figure 2. Age-standardised mortality rates per 100,000 population from chronic liver diseases (ICD-10 codes K72–K75) in the EU/EEA countries in 2015.

60.9% (25,044) of the deceased were males. The EU/EEA mortality rate was 10.0 among males and 6.1 among females, giving a male to female ratio of 1.6. Mortality rates among men were between three to four times higher than among women in Slovenia, Bulgaria and Cyprus. Male-to-female ratio was less than one in Norway and Finland (Supplementary File 2).

Most, 59.1% (24,319) of CLDs deaths were among persons 65 years of age or older (Supplementary File 3(B)).

Cirrhosis

In 2015, of the CLD deaths reported by EU/EEA countries, 34,567 (84%) were from cirrhosis, a rate of 6.7 per 100,000 population (Table 1).

Just over half (52.6%) of the deaths from cirrhosis were reported by three countries, Italy (4752, 13.7%), Germany (5942, 17.2%) and Romania (7482, 21.6%). National mortality rates ranged between 0.8 in Slovenia and 39.2 in Romania (Table 1). Nine countries had rates above the average EU/EEA rate (in an increasing order): Italy, Spain, Austria, Latvia, Croatia, Denmark, Lithuania, Bulgaria and Romania (Figure 3).

Figure 3. Age-standardised mortality rates per 100,000 population from cirrhosis (ICD-10 codes K74.3–K74.6) in the EU/EEA countries in 2015.

In 2015, 62% (21,519) of cirrhosis deaths were among men. The EU/EEA mortality rate per 100,000 population was 8.6 among men and 5.0 among women, a male-to-female rate ratio of 1.8. The male-to-female ratio was above 3.0 in Bulgaria and Cyprus and below 1.0 in Estonia, Finland and Slovenia (Supplementary File 2).

Over half (58.1%, 20,089) of the cirrhosis deaths were among people 65 years of age or older (Supplementary File 3(C)). In Bulgaria, Latvia, Estonia, Lithuania and Iceland more than 60% of the deaths were in people younger than 65 years.

In 2015, 6579 (16%) of deaths from CLD were not coded as cirrhosis (K74.3-K74.6). The ICD-10 coding for these cases included: K72 ‘hepatic failure’ (3825, 9.3%), K73 ‘chronic hepatitis, not else classified’ (666, 1.6%), K740 –K742 ‘hepatic fibrosis’ and ‘hepatic sclerosis’ separated or combined (534, 1.3%) and K75 ‘other inflammatory liver diseases’ (1554, 3.8%). At country level, the non-cirrhosis CLD deaths ranged from 0% (0/1) in Liechtenstein or 4% (8/202) in Latvia to 57% (70/123) in Denmark.

There was a strong correlation between national mortality rates from CLD and cirrhosis (p = .00) and no correlation between national mortality rates from CLD and ALD (p = .35) or from cirrhosis and ALD (p = .42) (Supplementary File 4).

Chronic viral hepatitis B and C

In 2015, 6475 persons died in EU/EEA from CHB (with or without delta-agent) and CHC; resulting in an EU/EEA rate of 1.3 per 100,000 (Table 1). Three countries reported two-thirds (66.1%) of the cases: Italy (40.7%, 2637), Germany (13.2%, 855) and Spain (12.2%, 790); no deaths were reported from Liechtenstein and Malta. National mortality rates were above the EU/EEA average rate in Croatia, Spain, Hungary, Latvia, Austria and Italy (Figure 4).

Figure 4. Age-standardised mortality rates per 100,000 population from chronic viral hepatitis B and C (ICD-10 codes B18.0, B18.1 and B18.2) in the EU/EEA countries in 2015.

52.5% (3417) of deaths were among men. The mortality rate was 1.4 per 100,000 among men and 1.2 per 100,000 among women, an EU/EEA male to female ratio of 1.2 (Supplementary File 2).

Most (64.4%, 4168) of the deaths were among people 65 years of age or older (Supplementary File 3(D)).

In 2015, 89.2% (5775) of the deaths from chronic viral hepatitis were due to HCV infection, 10.2% (660) due to HBV and 0.6% (40) due to HBV with delta agent.

There was no correlation between national mortality rates from CHB/CHC and CLD (p = .90) or cirrhosis (p = .85) and between CHB/CHC and HCC (p = .07) (Supplementary File 4).

EU/EEA mortality baseline 2015

In 2015, 23,883 deaths from HCC and 41,146 from CLD (with 84% coded as cirrhosis) were reported in the EU/EEA, summing up to a total of 65,029 deaths from liver diseases as defined by WHO C10.

When using the less specific definitions of liver diseases for which AF estimates were available, mortality figure in 2015 in the EU/EEA rose to 53,250 live cancer deaths and 78,094 cirrhosis and other chronic liver diseases (that includes for example alcoholic liver diseases and chronic viral hepatitis B and C). When applying the country specific AF estimates (Table 2) to the number of deaths in each country from liver cancer (53,250) and cirrhosis and other CLD (78,094), the number of deaths from these conditions that can be attributable to HBV and HCV in 2015 was 29,029 and 34,898 respectively (Figure 5). They represented 55% of all liver cancer deaths and 45% of cirrhosis and other chronic liver diseases deaths in the EU/EEA. Mortality baseline that can be attributed to HBV and HCV in 2015 can thus be estimated at 63,927 deaths. A breakdown by country is presented in Table 2.

Figure 5. Mortality from liver diseases in the EU/EEA in 2015 and the fraction attributable to hepatitis B and C.

Note: Total mortality was calculated by summing up the number of deaths from liver cancer (ICD-10 code C22) and ‘cirrhosis and other chronic liver diseases’ (a broader definition of chronic liver diseases than that of WHO, including ICD-10 codes B18–B18.9, I85–I85.9, I98.2, K70–K70.3, K71.7, K74–K74.9, K75.2, K75.4–K76.2, K76.4–K76.9 and K77.8) extracted from Eurostat for each EU/EEA country. Mortality attributable to HBV and HCV was estimated by adjusting mortality figures for each country with the country-specific aetiology fraction estimates for HBV and HCV available from GBD publications. Overall for the EU/EEA, 45% or cirrhosis and other chronic liver diseases deaths (n = 34,898) and 55% of liver cancer deaths (n = 29,029) could be attributable to HBV and HCV. Baseline mortality attributable to HBV and HCV is thus, 63,927.

Table 2. Mortality attributable to HBV and HCV in 2015 in the EU/EEA – number of death from Eurostat adjusted by aetiology fraction (AF) estimates from Global Burden of Disease (GBD).

	Cirrhosis and other chronic liver disease			Liver cancer			Total deaths	Total mortality attributable to HBV and HCV
	(B18–B18.9, I85-I85.9, I98.2, K70–K70.3, K71.7, K74–K74.9, K75.2, K75.4–K76.2, K76.4–K76.9 and K77.8)			(ICD-10 C22 ‘Malignant neoplasm of liver and intrahepatic bile duct’)
	Deaths	AF GBD^a	Mortality attributable to HBV and HCV (deaths × AF GBD*)	Deaths	AF GBD^b	Mortality attributable to HBV and HCV (deaths × AF GBD^b)
	(a)		(b)	(c)		(d)	(a + c)	(b + d)
Austria	1739	0.43	750	929	0.45	418	2668	1168
Belgium	1440	0.34	488	948	0.44	417	2388	905
Bulgaria	1775	0.45	795	677	0.48	325	2452	1120
Croatia	1002	0.41	409	495	0.36	178	1497	587
Cyprus	53	0.44	23	51	0.58	30	104	53
Czech Republic	1798	0.43	775	818	0.39	319	2616	1094
Denmark	585	0.42	246	441	0.44	194	1026	440
Estonia	290	0.42	121	103	0.33	34	393	155
Finland	1062	0.45	476	505	0.54	273	1567	749
France	7936	0.43	3396	8544	0.53	4528	16480	7924
Germany	15,120	0.42	6301	7870	0.41	3227	22,990	9528
Greece	888	0.45	401	1558	0.6	935	2446	1336
Hungary	3142	0.42	1331	862	0.4	345	4004	1676
Iceland	13	0.38	5	19	0.61	12	32	17
Ireland	305	0.38	116	295	0.55	162	600	278
Italy	9395	0.70	6530	9702	0.71	6888	19,097	13,418
Latvia	434	0.43	187	134	0.55	74	568	261
Liechtenstein	1	NA	NA	0		0	1	NA
Lithuania	808	0.42	340	210	0.35	74	1018	414
Luxembourg	65	0.38	24	43	0.53	23	108	47
Malta	6	0.46	3	25	0.63	16	31	19
Netherlands	888	0.42	372	956	0.55	526	1844	898
Norway	206	0.45	93	265	0.63	167	471	260
Poland	5529	0.42	2321	2031	0.47	955	7560	3276
Portugal	1213	0.41	498	1134	0.54	612	2347	1110
Romania	8777	0.40	3516	3061	0.38	1163	11,838	4679
Slovakia	1356	0.44	596	403	0.41	165	1759	761
Slovenia	423	0.44	186	250	0.4	100	673	286
Spain	5608	0.37	2074	5044	0.72	3632	10,652	5706
Sweden	687	0.24	163	688	0.56	385	1375	548
United Kingdom	5550	0.44	2422	5189	0.55	2854	10,739	5276
EU/EEA	78,094	0.45	34,898	53,250	0.55	29,029	131,344	63,927

NA: not applicable.

Note: ‘cirrhosis and chronic liver diseases’ and liver cancer as defined by GBD; number of death reported by each country to Eurostat were adjusted by aetiology fraction (AF) estimates published by GBD.

^aGlobal Burden of Disease Collaborative Network. Global Burden of Disease Study 2016 (GBD 2016) Results. Available from http://ghdx.healthdata.org/gbd-results-tool

^bGlobal Burden of Disease Liver Cancer Collaboration. The burden of primary liver cancer and underlying aetiologies from 1990 to 2015 at the global, regional, and national level: results from the Global Burden of Disease Study 2015. 2017. JAMA Oncology.

EU/EEA trends 2011–2015

Table 3 shows the changes in annual mortality rates from HCC, cirrhosis, CHB/CHC and CLD during 2011–2015 and the results of Poisson regression for trends. When compared with 2011, the mortality rate in 2015 from HCC increased by 5.3% (1456 more deaths) and from CHB/CHC by 2.3% (225 more deaths). In contrast, the mortality rate from cirrhosis decreased by 9.5% (2934 less deaths) and from CLD by 7.2% (2479 less deaths). None of these trends was statistically significant.

Table 3. Mortality rates per 100,000 population from hepatocellular carcinoma, cirrhosis and chronic liver diseases as defined by WHO core 10 indicator, and chronic viral hepatitis B and C in the EU/EEA during 2011–2015.

	2011	2012	2013	2014	2015	% change 2011–2015^a	Difference in number of cases	Poisson regression for trend, p value
Hepatocellular carcinoma (C22.0)	4.47	4.60	4.57	4.68	4.71	5.30%	1456	.935
Cirrhosis (K74.3–K74.6)	7.30	7.20	6.90	6.80	6.60	−9.50%	−2934	.83
Chronic hepatitis B and C (B18.0, B18.1 and B18.2)	1.26	1.31	1.28	1.25	1.29	2.30%	225	.999
Chronic liver disease (K72–K75)	8.40	8.30	8.00	7.90	7.80	−7.20%	−2479	.857

^a(2015 rate–2011 rate)/2011 rate; countries reporting in ICD-9 codes format (Greece) or in ICD-10 format with a three-digits precision (Bulgaria and Slovakia) at any time during the period, were not included.

Discussion

This study provides a comprehensive descriptive analysis of mortality data from liver diseases for the EU/EEA as defined by the WHO C10 indicator and proposes a 2015 baseline estimate for the mortality attributable to hepatitis B and C that can be used for monitoring progress towards reaching the WHO mortality targets.

There was a total of 65,029 deaths reported in EU/EEA in 2015 from liver diseases that were identified by WHO as relevant for mortality monitoring, of which 23,883 (37%) were from HCC and 41,146 (63%) from CLD. In addition, and not included in the WHO C10 indicator, there were 6475 deaths from chronic viral hepatitis B and C. There were important variations in gender and age-groups distribution of these deaths across Member States. Over the period 2011–2015, any trends in the number of deaths from HCC, CLD, and CHB/CHC were not statistically significant.

Deaths from HCC (C22.0) in 2015 represented 0.5% of all the recorded deaths (5,259,680) in EU/EEA countries, 1.8% of the deaths from malignant neoplasms (C00–C97) and 45% of the deaths reported as liver cancer (C22) [18]. Data suggest a geographical South-West to North-East gradient, with HCC mortality rates more than five-fold higher in Italy and France, compared to Poland and Cyprus and with France, Germany, Italy and Spain all reporting high numbers of deaths (more than 2000 in 2015). A higher mortality for the Western European countries has been previously highlighted by Bertuccio et al. [19] when comparing mortality from primary liver cancer across thirteen EU countries. Differences across EU/EEA countries in the prevalence of risk factors for HCC such as chronic HBV and HCV, alcohol consumption, obesity and metabolic syndrome (leading to non-alcoholic fatty liver disease) may explain this heterogeneity [12,20]. The synergistic effect of interactions between these risk factors may further explain the variations in HCC occurrence [21–23]. Country differences in early diagnosis and access to effective therapies may further influence the different national risk patterns of dying from HCC [24,25].

Our analysis indicates a more than three-fold higher HCC mortality rate among the EU/EEA men than among women. This is similar to the gender ratio (3.6 in men vs. 0.8 in women) reported by Bertuccio et al. [26] when comparing the death rates in 28 EU countries based on death certification data for HCC from the WHO database. We identified geographical variations in gender distribution of mortality from HCC with six- to seven-times more deaths among men than among women in Portugal and France as compared to Cyprus, Romania, Bulgaria and Iceland where the male to female ratio was two or lower. Gender differences in the prevalence of risk factors such as alcohol drinking patterns as reported by Ahlström et al. [27] in their analysis of nine European countries may explain these geographical variations. More specifically, the GBD 2016 Alcohol Collaboration study reported that 75% male vs. 47% female of all ages in Portugal were current drinkers in 2016 and 93% men and 87% women were current drinkers in France [28]. Alcohol consumption and non-alcoholic steatohepatitis NASH are considered to be the leading causes of HCC in France [29].

As in previous studies, our analysis indicates that HCC mortality predominantly affects the older population, aged 65 years or older [30,31]. Besides the accumulation of risk factors over time, age itself may accelerate the process of hepato-carcinogenesis [32]. In addition, HBV vaccination, differing prevalence of behavioural risk factors such as less tobacco [33] and alcohol use [34], lower exposure to environmental risk factors and greater coverage by prevention programmes (e.g. screening of those at risk of HCC) and effective therapies, may have a greater protective effect among the younger populations against dying from HCC [35].

Most (84%) of the CLD deaths in the EU/EEA in 2015 were due to cirrhosis (n = 34567). Geographical variation in mortality rate from cirrhosis was larger than for HCC, with the mortality rate in Romania (39.2 per 100,000) almost over 50 times greater than that of Slovenia (0.8 per 100,000). In contrast to HCC, the highest mortality rates from cirrhosis were in countries from South-East and East of the EU/EEA, consistent with previous analysis by Zatoński et al. [36]. This reverse geographical gradient suggests that cirrhosis mortality rates do not follow the same geographical pattern as HCC rates, and this was confirmed by the lack of significant correlation between national HCC and cirrhosis rates (p = .97). The explanation for this divergence in geographical trends is not clear but certainly could be related to the impact of differing levels of access to diagnostic and treatment services across the region.

While as for HCC, men were more likely to die from cirrhosis than women (male-to-female ratio 1.7), the mortality rate from cirrhosis among EU/EEA women was more than double than that from HCC (5.0 vs. 2.1). A study by Guy J and Peters M in 2013 explored the influence of gender on differences in liver diseases natural history and patient outcomes, indicating a potential role of sex hormones as well as varying health behaviours and treatment preferences based on gender that lead to women being more commonly affected by cirrhosis than liver cancer [37].

Overall in EU/EEA in 2015, people died at a younger age from cirrhosis than from HCC (42% vs. 27% of deaths among <65 years old) and with larger variations across countries in age-group distribution than for HCC. Mortality among people under 65 years old was higher in the countries in the South-East or East of the EU (e.g. Lithuania, Estonia, Latvia, Bulgaria, Poland, Slovakia and Romania). Whilst the cause of this variation is unclear, it is likely to be multi-factorial, and, as for HCC may also relate to the timing of diagnosis and linkage to appropriate treatment. In a study by Chung et al. [38], conducted in Korea between 2002 and 2010, the relative mortality from liver cirrhosis was greater [hazard ratio 1.47 (95% CI 1.28–1.67)] than mortality from five major cancers (lung, colorectal, stomach, liver, and breast cancers) even after adjusting for age, gender, area of residence, type of insurance, income level and comorbidities. The same study found that 70.9% of liver cirrhosis patients died before the age of 65 years, while 54.6% of the patients with the five cancers studied died after the age of 65 years, which is similar with our findings.

We did not identify any significant trends in mortality from liver diseases as defined by WHO C10 indicator (HCC, cirrhosis and CLD) and deaths from CHB/CHC during 2011 to 2015 in the EU/EEA, notwithstanding small variations in the annual number of deaths. The fact that this was done for a relatively short time period may have contributed to the lack of a clear trend. We also did not stratify our trend analysis by country or gender but some insight is available from literature. A stable pattern of mortality from HCC for a 10-year period 2002–2012 was reported by Bertuccio et al. [26] among men from 28 countries in the EU despite divergent trends noted at country level. In contrast, the same study reported a 13% reduction in mortality rates from HCC among EU women (from 0.9 to 0.8/100,000) during the same period. When looking at mortality trends for liver cirrhosis for a longer period (1970–2015) in the 34 European countries (all the 28 EU countries included), Pimpin et al. [12] found important sub-regional European variations. Decreasing non-HCC related liver mortality associated with HBV has been previously reported from Australia, related to improvements in HBV treatment and uptake [39]. Access to more effective treatment for patients with both HBV and HCV may explain the decreasing number of deaths related to cirrhosis reported in EU/EEA [40,41].

We aimed to calculate the EU/EEA baseline mortality for 2015 following the WHO C10 definitions for HCC and CLD and using Eurostat data. AF estimates for these specific definitions were however lacking and we had to use liver cancer and cirrhosis and other chronic liver diseases (the broader definition that includes for example alcoholic liver disease and chronic hepatitis B and C) instead. There are pros and cons for using specific definitions vs. broader definitions, beside of availability of AF estimates. An underestimation of mortality when using more specific definitions is likely since some deaths from primary malignant neoplasm of the liver HCC ICD-10 code C22.0 may be classified under C22.9, as observed by Hofman et al. [42]. The impact of using different definitions for liver cirrhosis was underlined by Ratib et al. [43] in a study that found important variations in the estimated burden of cirrhosis in England depending on the ICD-10 codes included.

While more specific definitions for HCC and CLD (or cirrhosis) as suggested by WHO indicator would yield a more accurate calculation of a baseline since alcoholic liver disease for example is not included, in a next step, HBV and HCV attributable fraction estimates to fit these specific ICD-10 codes are needed. We identified estimates for less specific definitions of both HCC and CLD than proposed by WHO C10 indicator (e.g. deaths from liver cancer (C22) vs. HCC and cirrhosis and other chronic liver diseases (B18–B18.9, I85–I85.9, I98.2, K70–K70.3, K71.7, K74–K74.9, K75.2, K75.4–K76.2, K76.4–K76.9, K77.8) vs. CLD (K72–K75). Understanding the proportion of mortality directly attributable to HBV and HCV is pivotal for monitoring progress in the elimination of HBV and HCV as public health problem and reaching WHO 2020 and 2030 targets [3,5].

Conclusions

Robust estimation of the mortality attributed to HBV and HCV infections is challenging. As emerged from this analysis, the 2015 EU/EEA baseline mortality is about 64,000 deaths. This analysis also indicates that for overall the EU/EEA, mortality attributable to HBV and HCV is about 55% for liver cancer (C22) and 45% for chronic liver diseases (also named cirrhosis and other chronic liver diseases, ICD-10 codes: B18–B18.9, I85–I85.9, I98.2, K70–K70.3, K71.7, K74–K74.9, K75.2, K75.4–K76.2, K76.4–K76.9 and K77.8). In order to reach the mortality target proposed by WHO, a total of 41,553 deaths should be prevented by 2030 (65% of the 2015 baseline of 63,927).

While the Eurostat mortality data can be confidently used as basis for monitoring mortality in the EU/EEA, up to date and reliable estimates of the HBV and HCV attributable fraction are lacking. The collection of this information should be considered by countries, ideally in an EU/EEA standardised way, to help better understand the true burden of morbidity and mortality associated with HBV and HCV.

Despite the shortcomings in the available data, the current information suggests a high burden of mortality associated with HBV and HCV in EU/EEA countries that far exceeds that from either tuberculosis or HIV and highlights the importance of continued efforts to increase access to diagnosis and care for those at risk of HBV or HCV infection.

Abbreviations
EU/EEA	=	European Union/European Economic Area
ALD	=	Alcoholic liver disease
CLD	=	Chronic liver disease
CHB	=	Chronic viral hepatitis B
CHC	=	Chronic viral hepatitis C
GHSS	=	Global Health Sector Strategy
HBV	=	Hepatitis B virus
HCV	=	Hepatitis C virus
HCC	=	Hepatocellular carcinoma
WHO	=	World Health Organisation.

Disclosure statement

No potential conflict of interest was reported by the author(s).