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The burden of liver disease in Europe: A review of available epidemiological data

  • Martin Blachier
    Affiliations
    Department of Public Health, Hôpital Henri Mondor, Université Paris-Est Créteil, France
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  • Henri Leleu
    Affiliations
    Department of Public Health, Hôpital Henri Mondor, Université Paris-Est Créteil, France
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  • Markus Peck-Radosavljevic
    Correspondence
    Corresponding authors. Addresses: Dept. of Gastroenterology & Hepatology, Medizinische Universität Wien, Währinger Gürtel 18-20, A-1090 Vienna, Austria (M. Peck-Radosavljevic), Department of Public Health, Hôpital Henri Mondor, Université Paris-Est Créteil, France (F. Roudot-Thoraval).
    Affiliations
    Dept. of Gastroenterology & Hepatology, Medizinische Universität Wien, Währinger Gürtel 18-20, A-1090 Vienna, Austria
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  • Dominique-Charles Valla
    Affiliations
    Service d’hépatologie, Hôpital Beaujon, AP-HP, Université Paris Diderot and INSERM U773, Clichy-la-Garenne, France
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  • Françoise Roudot-Thoraval
    Correspondence
    Corresponding authors. Addresses: Dept. of Gastroenterology & Hepatology, Medizinische Universität Wien, Währinger Gürtel 18-20, A-1090 Vienna, Austria (M. Peck-Radosavljevic), Department of Public Health, Hôpital Henri Mondor, Université Paris-Est Créteil, France (F. Roudot-Thoraval).
    Affiliations
    Department of Public Health, Hôpital Henri Mondor, Université Paris-Est Créteil, France
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      Summary

      To survey the burden of liver disease in Europe and its causes 260 epidemiological studies published in the last five years were reviewed.
      The incidence and prevalence of cirrhosis and primary liver cancer are key to understand the burden of liver disease. They represent the end-stage of liver pathology and thus are indicative of the associated mortality. About 0.1% of Hungarian males will die of cirrhosis every year compared with 0.001% of Greek females. WHO estimate that liver cancer is responsible for around 47,000 deaths per year in the EU.
      Harmful alcohol consumption, viral hepatitis B and C and metabolic syndromes related to overweight and obesity are the leading causes of cirrhosis and primary liver cancer in Europe.
      Chronic hepatitis B affects 0.5–0.7% of the European population. In the last decade the prevalence of chronic hepatitis C was 0.13–3.26%. It is of great concern that about 90% of people in Europe infected by viral hepatitis are unaware of their status. Available data suggest the prevalence rate of NAFLD is 2–44% in the general European population (including obese children) and 42.6–69.5% in people with type 2 diabetes.
      Each of these four major causes of liver disease is amenable to prevention and treatment, reducing the burden of liver disease in Europe and saving lives. Further surveys are urgently needed to implement cost-effective prevention programmes and novel treatments to tackle this problem.

      Keywords

      Introduction

      In the past 30 years there has been major progress in the knowledge and management of liver disease yet approximately 29 million persons in the European Union still suffer from a chronic liver condition. Difficulties in accessing data from individual countries hinder comprehensive evaluation of the burden of liver disease in Europe and comparison with other diseases. Moreover, very few reviews have studied both chronic liver conditions, such as cirrhosis and cancer, and their major causes, such as viral hepatitis, alcohol intake, and metabolic syndrome. It is likely that the causes of chronic liver diseases differ from country to country, but no reliable data exist about this. A large systematic review of all epidemiological data available for European countries has hitherto not been undertaken.
      Here we review evidence of the burden and causes of liver disease in Europe, drawing on a survey of all epidemiological data published in the last five years.

      Methods

      MEDLINE, EMBASE, and the Cochrane Library were searched for relevant articles using the following medical subject headings (MeSH) terms: ‘liver’ and [‘disease’ or ‘epidemiology’]. The search encompassed articles published in the last five years in any European language. Studies were included if: (1) they presented epidemiological data; (2) they included patients who lived in the European Union (EU27) or Norway (but not necessarily exclusively so); (3) they were published or accepted for publication as full-length articles. Studies were excluded if: (1) they estimated prevalence or incidence from data collected before 1995; (2) they studied very specific populations; (3) they were published only in abstract form so that the methodological quality could not be assessed. When the results of a single study were reported in more than one publication, only the most recent and complete data were included in the systematic review.
      A manual search of references cited in retrieved articles was also conducted to identify studies not found in the database search. Data presented in World Health Organization (WHO) reports, in European Centre for Disease Prevention and Control (ECDC) reports and on EUROHEP.NET were also included.
      All available data on liver disease incidence and prevalence and on associated mortality and trends were extracted from the reviewed articles. Most mortality statistics were derived from official causes of death recorded on death certificates. Of 4256 reviewed studies, 260 met the inclusion criteria.
      The European Liver Transplant Registry (ELTR) was used to describe the epidemiology of liver transplantation in Europe as it represents more than 95% of all official published European data (Fig. 5).
      Figure thumbnail gr5
      Fig. 5Hospitalisation for hepatitis A, incidence per 100,000 inhabitants in Europe; EUROHEP.NET.
      Geographical factors necessitate caution in the interpretation of parts of this review for two reasons: (1) inter-country variation in death-reporting processes; therefore caution must be exercised when making comparisons between countries; (2) the definition of the European zone varies according to the source, so care must be taken when assessing data reported at the European level. According to WHO, European countries include all eastern and central European countries as well as the Russian Federation. By contrast, data given for the EU27 refer only to countries that belong to the European Union.

      Cirrhosis

      Figure thumbnail fx12
      Figure thumbnail gr1
      Fig. 1Age-standardized death rates per 100,000 population from liver cirrhosis in European countries, males and females aged 20–64; WHO mortality database 2000–2002
      [
      • Zatonski W.A.
      • Sulkowska U.
      • Manczuk M.
      • Rehm J.
      • Boffetta P.
      • Lowenfels A.B.
      • et al.
      Liver cirrhosis mortality in Europe, with special attention to Central and Eastern Europe.
      ]
      .
      Alcohol is the strongest risk factor for liver cirrhosis [
      • Mann R.E.
      • Smart R.G.
      • Govoni R.
      The epidemiology of alcoholic liver disease.
      ,
      • Rehm J.
      • Taylor B.
      • Mohapatra S.
      • Irving H.
      • Baliunas D.
      • Patra J.
      • et al.
      Alcohol as a risk factor for liver cirrhosis: a systematic review and meta-analysis.
      ] and cirrhosis mortality is a valid indicator for tracing the health consequences of alcohol abuse. However, infections by the hepatitis B and C viruses (HBV and HCV) are also important determinants of cirrhosis, and their possible contribution to temporal trends should be taken into account. A study based on the WHO mortality database (http://data.euro.who.int) reports radical increases in liver cirrhosis mortalities from the 1970s within a group of several south-eastern European countries. For example, in Hungary from the mid-1970s to the mid-1990s, cirrhosis mortality rates increased from 20 to 148 per 100,000 males (the highest level ever registered in any European country) and from about 8 to 48 per 100,000 females [
      • Zatonski W.A.
      • Sulkowska U.
      • Manczuk M.
      • Rehm J.
      • Boffetta P.
      • Lowenfels A.B.
      • et al.
      Liver cirrhosis mortality in Europe, with special attention to Central and Eastern Europe.
      ]. By 2002 these rates had slightly declined to 103 per 100,000 males and 32 per 100,000 females [
      • Zatonski W.A.
      • Sulkowska U.
      • Manczuk M.
      • Rehm J.
      • Boffetta P.
      • Lowenfels A.B.
      • et al.
      Liver cirrhosis mortality in Europe, with special attention to Central and Eastern Europe.
      ]. Dramatic changes were also observed in north-eastern European countries (e.g. Estonia, Latvia, Lithuania and Poland).
      Appreciable declines in cirrhosis mortality were observed in Mediterranean countries (e.g. France, Italy, Spain, Portugal and Greece) that historically had the highest cirrhosis mortality levels in both sexes. HBV vaccination, reduced alcohol consumption and reduction of HCV transmission have probably contributed to this decrease. Perhaps bucking this trend is a French study that found 0.3% of screened males (aged >40 years) had liver cirrhosis; however, the subjects were seen within a free screening programme and therefore were potentially at high risk of liver fibrosis [
      • Poynard T.
      • Lebray P.
      • Ingiliz P.
      • Varaut A.
      • Varsat B.
      • Ngo Y.
      • et al.
      Prevalence of liver fibrosis and risk factors in a general population using non-invasive biomarkers (FibroTest).
      ]. The associated causes of liver disease in this study were alcoholic and NAFLD (66%), NAFLD only (13%), alcohol (9%), HCV (6%), and other causal factors (6%) [
      • Poynard T.
      • Lebray P.
      • Ingiliz P.
      • Varaut A.
      • Varsat B.
      • Ngo Y.
      • et al.
      Prevalence of liver fibrosis and risk factors in a general population using non-invasive biomarkers (FibroTest).
      ]. Factors independently associated with fibrosis were age, male gender, waist circumference, presence of HCV antibody and alcohol consumption [
      • Poynard T.
      • Lebray P.
      • Ingiliz P.
      • Varaut A.
      • Varsat B.
      • Ngo Y.
      • et al.
      Prevalence of liver fibrosis and risk factors in a general population using non-invasive biomarkers (FibroTest).
      ]. These results suggest that alcohol and NAFLD are two causal factors with the potential to keep levels of liver cirrhosis relatively high in western European countries.
      A summary of cirrhosis rates in four northern European countries is presented in Table 1.
      Table 1European studies assessing the prevalence or incidence of liver cirrhosis.
      • Jepsen P.
      • Vilstrup H.
      • Sorensen H.T.
      Alcoholic cirrhosis in Denmark – population-based incidence, prevalence, and hospitalization rates between 1988 and 2005: a descriptive cohort study.
      ,
      • Gunnarsdottir S.A.
      • Olsson R.
      • Olafsson S.
      • Cariglia N.
      • Westin J.
      • Thjodleifsson B.
      • et al.
      Liver cirrhosis in Iceland and Sweden: incidence, aetiology and outcomes.
      ,
      • Fleming K.M.
      • Aithal G.P.
      • Solaymani-Dodaran M.
      • Card T.R.
      • West J.
      Incidence and prevalence of cirrhosis in the United Kingdom, 1992–2001: a general population-based study.
      ,
      • Liu B.
      • Balkwill A.
      • Roddam A.
      • Brown A.
      • Beral V.
      Million Women Study C
      Separate and joint effects of alcohol and smoking on the risks of cirrhosis and gallbladder disease in middle-aged women.

      Primary liver cancer

      Hepatocellular carcinoma (HCC), accounts for 70–90% of primary liver cancers (PLC). The management of HCC is complicated by the presence of liver cirrhosis in more than 80% of patients.
      Over half a million new cases of HCC are diagnosed each year worldwide [
      • Bosch F.X.
      • Ribes J.
      • Diaz M.
      • Cleries R.
      Primary liver cancer: worldwide incidence and trends.
      ,
      • Parkin D.M.
      • Bray F.
      • Ferlay J.
      • Pisani P.
      Estimating the world cancer burden: globocan 2000.
      ,
      • Yu M.C.
      • Yuan J.M.
      Environmental factors and risk for hepatocellular carcinoma.
      ]. In recent years decreasing incidence has been reported in some high incidence countries, while significant increases have been reported in several low incidence countries [
      • Bosch F.X.
      • Ribes J.
      • Diaz M.
      • Cleries R.
      Primary liver cancer: worldwide incidence and trends.
      ,
      • Fattovich G.
      • Stroffolini T.
      • Zagni I.
      • Donato F.
      Hepatocellular carcinoma in cirrhosis: incidence and risk factors.
      ,
      • Sherman M.
      Hepatocellular carcinoma: epidemiology, risk factors, and screening.
      ]. The GLOBOCAN project (http://globocan.iarc.fr) provides estimates of liver cancer incidence rates for each EU27 country. In the EU27 in 2008, liver cancer incidence was 10.6 and 3.6 per 100,000 persons for men and women, respectively [
      • Ferlay J.
      • Parkin D.M.
      • Steliarova-Foucher E.
      Estimates of cancer incidence and mortality in Europe in 2008.
      ]. For men, the highest incidence was in Italy and the lowest was in the Netherlands [
      • Ferlay J.
      • Parkin D.M.
      • Steliarova-Foucher E.
      Estimates of cancer incidence and mortality in Europe in 2008.
      ]. As expected, estimated mortality rates were very close to incidence rates, indeed the two measures were exactly the same for the EU27 overall (Fig. 2) [
      • Ferlay J.
      • Parkin D.M.
      • Steliarova-Foucher E.
      Estimates of cancer incidence and mortality in Europe in 2008.
      ].
      Figure thumbnail gr2
      Fig. 2(A) Estimated age-standardized incidence rates of liver cancer per 100,000 in 2008; WHO, GLOBOCAN, 2008. (B) Estimated age-standardized mortality rates per 100,000 for liver cancer in 2008; WHO, GLOBOCAN, 2008.
      The few European studies that have investigated the incidence of PLC were all based on local or national registries (Table 2). Liver cancer is responsible for 46,801 deaths per annum in Europe, according to the WHO mortality database. Unlike other cancers, the mortality rate is very close to the incidence rate because of the very low associated survival rate.
      Table 2European studies assessing incidence of primary liver cancer.
      • Erichsen R.
      • Jepsen P.
      • Jacobsen J.
      • Norgaard M.
      • Vilstrup H.
      • Sorensen H.T.
      Time trends in incidence and prognosis of primary liver cancer and liver metastases of unknown origin in a Danish region, 1985–2004.
      ,
      • Caumes J.L.
      • Nousbaum J.B.
      • Bessaguet C.
      • Faycal J.
      • Robaszkiewicz M.
      • Gouerou H.
      Epidemiology of hepatocellular carcinoma in Finistere. Prospective study from June 2002 to May 2003.
      ,
      • Binder-Foucard F.
      • Doffoel M.
      • Velten M.
      Epidemiology of hepatocellular carcinoma in Bas-Rhin: analysis of all incident cases from 1990 to 1999.
      ,
      • Dal Maso L.
      • Lise M.
      • Zambon P.
      • Crocetti E.
      • Serraino D.
      • Ricceri F.
      • et al.
      Incidence of primary liver cancer in Italy between 1988 and 2002: an age-period-cohort analysis.

      Liver transplantation

      More than 5500 liver transplants (LTs) are currently performed in Europe per year [

      Evolution of liver tranplantations in Europe from 05/1968 to 12/2009. European Liver Transplant Registry [cited 28 June 2012]. Available from: <http://www.eltr.org>.

      ] (Fig. 3). After rapid growth in the 1980s and 1990s the annual number of LTs has stopped growing in the last 10 years. Donor shortage currently represents the most important limiting factor for LT [
      • Arulraj R.
      • Neuberger J.
      Liver transplantation: filling the gap between supply and demand.
      ,
      • Roels L.
      • Rahmel A.
      The European experience.
      ]. Furthermore, alternatives to standard cadaveric LT, such as split (one liver divided for two recipients) or living related (a portion of a healthy person’s liver is used) LT’s now account for 11% of all procedures [
      • Adam R.
      • Cailliez V.
      • Majno P.
      • Karam V.
      • McMaster P.
      • Caine R.Y.
      • et al.
      Normalised intrinsic mortality risk in liver transplantation: European liver transplant registry study.
      ,
      • Adam R.
      • McMaster P.
      • O’Grady J.G.
      • Castaing D.
      • Klempnauer J.L.
      • Jamieson N.
      • et al.
      Evolution of liver transplantation in Europe: report of the European liver transplant registry.
      ].
      Figure thumbnail gr3
      Fig. 3Number of liver transplantations in European countries, May 1968 to December 2009; ELTR
      [

      Evolution of liver tranplantations in Europe from 05/1968 to 12/2009. European Liver Transplant Registry [cited 28 June 2012]. Available from: <http://www.eltr.org>.

      ]
      .
      Of particular note is the fact that LT outcomes have improved significantly over time. Currently the 1-year survival rate is reported to be 83% (all indications considered). This improvement is probably due to greater technical expertise, better selection of patients, and improved post-LT management of complications and immunosuppressive therapy.

      Alcohol and liver disease

      Europe is the heaviest drinking region in the world in terms of the prevalence of alcohol consumption [

      WHO. European status report on alcohol and health: World Health Organization. Regional Office for Europe; 2010.

      ]. Over 20% of the European population aged ⩾15 reported heavy episodic drinking (defined as five or more drinks on one occasion, or 50 g alcohol) at least once a week [

      WHO. European status report on alcohol and health: World Health Organization. Regional Office for Europe; 2010.

      ].
      Alcohol is the main cause of liver disease, including liver cirrhosis. Indeed, the cirrhosis mortality rate is a good indicator of alcohol-related mortality [
      • Zatonski W.A.
      • Sulkowska U.
      • Manczuk M.
      • Rehm J.
      • Boffetta P.
      • Lowenfels A.B.
      • et al.
      Liver cirrhosis mortality in Europe, with special attention to Central and Eastern Europe.
      ]. In turn, cirrhosis can lead to hepatocellular carcinoma. In France, 69% of PLC cases are caused by excessive alcohol consumption, making it the main risk factor, although viral aetiology is growing [
      • Borie F.
      • Tretarre B.
      • Bouvier A.M.
      • Faivre J.
      • Binder F.
      • Launoy G.
      • et al.
      Primitive liver cancers: epidemiology and geographical study in France.
      ]. Alcohol-related cirrhosis has increased in Estonia [
      • Parna K.
      • Rahu K.
      Dramatic increase in alcoholic liver cirrhosis mortality in Estonia in 1992–2008.
      ] and in Denmark [
      • Jepsen P.
      • Vilstrup H.
      • Andersen P.K.
      • Lash T.L.
      • Sorensen H.T.
      Comorbidity and survival of Danish cirrhosis patients: a nationwide population-based cohort study.
      ] in the last decade corresponding with increases in alcohol consumption in the 1990s in those countries.
      Standardized mortality rates for alcohol-related liver diseases among men and women during 2000–2005 in 24 European countries show a significant impact of chronic alcohol consumption on health in Europe (Fig. 4). The figures vary greatly between countries, ranging from 3 to 47 per 100,000 men in Latvia and Hungary, respectively. These data should be interpreted cautiously because of inter-country variation in the way mortality is declared and how alcohol-related diseases are reported in death certificates. Countries such as Norway and Sweden demonstrate the mortality reductions that can be achieved with the implementation of appropriate alcohol policies.
      Figure thumbnail gr4
      Fig. 4(A) Mortality from alcohol-related liver diseases among men in European countries in 2005; WHO 2010
      [

      WHO. European status report on alcohol and health: World Health Organization. Regional Office for Europe; 2010.

      ]
      . (B) Mortality from alcohol-related liver diseases among women in European countries in 2005; WHO 2010
      [

      WHO. European status report on alcohol and health: World Health Organization. Regional Office for Europe; 2010.

      ]
      .
      Data on the acute consequences of alcohol is scarce. From 1999 to 2008, the annual incidence rate of alcoholic hepatitis in the Danish population rose from 37 to 46 and from 24 to 34 per 100,000 for men and women, respectively. The 5-year mortality was 47% without cirrhosis, 69% with cirrhosis and 56% overall [
      • Sandahl T.D.
      • Jepsen P.
      • Thomsen K.L.
      • Vilstrup H.
      Incidence and mortality of alcoholic hepatitis in Denmark 1999–2008: a nationwide population based cohort study.
      ].
      Alcohol consumption in Europe decreased during the 1990s, but increased and stabilized at a higher level between 2004 and 2006, with huge variations among European countries [

      WHO. European status report on alcohol and health: World Health Organization. Regional Office for Europe; 2010.

      ]. The burden of liver disease attributable to the harmful use of alcohol is significant compared to other aetiologies. Moreover, the burden of general health, social and economic issues related to alcohol consumption is substantial.

      Hepatitis A

      In most European countries recent decades have seen a dramatic drop in the incidence of hepatitis A and a shift in the age-specific seroprevalence rates. This trend is largely due to improvements in hygiene and sanitation coupled with economic and social advancement (Table 3). As a consequence, a smaller fraction of the population is immune, especially early in life when hepatitis A virus (HAV) infection is mainly asymptomatic. The yearly incidence rate of hepatitis A in Europe today is between 0.55 and 1.5 cases per 100,000 inhabitants (Table 3), but there is significant inter-country variation. Hospitalization rates for HAV infection range from 0.2 per 100,000 inhabitants in the Netherlands to 94 per 100,000 in Romania (Fig. 5).
      Table 3Incidence rates of HAV infection in Europe.
      • Tosti M.E.
      • Spada E.
      • Romano L.
      • Zanetti A.
      • Mele A.
      Group Sc
      Acute hepatitis A in Italy: incidence, risk factors and preventive measures.
      ,
      • Suijkerbuijk A.W.
      • Lindeboom R.
      • van Steenbergen J.E.
      • Sonder G.J.
      • Doorduyn Y.
      Effect of hepatitis A vaccination programs for migrant children on the incidence of hepatitis A in The Netherlands.
      ,
      • Baumann A.
      Hepatitis A in Poland in the years 2006–2007.
      ,
      • Baumann A.
      Hepatitis A in Poland in 2008.
      ,
      • Arteaga A.
      • Carrasco-Garrido P.
      • de Andres A.L.
      • de Miguel A.G.
      • Jimenez-Garcia R.
      Trends of hepatitis A hospitalizations and costs associated with the hospitalization in Spain (2000–2005).
      ,
      • Arteaga-Rodriguez A.
      • Carrasco-Garrido P.
      • de Andres A.L.
      • de Miguel A.G.
      • Santos J.
      • Jimenez-Garcia R.
      Changes in the epidemiology of hepatitis A in Spain (2005–2008): trends of acute hepatitis A hospitalizations, comorbidities, and costs associated with the hospitalization.
      Declining HAV incidence and seroprevalence have delayed the age at which individuals become infected until adulthood when the likelihood of developing the symptomatic illness is considerably higher. Because of the greater disease burden of late HAV infections several countries have considered systematic vaccination programmes, which can reduce incidence, outbreaks, mortality rates, and hospitalization [
      • Hendrickx G.
      • Van Herck K.
      • Vorsters A.
      • Wiersma S.
      • Shapiro C.
      • Andrus J.K.
      • et al.
      Has the time come to control hepatitis A globally? Matching prevention to the changing epidemiology.
      ]. One strategy is to combine HAV and hepatitis B virus (HBV) vaccination. Cost effectiveness analyses performed in Ireland showed vaccination to be the strategy of choice where HAV immunity is 45% or less [
      • Rajan E.
      • Shattock A.G.
      • Fielding J.F.
      Cost-effective analysis of hepatitis A prevention in Ireland.
      ] (Table 4).
      Table 4Prevalence rates of HAV infection in Europe.
      • Quoilin S.
      • Hutse V.
      • Vandenberghe H.
      • Claeys F.
      • Verhaegen E.
      • De Cock L.
      • et al.
      A population-based prevalence study of hepatitis A, B and C virus using oral fluid in Flanders, Belgium.
      ,
      • Kyrka A.
      • Tragiannidis A.
      • Cassimos D.
      • Pantelaki K.
      • Tzoufi M.
      • Mavrokosta M.
      • et al.
      Seroepidemiology of hepatitis A among Greek children indicates that the virus is still prevalent: implications for universal vaccination.
      ,
      • D’Amelio R.
      • Mele A.
      • Mariano A.
      • Romano L.
      • Biselli R.
      • Lista F.
      • et al.
      Hepatitis A, Italy.
      Reduced population protection leads to more symptomatic cases and to outbreaks; therefore HAV remains a threat to European public health, despite declining incidence. Epidemics were responsible for a 10-fold increase in the incidence rate in the Czech Republic in 2008 [
      • Castkova J.
      • Benes C.
      Increase in hepatitis A cases in the Czech Republic in 2008 – an update.
      ,
      • Fabianova K.
      • Castkova J.
      • Benes C.
      • Kyncl J.
      • Kriz B.
      Increase in hepatitis A cases in the Czech Republic in 2008–preliminary report.
      ] and an incidence rate of 124 per 100,000 inhabitants in Latvia in 2008 [
      • Perevoscikovs J.
      • Lucenko I.
      • Magone S.
      • Brila A.
      • Curikova J.
      Community-wide outbreak of hepatitis A in Latvia, in 2008.
      ]. Finnish epidemics in 1994–1995 and 2002–2003 began with intravenous drug users before spreading to the rest of the population [
      • Broman M.
      • Jokinen S.
      • Kuusi M.
      • Lappalainen M.
      • Roivainen M.
      • Liitsola K.
      • et al.
      Epidemiology of hepatitis A in Finland in 1990–2007.
      ]. The economic impact of a HAV outbreak can be substantial, ranging from USD 3824 to USD 200,480 per case [
      • Luyten J.
      • Beutels P.
      Costing infectious disease outbreaks for economic evaluation: a review for hepatitis A.
      ].

      Hepatitis B

      The hepatitis B virus (HBV) has sometimes been called ‘the silent killer’ because infected adults often remain undiagnosed and thus untreated until it is too late. Throughout Europe, an average of 23% of patients knew of hepatitis B at the time of their diagnosis and only 27% knew they were at risk of contracting it [

      European Liver Patients Association. Report on hepatitis patient self-help in Europe; 2011. <http://www.hepbcppa.org/wp-content/uploads/2011/11/Report-on-Patient-Self-Help.pdf>.

      ]. In France 18% of identified patients were detected by standard testing during pregnancy [
      • Cadranel J.F.
      • Lahmek P.
      • Causse X.
      • Bellaiche G.
      • Bettan L.
      • Fontanges T.
      • et al.
      Epidemiology of chronic hepatitis B infection in France. Risk factors for significant fibrosis–results of a nationwide survey.
      ].
      The yearly incidence of new cases of HBV shows large variation from 0.2 to 11.2 cases per 100,000 inhabitants in France and Iceland, respectively (Fig. 6).
      Figure thumbnail gr6
      Fig. 6Incidence rates of hepatitis B in EU27 countries in 2005; ECDC 2007. NB: there is no of standardized definition of new HBV cases; sometimes reactivations are included.
      Estimates for the prevalence of chronic HBV infections, based on hepatitis B surface antigen (HBsAg) identification in sera collected from the general population, range from 0.1–0.7%, with the exception of Romania (5.6%) and Greece (3.4%) (Table 5, Table 7).
      Table 5Age-specific HBV seroprevalence in European countries
      • Nardone A.
      • Anastassopoulou C.G.
      • Theeten H.
      • Kriz B.
      • Davidkin I.
      • Thierfelder W.
      • et al.
      A comparison of hepatitis B seroepidemiology in ten European countries.
      .
      Data added from Institut de Veille Sanitaire, 2004

      Sanitaire IdV. Prevalence of hepatitis B and Hepatitis C in France. 2004.

      .
      The disease burden of chronic hepatitis B in Europe is significant. Cirrhosis occurs in 20–30% of chronically infected patients [
      • Cadranel J.F.
      • Lahmek P.
      • Causse X.
      • Bellaiche G.
      • Bettan L.
      • Fontanges T.
      • et al.
      Epidemiology of chronic hepatitis B infection in France. Risk factors for significant fibrosis–results of a nationwide survey.
      ,
      • Mota A.
      • Areias J.
      • Cardoso M.F.
      Chronic liver disease and cirrhosis among patients with hepatitis B virus infection in northern Portugal with reference to the viral genotypes.
      ] with about 25% at risk of developing HCC, thus HBV is responsible for 10–15% of hepatocellular carcinoma [
      • Hatzakis A.
      • Wait S.
      • Bruix J.
      • Buti M.
      • Carballo M.
      • Cavaleri M.
      • et al.
      The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference∗.
      ]. HBV infected patients also have an excess risk of all-cause mortality and liver-related mortality [
      • Duberg A.S.
      • Torner A.
      • Davidsdottir L.
      • Aleman S.
      • Blaxhult A.
      • Svensson A.
      • et al.
      Cause of death in individuals with chronic HBV and/or HCV infection, a nationwide community-based register study.
      ], about 46% of which is explained by liver cancer. HBV infection is responsible for a mortality rate of 2.7 and 2.5 persons per 100,000 inhabitants per year in Spain and France, respectively [
      • Garcia-Fulgueiras A.
      • Garcia-Pina R.
      • Morant C.
      • Garcia-Ortuzar V.
      • Genova R.
      • Alvarez E.
      Hepatitis C and hepatitis B-related mortality in Spain.
      ,
      • Marcellin P.
      • Pequignot F.
      • Delarocque-Astagneau E.
      • Zarski J.P.
      • Ganne N.
      • Hillon P.
      • et al.
      Mortality related to chronic hepatitis B and chronic hepatitis C in France: evidence for the role of HIV coinfection and alcohol consumption.
      ].
      Data suggest there has been a reduction in the yearly incidence of HBV, accompanied by a decline in prevalence related to vaccination campaigns (Table 6, Table 7) [
      • Salleras L.
      • Dominguez A.
      • Bruguera M.
      • Plans P.
      • Espunes J.
      • Costa J.
      • et al.
      Seroepidemiology of hepatitis B virus infection in pregnant women in Catalonia (Spain).
      ,
      • Zacharakis G.
      • Kotsiou S.
      • Papoutselis M.
      • Vafiadis N.
      • Tzara F.
      • Pouliou E.
      • et al.
      Changes in the epidemiology of hepatitis B virus infection following the implementation of immunisation programmes in northeastern Greece.
      ]. However, a lack of reliable epidemiological data on HBV is one of the biggest barriers to the development of policies for its management. For example, surveillance data collected by the ECDC must be interpreted with caution because of the absence of a standardized definition of HBV infection.
      Table 6HBV incidence in Europe.
      • Czarkowski M.P.
      • Bobel D.
      Hepatitis B in Poland in 2006.
      ,
      • Czarkowski M.P.
      • Rosinska M.
      Hepatitis B in Poland in 2005.
      ,
      • Pitigoi D.
      • Rafila A.
      • Pistol A.
      • Arama V.
      • Molagic V.
      • Streinu-Cercel A.
      Trends in hepatitis B incidence in Romania, 1989-2005.
      Despite vaccination and decreased incidence, HBV infection remains a public health issue, not only because of its silent nature, but also because of its associated complications.

      Hepatitis C

      In Europe, a significant number of persons acquired hepatitis C virus (HCV) in the 1970s and 1980s before the virus was identified and a diagnostic test was available. Since then, the transmission of infection has been greatly reduced and it is now mainly concentrated in intravenous drug users. However the disease has a prolonged time-course – individuals developing cirrhosis within 20 years [
      • Freeman A.J.
      • Dore G.J.
      • Law M.G.
      • Thorpe M.
      • Von Overbeck J.
      • Lloyd A.R.
      • et al.
      Estimating progression to cirrhosis in chronic hepatitis C virus infection.
      ] – so the disease burden of HCV in Europe is at its peak only now.
      Table 7Seroprevalence of chronically HBV-infected patients in Europe.
      • Meffre C.
      • Le Strat Y.
      • Delarocque-Astagneau E.
      • Dubois F.
      • Antona D.
      • Lemasson J.M.
      • et al.
      Prevalence of hepatitis B and hepatitis C virus infections in France in 2004: social factors are important predictors after adjusting for known risk factors.
      ,
      • Papaevangelou V.
      • Hadjichristodoulou C.
      • Cassimos D.C.
      • Pantelaki K.
      • Tzivaras A.
      • Hatzimichael A.
      • et al.
      Seroepidemiology of hepatitis B in Greek children 6 years after the implementation of universal vaccination.
      ,
      • Fabris P.
      • Baldo V.
      • Baldovin T.
      • Bellotto E.
      • Rassu M.
      • Trivello R.
      • et al.
      Changing epidemiology of HCV and HBV infections in Northern Italy: a survey in the general population.
      ,
      • Baaten G.G.
      • Sonder G.J.
      • Dukers N.H.
      • Coutinho R.A.
      • Van den Hoek J.A.
      Population-based study on the seroprevalence of hepatitis A, B, and C virus infection in Amsterdam, 2004.
      ,
      • Voiculescu M.
      • Iliescu L.
      • Ionescu C.
      • Micu L.
      • Ismail G.
      • Zilisteanu D.
      • et al.
      A cross-sectional epidemiological study of HBV, HCV, HDV and HEV prevalence in the SubCarpathian and South-Eastern regions of Romania.
      ,
      • Salleras L.
      • Dominguez A.
      • Bruguera M.
      • Plans P.
      • Costa J.
      • Cardenosa N.
      • et al.
      Declining prevalence of hepatitis B virus infection in Catalonia (Spain) 12 years after the introduction of universal vaccination.
      Reliable epidemiological data on HCV in Europe is lacking [
      • Muhlberger N.
      • Schwarzer R.
      • Lettmeier B.
      • Sroczynski G.
      • Zeuzem S.
      • Siebert U.
      HCV-related burden of disease in Europe: a systematic assessment of incidence, prevalence, morbidity, and mortality.
      ]. The annual average incidence rate is estimated at 6.19 per 100,000 inhabitants (95% CI 4.90–7.48) [
      • Muhlberger N.
      • Schwarzer R.
      • Lettmeier B.
      • Sroczynski G.
      • Zeuzem S.
      • Siebert U.
      HCV-related burden of disease in Europe: a systematic assessment of incidence, prevalence, morbidity, and mortality.
      ]. Overall prevalence in Europe, estimated from serum antibodies, varies between 0.13% and 3.26% (Table 8), which aligns with the 0.003–4.5% prevalence rate reported by WHO for the wider European region [
      • Muhlberger N.
      • Schwarzer R.
      • Lettmeier B.
      • Sroczynski G.
      • Zeuzem S.
      • Siebert U.
      HCV-related burden of disease in Europe: a systematic assessment of incidence, prevalence, morbidity, and mortality.
      ]. In intravenous drug users prevalence rates range from up to 50% in Cyprus [
      • Demetriou V.L.
      • van de Vijver D.A.
      • Hezka J.
      • Kostrikis L.G.
      • Cyprus I.N.
      • Kostrikis L.G.
      Hepatitis C infection among intravenous drug users attending therapy programs in Cyprus.
      ], 59.8% (95% CI 50.7–68.3) in France [
      • Jauffret-Roustide M.
      • Le Strat Y.
      • Couturier E.
      • Thierry D.
      • Rondy M.
      • Quaglia M.
      • et al.
      A national cross-sectional study among drug-users in France: epidemiology of HCV and highlight on practical and statistical aspects of the design.
      ], 75% for those admitted for opiate detoxification in Germany and 83.2% in Italy [
      • Camoni L.
      • Regine V.
      • Salfa M.C.
      • Nicoletti G.
      • Canuzzi P.
      • Magliocchetti N.
      • et al.
      Continued high prevalence of HIV, HBV and HCV among injecting and noninjecting drug users in Italy.
      ,
      • Reimer J.
      • Lorenzen J.
      • Baetz B.
      • Fischer B.
      • Rehm J.
      • Haasen C.
      • et al.
      Multiple viral hepatitis in injection drug users and associated risk factors.
      ].
      Table 8HCV prevalence in Europe.
      • Cozzolongo R.
      • Osella A.R.
      • Elba S.
      • Petruzzi J.
      • Buongiorno G.
      • Giannuzzi V.
      • et al.
      Epidemiology of HCV infection in the general population: a survey in a southern Italian town.
      ,
      • Gheorghe L.
      • Csiki I.E.
      • Iacob S.
      • Gheorghe C.
      • Smira G.
      • Regep L.
      The prevalence and risk factors of hepatitis C virus infection in adult population in Romania: a nationwide survey 2006–2008.
      Up to 85% of infected patients develop a chronic infection, with 10–20% progressing to cirrhosis [
      • Alter M.J.
      Epidemiology of hepatitis C.
      ]. About 7% of cirrhosis patients develop HCC [
      • Di Bisceglie A.M.
      Hepatitis C and hepatocellular carcinoma.
      ] and HCV is an important risk factor for this cancer [
      • Hatzakis A.
      • Wait S.
      • Bruix J.
      • Buti M.
      • Carballo M.
      • Cavaleri M.
      • et al.
      The state of hepatitis B and C in Europe: report from the hepatitis B and C summit conference∗.
      ]. HCV is also the main indication for virus-related liver transplantation. Patients diagnosed with hepatitis C show increased morbidity, higher hospital admission rates [
      • McDonald S.A.
      • Hutchinson S.J.
      • Bird S.M.
      • Mills P.R.
      • Hayes P.
      • Dillon J.F.
      • et al.
      Excess morbidity in the hepatitis C-diagnosed population in Scotland, 1991–2006.
      ] and mortality rates three times higher than that of the general population, due to both drug use and liver disease [
      • Neal K.R.
      • Trent Hepatitis C.S.G.
      • Ramsay S.
      • Thomson B.J.
      • Irving W.L.
      Excess mortality rates in a cohort of patients infected with the hepatitis C virus: a prospective study.
      ]. In France there are 2.5 HCV-associated deaths per 100,000 inhabitants (95% with cirrhosis and 33% with HCC at death) [
      • Marcellin P.
      • Pequignot F.
      • Delarocque-Astagneau E.
      • Zarski J.P.
      • Ganne N.
      • Hillon P.
      • et al.
      Mortality related to chronic hepatitis B and chronic hepatitis C in France: evidence for the role of HIV coinfection and alcohol consumption.
      ]. In Spain, the mortality rate due to HCV infection is 11.25 per 100,000 inhabitants [
      • Garcia-Fulgueiras A.
      • Garcia-Pina R.
      • Morant C.
      • Garcia-Ortuzar V.
      • Genova R.
      • Alvarez E.
      Hepatitis C and hepatitis B-related mortality in Spain.
      ]. Cost analysis, including the cost of complications, shows that the median lifetime cost for treating one patient with dual therapy (pegylated interferon and ribavirin) is EUR 7517 to EUR 21,229, depending on the virus genotype [
      • Haj-Ali Saflo O.
      • Hernandez Guijo J.M.
      [Cost-effectiveness of chronic hepatitis C treatment in Spain].
      ]. In cost effectiveness analyses of new protease inhibitors for treating chronic hepatitis C universal triple therapy costs an additional USD 70,100 per QALY (mild fibrosis) and USD 36,300 per QALY (advanced fibrosis) compared with standard pegylated interferon plus ribavirin therapy [
      • Liu S.
      • Cipriano L.E.
      • Holodniy M.
      • Owens D.K.
      • Goldhaber-Fiebert J.D.
      New protease inhibitors for the treatment of chronic hepatitis C: a cost-effectiveness analysis.
      ].
      Models suggest that HCV-related morbidity will rapidly increase in the short term. In the UK, HCV-related cirrhosis and death from HCC are projected to increase dramatically in the next decade, reflecting the increased incidence of HCV infection in the early 1980’s [
      • Sweeting M.J.
      • De Angelis D.
      • Brant L.J.
      • Harris H.E.
      • Mann A.G.
      • Ramsay M.E.
      The burden of hepatitis C in England.
      ]. Modelling also suggests that treatment with pegylated interferon and additional effects of triple therapy with a protease inhibitor could reduce HCV genotype 1-related cumulative incidence by 17.7% and mortality by 9.7% between 2012 and 2021 [
      • Deuffic-Burban S.
      • Mathurin P.
      • Valleron A.J.
      Modelling the past, current and future HCV burden in France: detailed analysis and perspectives.
      ].
      Although HCV transmission has been greatly reduced and prevention strategies have been effective [
      • Delarocque-Astagneau E.
      • Meffre C.
      • Dubois F.
      • Pioche C.
      • Le Strat Y.
      • Roudot-Thoraval F.
      • et al.
      The impact of the prevention programme of hepatitis C over more than a decade: the French experience.
      ], patients now chronically infected with HCV will represent a heavy disease burden in the coming years.

      Hepatitis D

      Hepatitis delta virus (HDV) can only infect an individual co-infected or super-infected by HBV [
      • Rizzetto M.
      Hepatitis D: thirty years after.
      ]. Most patients with HBV/HDV co-infection develop chronic infection and have more severe liver disease [
      • Govindarajan S.
      • Chin K.P.
      • Redeker A.G.
      • Peters R.L.
      Fulminant B viral hepatitis: role of delta agent.
      ,
      • Hadler S.C.
      • De Monzon M.
      • Ponzetto A.
      • Anzola E.
      • Rivero D.
      • Mondolfi A.
      • et al.
      Delta virus infection and severe hepatitis. An epidemic in the Yucpa Indians of Venezuela.
      ], more rapid progression to cirrhosis [
      • Fattovich G.
      • Boscaro S.
      • Noventa F.
      • Pornaro E.
      • Stenico D.
      • Alberti A.
      • et al.
      Influence of hepatitis delta virus infection on progression to cirrhosis in chronic hepatitis type B.
      ,
      • Saracco G.
      • Rosina F.
      • Brunetto M.R.
      • Amoroso P.
      • Caredda F.
      • Farci P.
      • et al.
      Rapidly progressive HBsAg-positive hepatitis in Italy. The role of hepatitis delta virus infection.
      ] and increased hepatic decompensation and death [
      • Romeo R.
      • Del Ninno E.
      • Rumi M.
      • Russo A.
      • Sangiovanni A.
      • de Franchis R.
      • et al.
      A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma.
      ] compared with patients who have chronic HBV infection alone.
      The highest prevalence is seen in central Africa, the Horn of Africa, the Amazon Basin, eastern and Mediterranean Europe, the Middle East, and parts of Asia [
      • Hughes S.A.
      • Wedemeyer H.
      • Harrison P.M.
      Hepatitis delta virus.
      ]. Most cases recorded in other European countries are found in populations originating from endemic regions. Limited data are available for basing an estimate of HDV prevalence in European countries.
      Among 16,597 HIV patients enrolled in EuroSIDA, 61 of 422 (14.5%) HBsAg-positive carriers were anti-HDV positive. HDV predominated in intravenous drug users and in southern and/or eastern Europe. Serum HDV-RNA was detectable in 87% of anti-HDV-positive patients [
      • Soriano V.
      • Grint D.
      • d’Arminio Monforte A.
      • Horban A.
      • Leen C.
      • Poveda E.
      • et al.
      Hepatitis delta in HIV-infected individuals in Europe.
      ].
      In Switzerland the prevalence of HDV infection in 1,699 patients with chronic hepatitis B was 5.9% [
      • Genne D.
      • Rossi I.
      Hepatitis delta in Switzerland: a silent epidemic.
      ]. In a German study hepatitis D prevalence increased from 4.1% to 6.2% among HBsAg carriers during the two decades, 1989 to 2008 (p <0.06). The proportion of patients originating from the former Soviet Union and Africa increased during the time period, whereas the proportion of patients from southern Europe decreased. Estimated survival and complication-free survival during 12 years were 72% and 45%, respectively in cirrhotic patients compared with 100% in non-cirrhotic patients (p <0.008 and p <0.0001, respectively) [
      • Erhardt A.
      • Hoernke M.
      • Heinzel-Pleines U.
      • Sagir A.
      • Gobel T.
      • Haussinger D.
      Retrospective analysis of chronic hepatitis D in a West German university clinic over two decades: migratory pattern, prevalence and clinical outcome.
      ].
      In an Italian study of HBsAg-positive patients, 4.2% and 17% of Italian patients and patients from outside of the EU, respectively, had anti-HDV antibodies [
      • Piccolo P.
      • Lenci I.
      • Telesca C.
      • Di Paolo D.
      • Bandiera F.
      • De Melia L.
      • et al.
      Patterns of chronic hepatitis B in Central Italy: a cross-sectional study.
      ]. In north western and southern Italy the prevalence of HDV infection was reported to be 5.7% and 9.7%, respectively [
      • Sagnelli E.
      • Stroffolini T.
      • Mele A.
      • Imparato M.
      • Almasio P.L.
      Italian Hospitals’ Collaborating G
      Chronic hepatitis B in Italy: new features of an old disease–approaching the universal prevalence of hepatitis B e antigen-negative cases and the eradication of hepatitis D infection.
      ,
      • Torre F.
      • Basso M.
      • Giannini E.G.
      • Feasi M.
      • Boni S.
      • Grasso A.
      • et al.
      Clinical and virological survey of patients with hepatitis B surface antigen in an Italian region: clinical considerations and disease burden.
      ].
      The prevalence of anti-HDV antibodies was 7.1% in adult UK patients with concomitant HBV-infection, most of whom were born in regions where HDV is endemic, e.g. southern or eastern Europe (28.1%), Africa (26.8%) or the Middle-East (7.3%) [
      • Cross T.J.
      • Rizzi P.
      • Horner M.
      • Jolly A.
      • Hussain M.J.
      • Smith H.M.
      • et al.
      The increasing prevalence of hepatitis delta virus (HDV) infection in South London.
      ].

      Hepatitis E

      The Hepatitis E virus (HEV) causes an acute form of hepatitis, although infection in immunocompromised patients can result in chronic disease. HEV is also known to cause infections in animals, particularly pigs. Although hepatitis E has been reported from many European countries [
      • FitzSimons D.
      • Hendrickx G.
      • Vorsters A.
      • Van Damme P.
      Hepatitis A and E: update on prevention and epidemiology.
      ] its incidence and the seroprevalence of the HEV infection is largely unknown in this region.
      In studies of the Madrid general population, Catalonian children and the Catalonian general population the prevalence of HEV infection was reported as 2.17%, 4.6%, and 7.3%, respectively [
      • Buti M.
      • Dominguez A.
      • Plans P.
      • Jardi R.
      • Schaper M.
      • Espunes J.
      • et al.
      Community-based seroepidemiological survey of hepatitis E virus infection in Catalonia.
      ,
      • Buti M.
      • Plans P.
      • Dominguez A.
      • Jardi R.
      • Rodriguez Frias F.
      • Esteban R.
      • et al.
      Prevalence of hepatitis E virus infection in children in the northeast of Spain.
      ,
      • Fogeda M.
      • Avellon A.
      • Echevarria J.M.
      Prevalence of specific antibody to hepatitis E virus in the general population of the community of Madrid, Spain.
      ].
      In two Swiss studies the prevalence of anti-HEV antibodies in HIV patients was 2.6% [
      • Kenfak-Foguena A.
      • Schoni-Affolter F.
      • Burgisser P.
      • Witteck A.
      • Darling K.E.
      • Kovari H.
      • et al.
      Hepatitis E Virus seroprevalence and chronic infections in patients with HIV, Switzerland.
      ], while anti-HEV antibodies were found in 4.9% of blood donor samples [
      • Kaufmann A.
      • Kenfak-Foguena A.
      • Andre C.
      • Canellini G.
      • Burgisser P.
      • Moradpour D.
      • et al.
      Hepatitis E virus seroprevalence among blood donors in Southwest Switzerland.
      ].
      Among rural and urban French blood donors, Parisian blood donors and HIV patients in Marseille the prevalence of anti-HEV antibodies was 16.6%, 3.2%, and 4.4%, respectively [
      • Boutrouille A.
      • Bakkali-Kassimi L.
      • Cruciere C.
      • Pavio N.
      Prevalence of anti-hepatitis E virus antibodies in French blood donors.
      ,
      • Kaba M.
      • Richet H.
      • Ravaux I.
      • Moreau J.
      • Poizot-Martin I.
      • Motte A.
      • et al.
      Hepatitis E virus infection in patients infected with the human immunodeficiency virus.
      ,
      • Mansuy J.M.
      • Legrand-Abravanel F.
      • Calot J.P.
      • Peron J.M.
      • Alric L.
      • Agudo S.
      • et al.
      High prevalence of anti-hepatitis E virus antibodies in blood donors from South West France.
      ].
      In the Italian cities of Rome and Rieti, the prevalence of anti-HEV antibodies among pig breeders and the general population was 3.3% and 2.9%, respectively [
      • Vulcano A.
      • Angelucci M.
      • Candelori E.
      • Martini V.
      • Patti A.M.
      • Mancini C.
      • et al.
      HEV prevalence in the general population and among workers at zoonotic risk in Latium Region.
      ]. The prevalence in subjects recruited in Rome and Rieti was 2.5% and 5.5%, respectively (p= 0.0004) [
      • Vulcano A.
      • Angelucci M.
      • Candelori E.
      • Martini V.
      • Patti A.M.
      • Mancini C.
      • et al.
      HEV prevalence in the general population and among workers at zoonotic risk in Latium Region.
      ].

      Non-alcoholic fatty liver disease (NAFLD)

      NAFLD is defined as the accumulation of liver fat exceeding 5% of hepatocytes in the absence of significant alcohol intake (20 g per day for men and 10 g per day for women), viral infection, or any other specific aetiology of liver disease. More than 50% of adults in the EU27 are overweight or obese, both of which are important risk factors for NAFLD. Therefore, NAFLD can be considered to be endemic in Europe and a major potential threat to public health.
      In the Barcelona and DIONYSOS studies, the prevalence of NAFLD was 26%. In the SHIP study it was 30.4% and in the RISC study 33% of patients had a high probability of having the disease [
      • Bedogni G.
      • Miglioli L.
      • Masutti F.
      • Castiglione A.
      • Croce L.S.
      • Tiribelli C.
      • et al.
      Incidence and natural course of fatty liver in the general population: the Dionysos study.
      ,
      • Castellares C.
      • Barreiro P.
      • Martin-Carbonero L.
      • Labarga P.
      • Vispo M.E.
      • Casado R.
      • et al.
      Liver cirrhosis in HIV-infected patients: prevalence, aetiology and clinical outcome.
      ,
      • Haring R.
      • Wallaschofski H.
      • Nauck M.
      • Dorr M.
      • Baumeister S.E.
      • Volzke H.
      Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels.
      ].
      A Romanian study estimated NAFLD prevalence to be 20% [
      • Radu C.
      • Grigorescu M.
      • Crisan D.
      • Lupsor M.
      • Constantin D.
      • Dina L.
      Prevalence and associated risk factors of non-alcoholic fatty liver disease in hospitalized patients.
      ]. A Greek study revealed evidence of NAFLD and of non-alcoholic steatohepatitis (NASH) in 31% and 40%, respectively, of autopsied cases of ischaemic heart disease or traffic accident death (after exclusion of hepatitis B seropositivity or known liver disease) [
      • Zois C.D.
      • Baltayiannis G.H.
      • Bekiari A.
      • Goussia A.
      • Karayiannis P.
      • Doukas M.
      • et al.
      Steatosis and steatohepatitis in postmortem material from Northwestern Greece.
      ]. A high prevalence (36–44%) of NAFLD was found in obese children, regardless of the manner used to diagnose the disease [
      • Caserta C.A.
      • Pendino G.M.
      • Amante A.
      • Vacalebre C.
      • Fiorillo M.T.
      • Surace P.
      • et al.
      Cardiovascular risk factors, nonalcoholic fatty liver disease, and carotid artery intima-media thickness in an adolescent population in southern Italy.
      ,
      • Imhof A.
      • Kratzer W.
      • Boehm B.
      • Meitinger K.
      • Trischler G.
      • Steinbach G.
      • et al.
      Prevalence of non-alcoholic fatty liver and characteristics in overweight adolescents in the general population.
      ,
      • Sartorio A.
      • Del Col A.
      • Agosti F.
      • Mazzilli G.
      • Bellentani S.
      • Tiribelli C.
      • et al.
      Predictors of non-alcoholic fatty liver disease in obese children.
      ]. NAFLD is known to be particularly prevalent in patients with diabetes. Two major European studies [
      • Targher G.
      • Bertolini L.
      • Padovani R.
      • Rodella S.
      • Tessari R.
      • Zenari L.
      • et al.
      Prevalence of nonalcoholic fatty liver disease and its association with cardiovascular disease among type 2 diabetic patients.
      ,
      • Williamson R.M.
      • Price J.F.
      • Glancy S.
      • Perry E.
      • Nee L.D.
      • Hayes P.C.
      • et al.
      Prevalence of and risk factors for hepatic steatosis and nonalcoholic fatty liver disease in people with type 2 diabetes: the Edinburgh type 2 diabetes study.
      ] reported NAFLD prevalence rates of 42.6–69.5% in large samples of type 2 diabetic patients (Table 9).
      Table 9European studies assessing the prevalence of NAFLD.
      Fatty Liver Index is based on BMI, waist circumference, triglycerides, and GGT.
      • Gastaldelli A.
      • Kozakova M.
      • Hojlund K.
      • Flyvbjerg A.
      • Favuzzi A.
      • Mitrakou A.
      • et al.
      Fatty liver is associated with insulin resistance, risk of coronary heart disease, and early atherosclerosis in a large European population.
      ,
      • Caballeria L.
      • Pera G.
      • Auladell M.A.
      • Toran P.
      • Munoz L.
      • Miranda D.
      • et al.
      Prevalence and factors associated with the presence of nonalcoholic fatty liver disease in an adult population in Spain.
      The presence of NAFLD carries an increased risk of overall mortality and of mortality related to cardiovascular disease (CVD) and liver disease. In a Danish study, after adjustment for sex, diabetes and cirrhosis at baseline, NAFLD-associated age-adjusted standardized mortality ratios (SMR) were 2.3 (95% CI 2.1–2.6) for all causes, 19.7 (95% CI 15.3–25.0) for hepatobiliary disease, and 2.1 (95% CI 1.8–2.5) for CVD [
      • Jepsen P.
      • Vilstrup H.
      • Mellemkjaer L.
      • Thulstrup A.M.
      • Olsen J.H.
      • Baron J.A.
      • et al.
      Prognosis of patients with a diagnosis of fatty liver–a registry-based cohort study.
      ]. In the SHIP study the odds ratios of all-cause mortality and CV mortality for male patients with ultrasonographic steatosis and highest GGT quintile were 1.98 (95% CI 1.21–3.27) and 2.41 (95% CI 1.05–5.55), respectively [
      • Haring R.
      • Wallaschofski H.
      • Nauck M.
      • Dorr M.
      • Baumeister S.E.
      • Volzke H.
      Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels.
      ]. The risk was not increased in women [
      • Haring R.
      • Wallaschofski H.
      • Nauck M.
      • Dorr M.
      • Baumeister S.E.
      • Volzke H.
      Ultrasonographic hepatic steatosis increases prediction of mortality risk from elevated serum gamma-glutamyl transpeptidase levels.
      ]. In a Swedish study the age, sex, and calendar-period adjusted mortality ratio was 1.69 (95% CI 1.24–2.25) for NAFLD compared to the general population, even after excluding cirrhotic patients at the baseline. CVD, malignancy, and liver disease were the top three causes of death [
      • Soderberg C.
      • Stal P.
      • Askling J.
      • Glaumann H.
      • Lindberg G.
      • Marmur J.
      • et al.
      Decreased survival of subjects with elevated liver function tests during a 28-year follow-up.
      ]. In the Italian Cremona study that followed >2000 middle-aged individuals for 15 years the fatty liver index was significantly associated with a higher liver-related mortality in a multi-adjusted analysis [
      • Calori G.
      • Lattuada G.
      • Ragogna F.
      • Garancini M.P.
      • Crosignani P.
      • Villa M.
      • et al.
      Fatty liver index and mortality: the Cremona study in the 15th year of follow-up.
      ].
      NAFLD already represents an important economic burden for European countries. A German study based on the SHIP cohort showed that subjects with sonographic fatty liver disease and increased serum alanine amino transferase (ALT) levels had 26% higher overall health-care costs at 5-year follow-up [
      • Baumeister S.E.
      • Volzke H.
      • Marschall P.
      • John U.
      • Schmidt C.O.
      • Flessa S.
      • et al.
      Impact of fatty liver disease on health care utilization and costs in a general population: a 5-year observation.
      ].

      Drug induced liver injuries (DILI)

      A large proportion of drug hepatotoxicity occurs as an idiosyncratic event, so that its prevalence and incidence is still only partially known despite recent improvements [
      • Andrade R.J.
      • Lucena M.I.
      • Fernandez M.C.
      • Pelaez G.
      • Pachkoria K.
      • Garcia-Ruiz E.
      • et al.
      Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period.
      ,
      • Larrey D.
      Epidemiology and individual susceptibility to adverse drug reactions affecting the liver.
      ]. A notable exception is accidental or suicidal paracetamol intoxication, which shows a dose-related liver toxicity, particularly when in combination with alcohol. The majority of data are provided by retrospective studies of databases from pharmacovigilance centres and/or pharmaceutical companies. In an analysis of a Swedish database, DILI, with at least a possible causal relationship, was found in 6.6% (77 cases) of 1664 cases. 3.3% (38 cases) were referred for evaluation to the out-patient clinic whereas 3% had a follow-up after hospitalization for DILI [
      • De Valle M.B.
      • Av Klinteberg V.
      • Alem N.
      • Olsson R.
      • Bjornsson E.
      Drug-induced liver injury in a Swedish university hospital out-patient hepatology clinic.
      ].
      The incidence of DILI in the UK general population has been estimated at 2.4 cases per 100,000 person years [
      • de Abajo F.J.
      • Montero D.
      • Madurga M.
      • Garcia Rodriguez L.A.
      Acute and clinically relevant drug-induced liver injury: a population based case-control study.
      ]. In an area of France the incidence has been estimated at 14 cases per 100,000 persons, corresponding to a number of events 16 times higher than that collected by pharmacovigilance centres [
      • Sgro C.
      • Clinard F.
      • Ouazir K.
      • Chanay H.
      • Allard C.
      • Guilleminet C.
      • et al.
      Incidence of drug-induced hepatic injuries: a French population-based study.
      ].
      Retrospective studies suggest that drugs may have caused around 10–20% of all cases of fulminant and subfulminant hepatitis [
      • Bjornsson E.
      • Jerlstad P.
      • Bergqvist A.
      • Olsson R.
      Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden.
      ,
      • Larrey D.
      • Pageaux G.P.
      Drug-induced acute liver failure.
      ]. In a French study, 5.5% of LTs were related to drug-induced acute liver failure, of which 36.4% were due to paracetamol (acetaminophen) intake [

      Larrey D, Pageaux GP, Gulmez E, et al. Rôle des causes médicamenteuses dans l’indication de transplantation hépatique pour hépatite aiguë grave chez les adultes en France. Journées francophones d’hepato-gastoentérologie et d’oncologie digestive 2011.

      ]. Of the 674 DILI references new to the HEPATOX database between September 2010 and August 2011, 16% concerned neuropsychiatric compounds, including carbamazepine, phenytoin, and valproic acid. These data are consistent with data collected in the Vigibase™ [
      • Suzuki A.
      • Andrade R.J.
      • Bjornsson E.
      • Lucena M.I.
      • Lee W.M.
      • Yuen N.A.
      • et al.
      Drugs associated with hepatotoxicity and their reporting frequency of liver adverse events in VigiBase: unified list based on international collaborative work.
      ].

      Haemochromatosis

      The non-specific symptoms of this hereditary condition may be attributed to other causes; therefore, diagnosis is often delayed.
      In England and Wales during 1989/1990–2002/2003, the hospital admission rate attributable to haemochromatosis among men rose from 0.64 to 2.36 per 100,000. In women, the rate rose from 0.21 to 0.81 per 100,000. Among men and women the age-standardized, day case admission rate rose from 2.78 to 34.9 and from 0.58 to 11.67 per 100,000, respectively [
      • Cowan M.L.
      • Westlake S.
      • Thomson S.J.
      • Rahman T.M.
      • Majeed A.
      • Maxwell J.D.
      • et al.
      The increasing hospital disease burden of haemochromatosis in England.
      ].
      The causative mutations in the HFE gene can be used to assess prevalence. In Norway, the prevalence of the homozygous C282Y mutation ranged from 0.05–0.22%. [
      • Broderstad A.R.
      • Smith-Sivertsen T.
      • Dahl I.M.
      • Ingebretsen O.C.
      • Lund E.
      Low prevalence of hereditary hemochromatosis in multiethnic populations in Northern Norway.
      ]. In a Romanian population the allelic frequency of the most prevalent mutant alleles was 1.75% (95% CI 0.7–3.7) for C282Y and 13.25% (95% CI 10.4–16.5) for H63D [
      • Voicu P.M.
      • Cojocariu C.
      • Petrescu-Danila E.
      • Covic M.
      • Stanciu C.
      • Rusu M.
      Prevalence of HFE (hemochromatosis) gene mutations C282Y and H63D in a Romanian population.
      ].
      In a south French registry the total prevalence of homozygous individuals was estimated at 1.83 per 10,000 (95% CI 1.63–2.02) in subjects >20 years old and 2.40 per 10,000 (95% CI 2.15–2.65) among subjects of European descent. Among Europeans, the total calculated penetrances were 15.8% for those in stage 2 haemochromatosis or higher, 12.1% for those in stage 3 or 4, and 2.9% for those in stage 4 [
      • Aguilar-Martinez P.
      • Bismuth M.
      • Blanc F.
      • Blanc P.
      • Cunat S.
      • Dereure O.
      • et al.
      The Southern French registry of genetic hemochromatosis: a tool for determining clinical prevalence of the disorder and genotype penetrance.
      ].
      The allelic prevalence of the most frequent HFE gene variants (C282Y allele, H63D and S65C) in ethnic Danish men was 5.6%, 12.8%, and 1.8%, respectively [
      • Pedersen P.
      • Milman N.
      Genetic screening for HFE hemochromatosis in 6,020 Danish men: penetrance of C282Y, H63D, and S65C variants.
      ].

      Autoimmune hepatitis (AIH)

      There is no single specific test for diagnosing AIH. Consequently, diagnosis relies on a combination of indicative features of AIH and on the exclusion of other causes of chronic liver diseases.
      Based on limited epidemiological data, the prevalence of AIH is estimated to range from 50–200 cases per million among the Caucasian population in western Europe and North America [
      • Strassburg C.P.
      • Manns M.P.
      Autoimmun hepat.
      ].
      Three recent population-based studies in Europe have estimated incidence and prevalence of AIH (Table 10). AIH is commonly associated with liver cirrhosis but not with HCC. 32% of 278 German patients with AIH were diagnosed with liver cirrhosis, but none of the cohort developed HCC (average follow-up 4.8 years). This study should be interpreted with caution because of its lack of power, but the incidence of HCC associated with AIH-induced cirrhosis could be significantly lower than that associated with other causes of liver cirrhosis, such as chronic viral hepatitis, alcohol or haemochromatosis [
      • Teufel A.
      • Weinmann A.
      • Centner C.
      • Piendl A.
      • Lohse A.W.
      • Galle P.R.
      • et al.
      Hepatocellular carcinoma in patients with autoimmune hepatitis.
      ].
      Table 10European studies assessing the prevalence and incidence of autoimmune hepatitis.
      • Boberg K.M.
      • Aadland E.
      • Jahnsen J.
      • Raknerud N.
      • Stiris M.
      • Bell H.
      Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population.
      ,
      • Primo J.
      • Maroto N.
      • Martinez M.
      • Anton M.D.
      • Zaragoza A.
      • Giner R.
      • et al.
      Incidence of adult form of autoimmune hepatitis in Valencia (Spain).
      ,
      • Werner M.
      • Prytz H.
      • Ohlsson B.
      • Almer S.
      • Bjornsson E.
      • Bergquist A.
      • et al.
      Epidemiology and the initial presentation of autoimmune hepatitis in Sweden: a nationwide study.

      Primary biliary cirrhosis (PBC)

      Epidemiological PBC data have generally been obtained passively and so might not indicate true rates in the general population. Indeed, the rarity of PBC precludes a population-based approach for the detection of cases. Differences in incidence and prevalence of PBC are probably secondary to variation in diagnostic criteria, case-finding methods, doctors’ awareness, and quality of health-care systems.
      Some researchers suggest that the incidence of PBC is growing. In the UK, incidence rates rose from 5.8 to 20.5 cases per million population per year in Sheffield between 1980 and 1999 [
      • Ray-Chadhuri D.
      • Rigney E.
      • McComack K.
      Epidemiology of PBC in Sheffield updated: demographics and relation to water supply.
      ] and from 11 to 32 cases per million population per year in Newcastle-upon-Tyne between 1976 and 1994 [
      • James O.F.
      • Bhopal R.
      • Howel D.
      • Gray J.
      • Burt A.D.
      • Metcalf J.V.
      Primary biliary cirrhosis once rare, now common in the United Kingdom?.
      ,
      • Myszor M.
      • James O.F.
      The epidemiology of primary biliary cirrhosis in north-east England: an increasingly common disease?.
      ]. This increase was paralleled by a rise in prevalence to more than 200 cases per million in the mid-to-late 1990s. In Finland, the age-standardized prevalence of PBC increased between 1988 and 1999 from 103 (95% CI 97–110) to 180 (95% CI 172–189) per million inhabitants. Over the same period, incidence increased from 12 (95% CI 10–14) to 17 (95% CI 15–20) per million inhabitants per year. The annual average increases in prevalence and incidence were 5.1% (95% CI 4.2–5.9%, p <0.0001) and 3.5% (95% CI 0.9–6.0%, p= 0.008), respectively [
      • Rautiainen H.
      • Salomaa V.
      • Niemela S.
      • Karvonen A.L.
      • Nurmi H.
      • Isoniemi H.
      • et al.
      Prevalence and incidence of primary biliary cirrhosis are increasing in Finland.
      ].
      The progression of PBC in patients is extremely variable and survival may be reduced when compared with an age- and gender-matched population. In a Canadian study of patients whose test results were compatible with PBC the standardized mortality ratio was 2.87 (95% CI 1.38–4.63) [
      • Springer J.
      • Cauch-Dudek K.
      • O’Rourke K.
      • Wanless I.R.
      • Heathcote E.J.
      Asymptomatic primary biliary cirrhosis: a study of its natural history and prognosis.
      ].

      Primary sclerosing cholangitis (PSC)

      PSC is a chronic cholestatic liver disease of unknown aetiology. It is particularly prevalent in the Nordic population. In a Swedish study an incidence of 1.22 (95% CI 1.06–1.40) per 100,000 person-years was observed between 1992 and 2005 [
      • Lindkvist B.
      • Benito de Valle M.
      • Gullberg B.
      • Bjornsson E.
      Incidence and prevalence of primary sclerosing cholangitis in a defined adult population in Sweden.
      ]. A UK study revealed an incidence of 0.91 (95% CI 0.68–1.21) per 100,000 person-years between 1984 and 2003 [
      • Kingham J.G.
      • Kochar N.
      • Gravenor M.B.
      Incidence, clinical patterns, and outcomes of primary sclerosing cholangitis in South Wales, United Kingdom.
      ]. A study based on the General Practice Research Database (GPRD), reported an incidence of 0.41 (95% CI 0.34–0.48) between 1991 and 2001 [
      • Card T.R.
      • Solaymani-Dodaran M.
      • West J.
      Incidence and mortality of primary sclerosing cholangitis in the UK: a population-based cohort study.
      ]. In this study, and compared to the general population, the risk of death or liver transplantation was more than tripled for PSC patients and the risk of all malignancy was more than doubled. Data from this last study must be interpreted with caution because the GPRD is not population-based and the code for PSC was not validated.
      It should also be noted that PSC is one of the principal aetiologies of LT in cases of cholestatic disease.

      Conclusion

      The data reviewed here clearly demonstrate the significant burden of liver disease in Europe. Liver disease associated mortality in this region is at least comparable with other diseases that are considered to be of major public health concern (Table 11). Diseases such as breast cancer are high on the public health agenda with dedicated screening programmes; therefore healthcare providers and governments must mobilise resources to see that liver disease is tackled in a similarly proactive fashion. This review in conjunction with further surveys of the liver disease burden in Europe will hopefully be the impetus for the design and implementation of strategies that will ameliorate this problem and ultimately save lives.
      Table 11Inter-country comparison of the number of deaths associated with selected diseases compared to liver diseases based on death certificates (age-standardized); WHO, 2008.

      Conflict of interest

      The authors do not have a relationship with the manufacturers of the drugs involved either in the past or present and did not receive funding from the manufacturers to carry out their research. The Authors received support from EASL.

      Acknowledgements

      EASL and the contributors would like to thank Ross Piper, PhD for medical writing and editorial assistance and Margaret Walker, EASL Director of EU Public Affairs, for her continued dedication and support to the project.

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