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Burden of liver disease in Europe: Epidemiology and analysis of risk factors to identify prevention policies

  • Laura Pimpin
    Affiliations
    UK Health Forum, London, United Kingdom
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  • Helena Cortez-Pinto
    Affiliations
    Departamento de Gastrenterologia, CHLN, Laboratório de Nutrição, Faculdade de Medicina, Universidade de Lisboa, Portugal
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  • Francesco Negro
    Affiliations
    Divisions of Gastroenterology and Hepatology and Clinical Pathology, University Hospitals of Geneva, Geneva, Switzerland
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  • Emily Corbould
    Affiliations
    UK Health Forum, London, United Kingdom
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  • Jeffrey V. Lazarus
    Affiliations
    Barcelona Institute for Global Health (ISGlobal), Hospital Clinic, University of Barcelona, Barcelona, Spain

    CHIP, Rigshospitalet, University of Copenhagen, Øster Alle 56, 5. sal, DK-2100 Copenhagen, Denmark
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  • Laura Webber
    Affiliations
    UK Health Forum, London, United Kingdom
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  • Nick Sheron
    Correspondence
    Corresponding author. Address: CES Academic Unit University of Southampton Level E, MP(811), South Academic Block, University Hospital Southampton, Tremona Road, Southampton SO16 6YD, United Kingdom. Tel.: +44 02381 205232.
    Affiliations
    University of Southampton, Southampton SO17 1BJ, United Kingdom
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  • and the members of theEASL HEPAHEALTH Steering Committee
    Author Footnotes
    † Collaborators: Members of the EASL HEPAHEALTH Steering Committee: Patrizia Burra, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padua, Italy; Olav Dalgard, Akershus University Hospital, Lørenskog, Norway; Goran Jankovic, Clinic for Gastroenterology and Hepatology, Clinical Centre of Serbia, School of Medicine, University of Belgrade, Serbia; Jerzy Jaroszewicz, Department of Infectious Diseases and Hepatology, Medical University of Silesia, Katowice, Poland; Jeffrey V Lazarus, Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Barcelona, Spain; Ansgar W. Lohse, Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Valery Lunkov, Department of Hepatology, Vasilenko Clinic of Internal Diseases, Department of Internal Medicine, Russia; Marina Mayevskaya, Department of Internal Medicine, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia; Alexander Nersesov, National Research Institute of Cardiology and Internal Diseases, Almaty, Kazakhstan; Marieta Simonova, Department of Gastroenterology, HPB Surgery and Transplantology, Military Medical Academy, Sofia, Bulgaria.
  • Author Footnotes
    † Collaborators: Members of the EASL HEPAHEALTH Steering Committee: Patrizia Burra, Gastroenterology, Department of Surgery, Oncology and Gastroenterology, Padova University Hospital, Padua, Italy; Olav Dalgard, Akershus University Hospital, Lørenskog, Norway; Goran Jankovic, Clinic for Gastroenterology and Hepatology, Clinical Centre of Serbia, School of Medicine, University of Belgrade, Serbia; Jerzy Jaroszewicz, Department of Infectious Diseases and Hepatology, Medical University of Silesia, Katowice, Poland; Jeffrey V Lazarus, Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Barcelona, Spain; Ansgar W. Lohse, Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Valery Lunkov, Department of Hepatology, Vasilenko Clinic of Internal Diseases, Department of Internal Medicine, Russia; Marina Mayevskaya, Department of Internal Medicine, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia; Alexander Nersesov, National Research Institute of Cardiology and Internal Diseases, Almaty, Kazakhstan; Marieta Simonova, Department of Gastroenterology, HPB Surgery and Transplantology, Military Medical Academy, Sofia, Bulgaria.

      Summary

      The burden of liver disease in Europe continues to grow. We aimed to describe the epidemiology of liver diseases and their risk factors in European countries, identifying public health interventions that could impact on these risk factors to reduce the burden of liver disease. As part of the HEPAHEALTH project we extracted information on historical and current prevalence and mortality from national and international literature and databases on liver disease in 35 countries in the World Health Organization European region, as well as historical and recent prevalence data on their main determinants; alcohol consumption, obesity and hepatitis B and C virus infections. We extracted information from peer-reviewed and grey literature to identify public health interventions targeting these risk factors. The epidemiology of liver disease is diverse, with variations in the exact composition of diseases and the trends in risk factors which drive them. Prevalence and mortality data indicate that increasing cirrhosis and liver cancer may be linked to dramatic increases in harmful alcohol consumption in Northern European countries, and viral hepatitis epidemics in Eastern and Southern European countries. Countries with historically low levels of liver disease may experience an increase in non-alcoholic fatty liver disease in the future, given the rise of obesity across most European countries. Liver disease in Europe is a serious issue, with increasing cirrhosis and liver cancer. The public health and hepatology communities are uniquely placed to implement measures aimed at reducing their causes: harmful alcohol consumption, child and adult obesity, and chronic infection with hepatitis viruses, which will in turn reduce the burden of liver disease.

      Graphical abstract

      Keywords

      Introduction

      Europe has the largest burden of liver disease in the world,

      Global burden of disease project, Institute for Health Metrics and Evaluation. Global Health Data Exchange. Available from: http://ghdx.healthdata.org/.

      with the burden expected to grow across many countries. However, the current and historical epidemiology of liver disease varies between countries within Europe. For example, Finland and the UK have observed staggering increases in liver disease mortality over the last 40 years while the inverse is true for countries such as France and Italy, where liver disease mortality began declining in the 1970s and has kept falling, largely because of effective policy and population-level measures.
      Differences in liver disease epidemiology occur in part because of the prevalence of modifiable risk factors, such as harmful alcohol consumption, obesity, and viral hepatitis. Worryingly, Europe has the highest per capita alcohol consumption and alcohol-related loss of disability adjusted life years of any of the global WHO regions.

      European association for the study of the liver. Prospects for liver disease in the EU. Available from: http://www.easl.eu/medias/EASLimg/News/EASL_HEPAMAP_Full_Report.pdf.

      Obesity has increased markedly over the past four decades,
      • Webber L.
      • Divajeva D.
      • Marsh T.
      • McPherson K.
      • Brown M.
      • Galea G.
      • et al.
      The future burden of obesity-related diseases in the 53 WHO European-Region countries and the impact of effective interventions: a modelling study.
      • Ng M.
      • Fleming T.
      • Robinson M.
      • Thomson B.
      • Graetz N.
      • Margono C.
      • et al.
      Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the Global Burden of Disease Study 2013.
      and as a result, non-alcoholic fatty liver disease (NAFLD) is an increasingly prevalent liver disease in Europe.

      European association for the study of the liver. Prospects for liver disease in the EU. Available from: http://www.easl.eu/medias/EASLimg/News/EASL_HEPAMAP_Full_Report.pdf.

      The prevalence of viral hepatitis is less well documented.

      European association for the study of the liver. Prospects for liver disease in the EU. Available from: http://www.easl.eu/medias/EASLimg/News/EASL_HEPAMAP_Full_Report.pdf.

      Prevention of these risk factors and types of liver disease is important in order to stop progression to other forms of liver disease, such as liver cancer. Liver disease principally affects working age people. Therefore, tackling risk factors will not only impact the individual and health system, but also the economy and business sectors.
      Differences in demographics, geography, and historical factors need to be considered when trying to understand the variance in liver disease risk factors, morbidity and mortality, as well as the interventions that best reduce the burden of liver disease. Importantly, liver disease risk factors are amenable to prevention and treatment, so liver disease can be reduced and deaths can be averted. Understanding the magnitude of liver disease prevalence, how and why it has changed over time, and what works to reduce the population’s risk is imperative if countries are to learn from each other and act to reduce the burden.

      Aim

      The European Association for the Study of the Liver (EASL) HEPAHEALTH project, summarised in a report, was commissioned to: i) collect and analyse data in order to best describe the burden of liver disease across 35 European countries (including all 28 European Union [EU] countries); ii) collect data on the largest, modifiable determinants of liver disease (alcohol, obesity and viral hepatitis) and describe their changes over time; and iii) review the evidence on policies or interventions that could reduce the exposure to these risk factors at a population level.

      Methods

      In order to maximise comparability across countries, and to use a standardised definition of liver disease, the majority of data on the epidemiology of liver disease and its risk factors were obtained for 35 countries (see Table 1 from online databases). It was beyond the scope of this study to include all 53 World Health Organization (WHO) European Region countries. The EU-28 countries were chosen plus additional countries where the study team had particular expertise and interest Table 2.
      Table 1List of countries included in the HEPAHEALTH project.
      AustriaBelgiumBulgariaCroatiaCyprus
      Czech RepublicDenmarkEstoniaFinlandFrance
      GermanyGreeceHungaryIcelandIreland
      ItalyKazakhstanLatviaLithuaniaLuxembourg
      MaltaNetherlandsNorwayPolandPortugal
      RomaniaRussiaSerbiaSlovakiaSlovenia
      SpainSwedenSwitzerlandUnited KingdomUzbekistan
      Table 2Summary of main findings of meta-review of systematic reviews on fiscal policies on diet (reproduced with permission).
      Food/beverage taxesNutrient-focused taxesSubsidies
      Effect on consumptionStrongest evidence for SSB taxes – reduce consumption by same percentage as tax rate.Reduce consumption of target but may increase consumption of non-target nutrients; may apply to core foods; better if paired with subsidy.Subsidies increase healthy food intake. Strongest evidence for fruit and vegetable subsidies.
      Effects on body weight/disease outcomesSubstitution will affect total calorie intake. Most effective to target SSBs. Limited evidence for disease outcomes.Disease outcome affected by substitution – nutrient profile taxes less likely to have unintended effects than single nutrient-based taxes.Subsidies may also increase total calorie intake and body weight. Very likely to reduce dietary NCD risk factors.
      Differential effectsMay be most effective for low-income populations; may have greater effect on those who consume most.May be more likely to have regressive effects as more likely to apply to core foods.Mixed socioeconomic status effects for population subsidies, may benefit wealth. Targeted low-income subsidies effective.
      Source: World Health Organization (2016). Fiscal policies for diet and prevention of noncommunicable diseases: technical meeting report, 5–6 May 2015, Geneva, Switzerland. World Health Organization. http://www.who.int/iris/handle/10665/250131.

      Data collection

      When insufficient data were available, additional sources of information were collected from a comprehensive review of the peer-reviewed and grey literature (that is, resources produced outside of the traditional academic publishing, such as reports from non-academic organisations) and identifying experts through the referral of other experts (“snowballing” of contacts) in the field of liver disease.
      The WHO European Detailed Mortality Data

      World Health Organization Regional Office for Europe. European Detailed Mortality Database. 23 August 2016.

      database combined raw mortality rates for 1994 to 2015 into eight broad liver disease categories (including alcoholic liver disease, NAFLD and viral hepatitis). This data was supplemented with data from WHO European Health for All database for broader categories of liver disease (1970 to 2015).

      World Health Organization. European Health for All Database (HFA-DB). 23 August 2017.

      The Global Burden of Disease (GBD) study (2016)

      Global burden of disease project, Institute for Health Metrics and Evaluation. Global Health Data Exchange. Available from: http://ghdx.healthdata.org/.

      provided prevalence estimates of cirrhosis, other chronic liver diseases and liver cancer caused by alcohol, hepatitis B, hepatitis C or other causes for the years 1990 to 2016.
      Data on liver transplantation in Europe was obtained from the European Liver Transplantation Registry (ELTR).

      European Liver and Intestine Transplant Association. European Liver Transplant Registry 2017. Available from: www.eltr.eu.

      Chronic hepatitis B and C prevalence data were obtained from the European Centres for Disease Prevention and Control (ECDC)

      European Centre for Disease Prevention and Control. Viral Hepatitis August 2017. Available from: https://ecdc.europa.eu/en/viral-hepatitis.

      and were complemented by hepatitis B and C modelled prevalence estimates from the Polaris Observatory.
      The Polaris Observatory HCV Collaborators
      Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study.

      The Polaris Observatory Collaborators. The Global Prevalence, Cascade of Care, and Prophylaxes Coverage of Hepatitis B in 2016. Lancet Gastroenterol Hepatol (submitted).

      In addition, published reviews of the latest data were used to triangulate infection prevalence, and data on prevalence of hepatitis B and C in people who inject drugs (PWID) were obtained from the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).

      European Monitoring Centre for Drugs and Drug Addition. Statistical Bulletin 2017. Available from: http://www.emcdda.europa.eu/emcdda-home-page_en.

      Average annual current consumption in litres of pure alcohol for total alcohol, beer, wine and spirits was extracted from the WHO European Health for All databases, for 1970 to 2015. Obesity prevalence data from 1993 to 2015 was obtained from a previous report commissioned by the WHO.
      • Webber L.
      • Divajeva D.
      • Marsh T.
      • McPherson K.
      • Brown M.
      • Galea G.
      • et al.
      The future burden of obesity-related diseases in the 53 WHO European-Region countries and the impact of effective interventions: a modelling study.

      Pineda E, Sanchez-Romero L, Brown M, Jaccard A, Jewell J, Galea G, et al. Feasibility of achieving the 2025 WHO global targets for body mass index: predicting obesity trends in 53 countries in the WHO European Region. Submitted to Obesity Facts, 2017.

      This project collected historical national prevalence data from a variety of national or regional sources. The sources for this can be found in the HEPAHEALTH report.
      Country-level type 2 diabetes prevalence data for 2007 to 2015 in adults was obtained from the International Diabetes Federation Diabetes Atlas project.

      International Diabetes Federation. IDF Diabetes Atlas.

      Information on injecting drug use, as one of the modes of transmission for hepatitis B and C was also collected from the EMCDDA.

      European Monitoring Centre for Drugs and Drug Addition. Statistical Bulletin 2017. Available from: http://www.emcdda.europa.eu/emcdda-home-page_en.

      Analysis

      Data on the prevalence and mortality of liver disease, and on the distribution of the largest modifiable risk factors for liver disease were analysed to present time trends, differences across sub-regions (UN Eastern, Northern, Southern and Western regions) and individual countries within these sub-regions. The historical trends in mortality and prevalence were overlaid with plots of alcohol consumption and obesity prevalence.
      A comprehensive review of PubMed, Embase, and Google Scholar was conducted to identify peer-reviewed and grey literature reviews that provided evidence on public health interventions aimed at reducing or preventing risk factors of liver disease, in particular, alcohol consumption, obesity and diabetes and chronic viral hepatitis. No language restrictions were applied.

      General data

       Present situation

      In modelled data from GBD, alcohol is the predominant aetiology of liver disease in most countries with a high prevalence of viral hepatitis B and C in Central and Eastern Europe.
      Data on prevalence of liver disease was collected using the GBD 2016 project data.

      Global burden of disease project, Institute for Health Metrics and Evaluation. Global Health Data Exchange. Available from: http://ghdx.healthdata.org/.

      The categories of liver disease present in the dataset are cirrhosis and chronic liver disease, the other being liver cancer. Cirrhosis and chronic liver disease are further broken down into four aetiologic categories: alcohol use, hepatitis B infection, hepatitis C infection and other causes. The age-adjusted prevalence for the latest year in the 35 countries for males and females, ranged from 447 (Iceland) to 1,100 (Romania) cases per 100,000, with a median of 833 (Fig. 1) relative contribution of these aetiologies follows a geographical pattern, with alcohol being predominant in Western countries and viral hepatitis B and C more prevalent in Eastern countries. In Central European countries, alcohol and viral hepatitis contribute equally to the burden of disease, with the caveat that GBD data is modelled. Hepatitis C is the most prevalent cause of viral hepatitis in most countries, with the exception of Kazakhstan and Uzbekistan, where hepatitis B is more frequent.
      Figure thumbnail gr1
      Fig. 1Age-standardised prevalence of cirrhosis and other liver diseases by aetiology in 2016 – modelled data.

      Global burden of disease project, Institute for Health Metrics and Evaluation. Global Health Data Exchange. Available from: http://ghdx.healthdata.org/.

      Median prevalence for alcohol use: 312 per 100,000; median prevalence for hepatitis B 130 per 100,000; median prevalence for hepatitis C: 212 per 100,000, median prevalence for other causes 116 per 100,000.
      Interestingly, when it concerns liver cancer, a north-south gradient is found, as illustrated in the wider HEPAHEALTH report, ranging from less than 2 cases per 100,000 to 15 cases per 100,000. Regarding the year 2015, the predominant aetiology of the underlying liver disease was viral hepatitis in the majority of countries, followed by alcohol use (see the wider HEPAHEALTH report).
      Mortality data comes from ICD coding of death certification records collected by WHO, using the primary cause of death. As a result, there is likely to be an underestimation of the true liver disease associated mortality. Notwithstanding, there is a good correlation with the prevalence data, as seen in Fig. 2, again showing Romania with the highest (36 per 100,000), and Iceland and Norway with the lowest death rates (below 10 per 100,000). Mortality rates shown (Fig. 2) represent a total of 151,513 deaths from liver disease, in the last year of available data on deaths for all European countries combined, ranging from 33 deaths in Iceland in 2015 to 23,533 in Germany in 2014.
      Figure thumbnail gr2
      Fig. 2Age-standardised mortality for all liver diseases – in most recent year.

      World Health Organization Regional Office for Europe. European Detailed Mortality Database. 23 August 2016.

      When looking at the consequent years of life lost, a very specific pattern is shown for liver diseases, with a higher rate of working life years lost vs. non-working life years lost, than most frequent chronic diseases such as ischaemic heart disease. This is mostly because two-thirds of liver disease patients die before 65 years of age.

       Trends

      The analysis of trends of cirrhosis and chronic liver disease in different countries may help understand the utility or disadvantages of different political and public health measures. Diverse patterns of evolution in mortality rate were observed in the timeframe of 1970–2015 for the 34 HEPAHEALTH countries (not including Russia), as shown (Fig. 3). Countries of Southern and Western Europe displayed a significant decrease in mortality rate (Austria, Croatia, France, Germany, Greece, Italy, Luxembourg, Portugal, Slovenia, Spain and Switzerland), while conversely, Eastern and Northern countries such as Bulgaria, Estonia, Finland, Hungary, Kazakhstan, Latvia, Lithuania, Romania and the UK, faced a significant increase. Yet, another group of countries remained stable-high (Slovakia and Uzbekistan), while others remained stable-low (Belgium, Cyprus, Czech Republic, Denmark, Iceland, Ireland, Malta, Netherlands, Norway, Poland, Serbia and Sweden).
      A worrying trend is the rising rate of liver cancer mortality in most European countries.
      Figure thumbnail gr3
      Fig. 3Total mortality from cirrhosis (top) and alcohol consumption (bottom) over time, for ages >15 years for countries in different trend groups. (A) Decreasing, (B) increasing, (C) stable-high, (D) stable-low.

      World Health Organization. European Health for All Database (HFA-DB). 23 August 2017.

      A concerning trend in liver cancer mortality rates, is the recognisable increase in the large majority of countries (Austria, Czech Republic, Finland, France, Germany, Greece, Ireland, Italy, Luxembourg, Portugal, Romania and the UK), although some countries have experienced small decreases in liver-related mortality (Bulgaria, Hungary, Kazakhstan, Poland and Spain). Again, other countries remained stable, either high or low (available in the HEPAHEALTH report).
      In the next sections, more detailed information regarding epidemiological data, risk factors and political interventions will be described for each of the major liver disease aetiologies: alcohol-related, non-alcoholic fatty liver and viral hepatitis.

      Alcohol consumption and liver disease

      According to the WHO, alcohol is a dose-related risk factor for more than 200 diseases. It causes 5.9% of all deaths globally and more than 25% of deaths in the age group 20–39 years.

      World Health Organisation. WHO factsheet 2015 [20/12/2017]. Available from: http://www.who.int/mediacentre/factsheets/fs349/en/.

      For most diseases including cancer and hypertension, the dose relationship is linear starting at zero, i.e. there is no safe threshold for alcohol consumption.
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      Importantly, for liver disease the relationship is exponential, with very heavy drinkers or extreme drinkers comprising a large proportion of patients with alcohol-related cirrhosis.
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      In addition to this, alcohol synergises with other risk factors for liver disease such as obesity and viral infections. For a body mass index (BMI) over 35 kg/m2, the hepatotoxicity of alcohol doubles: two bottles of wine per week effectively becomes four bottles as far as the liver is concerned.
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      Similarly, with hepatitis C virus (HCV) infection, alcohol consumption of more than 20 g per day (17.5 cl per week) increases mortality by 2.5-fold.
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      Systematic review: patient-reported outcomes in chronic hepatitis C–the impact of liver disease and new treatment regimens.
      In a Danish series of 5,779 HCV infected individuals, 57% of patients with cirrhosis also had evidence of alcohol misuse.
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      The European region has the highest levels of reported per capita alcohol consumption of any region.
      Organisation for Economic Co-operation and Development
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      Total alcohol consumption is summarised in the WHO European Health for All database (HFA-DB) as annual total litres of pure alcohol consumed per capita in individuals aged over 15 years. Four groups of countries emerged based on time trends for this consumption: Increasing trend, decreasing trend, stable-high trend and stable-low trend (Fig. 3). Although these trends are seen at national levels, alcohol consumption patterns are clustered within countries. For example the share of total alcohol consumed by the top 20% heaviest drinkers ranges from 50% in France and Switzerland, to above 80% in Hungary, based on national survey estimates by the Organisation for Economic Co-operation and Development (OECD).
      Organisation for Economic Co-operation and Development
      Tackling harmful alcohol use: economics and public health policy.
      Demographic patterns in alcohol consumption are changing too: consumption among younger people and women is growing while age of taking up drinking is decreasing. Patterns of drinking, including frequency, average consumption and type of alcohol consumed, have differential effects on mortality and risk of disease.
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      Patterns of drinking and liver cirrhosis–what do we know and where do we go?.

       The relationship between alcohol consumption and liver mortality

      The strong relationship between population-level alcohol consumption and population-level liver mortality, was detailed in a seminal paper by Milton Terris in 1967,
      • Terris M.
      Epidemiology of cirrhosis of the liver: national mortality data.
      who demonstrated that dramatic falls in cirrhosis mortality followed some world events, such as alcohol rationing in both world wars (Fig. 4).
      Figure thumbnail gr4
      Fig. 4Death rates, cirrhosis of the liver and alcohol consumption reproduced with permission from Terris (1967).
      • Terris M.
      Epidemiology of cirrhosis of the liver: national mortality data.
      An important aspect of this analysis that only recently received the attention it deserves
      • Roizen R.M.F.
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      was that the link was between strong alcohol (wine and spirits) and cirrhosis mortality. For example, in the UK the consumption of weak beer in pubs could be excluded from the model (Fig. 4).
      • Roizen R.M.F.
      • Fillmore M.
      • Kerr W.
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      Cirrhosis mortality and per capita consumption of distilled spirits, United States, 1949–1994: trend analysis.
      This makes sense, as by the time most patients with alcohol-related liver disease have graduated to cirrhosis, the majority are drinking strong alcohol.
      • Sheron N.
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      • Matthews L.
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      • Thomas M.
      Impact of minimum price per unit of alcohol on patients with liver disease in the UK.
      These two principles are critical to understanding the relationship between alcohol consumption and cirrhosis mortality today. Substantial falls in overall alcohol consumption in France were associated with equally substantial falls in cirrhosis mortality, with no real differential impact by beverage type (Fig. 5). Similar changes have occurred in Italy and Spain.
      Figure thumbnail gr5
      Fig. 5Alcohol consumption and age-standardised mortality from cirrhosis and chronic liver diseases (blue filled) on the left and alcoholic liver disease mortality (blue dashed) (left) and total consumption of alcohol by type of alcohol ages >15 yr (right) in four countries. (A) France, (B) UK, (C) Czech Republic.

      World Health Organization. European Health for All Database (HFA-DB). 23 August 2017.

      While fourfold increases in mortality from chronic liver disease in the UK have followed relatively modest increases in overall alcohol consumption, the key difference is that consumption has shifted from weak beer consumed in pubs, to stronger alcohol (wine, spirits and strong cider) bought cheaply and drunk at home.
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      In Finland rapid and substantial increases in liver mortality occurred in the early 2000’s when Estonia joined the EU and import controls were relaxed, leading to a flood of cheap alcohol, but with little change in overall recorded alcohol consumption (Fig. 6). The subsequent policy response, including an increase in alcohol tax rates and changes in the availability of alcohol, effectively curtailed the increase, and liver mortality stabilised albeit at a higher level than before.
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      World Health Organization. Alcohol Policy Timeline Database. 2016.

      Figure thumbnail gr6
      Fig. 6Trends in liver mortality in Finland following entry of Estonia into the EU, a dramatic increase in liver mortality was stabilised by a strong policy response.
      The ecological correlation between alcohol consumption trends and mortality from alcoholic liver disease and mortality from any chronic liver disease and cirrhosis also holds for countries with stable patterns of alcohol intake. For example, the Czech Republic has a relatively high alcohol consumption trend which is apparently unchanged over time (Fig. 5).

       Interventions to reduce alcohol consumption and harm from alcohol

      Evidence on the effectiveness on interventions to reduce alcohol consumption is strong and consistent in reviews by a number of major health bodies; taxation and price regulation are the most effective and cost-effective means to reduce alcohol related mortality.
      The evidence on the effectiveness of alcohol policy is strong and consistent in reviews by the WHO,

      Bloom D, Chisholm D, Llopis E, Prettner K, Stein A, Feigl A. From burden to best buys”: reducing the economic impact of non-communicable disease in low-and middle-income countries. 2011.

      OECD,
      Organisation for Economic Co-operation and Development
      Tackling harmful alcohol use: economics and public health policy.
      Public Health England
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      Calling time – the nation’s drinking as a major health issue.

      Eurocare European Alcohol Policy Alliance. Taxation 2017. Available from: www.eurocare.org/resources/policy_issues/taxation.

      Public health approaches include population-level policies such as fiscal policies, policies regulating the marketing of alcohol and policies managing the drink environment and availability of alcohol, as well as individual-level interventions like screening, brief interventions and alcohol treatment.
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       Fiscal policy

      As with tobacco, the most effective and cost effective means to reduce alcohol-related harm is to decrease the affordability of alcohol through fiscal policy.
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      • Yach D.
      The origins, development, effects, and future of the WHO Framework Convention on Tobacco Control: a personal perspective.
      The OECD report on Tackling Harmful Alcohol Use highlights excise duties and value added taxes as the most common combined approach.
      Organisation for Economic Co-operation and Development
      Tackling harmful alcohol use: economics and public health policy.
      The effect of increased alcohol taxation on consumption depends on the degree to which the tax is passed on to consumers and the most recent development in alcohol policy is the concept of setting a minimum price for a unit of alcohol (MUP).
      Organisation for Economic Co-operation and Development
      Tackling harmful alcohol use: economics and public health policy.
      • Sheron N.
      • Hawkey C.
      • Gilmore I.
      Projections of alcohol deaths—a wake-up call.
      • Rowe I.A.
      Lessons from epidemiology: the burden of liver disease.
      This model was implemented in the Canadian province of British Columbia and as a result there have been dramatic reductions in liver disease mortality, despite increasing densities of private liquor stores during the same period.
      • Zhao J.
      • Stockwell T.
      • Martin G.
      • Macdonald S.
      • Vallance K.
      • Treno A.
      • et al.
      The relationship between minimum alcohol prices, outlet densities and alcohol-attributable deaths in British Columbia, 2002–09.
      Legislation enabling the introduction of MUP was passed in Scotland in 2012, despite legal challenges by the Scotch Whiskey Association, as justification of strong public health grounds overruled the commercial considerations. MUP legislation was specifically targeted at the very cheap alcohol preferred by the extreme drinker who develop cirrhosis, and thus is more likely to be effective than tax or duty increases.

      Lord Neuberger LH, Lord Mance, Lord Kerr, Lord Sumption, Lord Reed, Lord Hodge. Scotch Whisky Association and others (Appellants) v The Lord Advocate and another (Respondents) (Scotland). In: Court US, (Ed.) https://www.supremecourt.uk/cases/uksc-2017-0025.html2017.

      Justice ECo. Judgment of the Court (Second Chamber) of 23 December 2015, Scotch Whisky Association and Others v The Lord Advocate and The Advocate General for Scotland. 2015.

      In-depth summaries of studies estimating the effect of alcohol policy scenarios, modelling studies, natural experiments and case-studies, on alcohol consumption, hospital admissions and liver disease mortality are available in the wider HEPAHEALTH report.

       Marketing restriction

      After tobacco, the marketing of which has been regulated, alcohol is the most dangerous and unhealthy commodity currently marketed in Europe.
      • Monteiro M.G.
      • Babor T.F.
      • Jernigan D.
      • Brookes C.
      Alcohol marketing regulation: from research to public policy.
      The landscape for alcohol marketing is changing and uses multiple avenues (radio, television sports events, celebrity endorsements, websites, product placement, social media, and others).
      • Monteiro M.G.
      • Babor T.F.
      • Jernigan D.
      • Brookes C.
      Alcohol marketing regulation: from research to public policy.
      The marketing of alcoholic beverages is one of the 10 areas for policy action in the WHO Global strategy to reduce the harmful use of alcohol.
      The evidence was reviewed recently by Babor and colleagues
      • Monteiro M.G.
      • Babor T.F.
      • Jernigan D.
      • Brookes C.
      Alcohol marketing regulation: from research to public policy.
      who found positive associations between exposure to marketing and some measure of subsequent drinking behaviour and/or negative consequences of drinking.
      • Jernigan D.
      • Noel J.
      • Landon J.
      • Thornton N.
      • Lobstein T.
      Alcohol marketing and youth alcohol consumption: a systematic review of longitudinal studies published since 2008.
      For digital marketing there was a need ‘for policies to control and restrict alcohol promotion, and especially to protect underage youth from commercial incentives to engage in drinking behaviour’.
      • Lobstein T.
      • Landon J.
      • Thornton N.
      • Jernigan D.
      The commercial use of digital media to market alcohol products: a narrative review.
      This suggests that current systems of self-regulation would need major modifications if they are to serve public health objectives.
      • Noel J.K.
      • Babor T.F.
      Does industry self-regulation protect young people from exposure to alcohol marketing? A review of compliance and complaint studies.
      • Noel J.K.
      • Babor T.F.
      • Robaina K.
      Industry self-regulation of alcohol marketing: a systematic review of content and exposure research.
      They concluded that regulations should be statutory, enforced not by the alcohol industry, but by a public health agency and that global agreement on the marketing of alcoholic beverages would support national efforts to move towards a comprehensive ban on alcohol advertising, promotion and sponsorship.

       Screening and behavioural interventions

      A recent narrative review of 24 systematic reviews was conducted on the effect of brief alcohol intervention effects. The authors reported that brief interventions were consistently reported to be effective for addressing hazardous and harmful drinking in primary healthcare, and particularly in middle-aged, male drinkers.
      • O’donnell A.
      • Anderson P.
      • Newbury-Birch D.
      • Schulte B.
      • Schmidt C.
      • Reimer J.
      • et al.
      The impact of brief alcohol interventions in primary healthcare: a systematic review of reviews.
      A recent review of 20 trials in public healthcare settings and eight in emergency departments confirmed that brief interventions to reduce alcohol consumption are associated with reducing weekly alcohol consumption among hazardous and harmful drinkers at 6 and 12 month follow-up.
      • Elzerbi C.
      • Donoghue K.
      • Drummond C.
      A comparison of the efficacy of brief interventions to reduce hazardous and harmful alcohol consumption between European and non-European countries: a systematic review and meta-analysis of randomized controlled trials.
      In primary health care, brief interventions resulted in 31 g/week reduction in alcohol intake after 12 months, and 18 g/week for interventions in emergency departments.
      The Lancet Liver Commission identified late diagnosis of liver disease as perhaps the most important clinical issue, and estimated that around 75% of patients with fatal cirrhosis were unaware of their disease until presenting as an emergency with acute-on-chronic liver failure or variceal bleeding. A liver disease admission can have a profound impact on alcohol misuse, with around 40% of individuals becoming abstinent as a result
      • Altamirano J.
      • Lopez-Pelayo H.
      • Michelena J.
      • Jones P.D.
      • Ortega L.
      • Gines P.
      • et al.
      Alcohol abstinence in patients surviving an episode of alcoholic hepatitis: prediction and impact on long-term survival.
      • Verrill C.
      • Markham H.
      • Templeton A.
      • Carr N.J.
      • Sheron N.
      Alcohol-related cirrhosis–early abstinence is a key factor in prognosis, even in the most severe cases.
      and some evidence that earlier primary care based liver diagnosis may also promote behaviour change.
      • Sheron N.
      • Moore M.
      • O'Brien W.
      • Harris S.
      • Roderick P.
      Feasibility of detection and intervention for alcohol-related liver disease in the community: the Alcohol and Liver Disease Detection study (ALDDeS).
      As a result screening for liver disease in harmful and dependent drinkers has been recommended by the UK based National Institute for Health and Care Excellence,

      Nice. Assessment and management of cirrhosis 2016.

      further research will be needed to judge whether this approach can reduce liver mortality and morbidity.

      Obesity, diabetes and NAFLD

       The current and historical burden

      The main risk factors that have been associated with NAFLD are obesity (predominantly central adiposity) as well as type 2 diabetes. The time trend in NAFLD/non-alcoholic steatohepatitis (NASH) mortality from WHO detailed data are presented (Fig. 7).

      World Health Organization Regional Office for Europe. European Detailed Mortality Database. 23 August 2016.

      NAFLD/NASH represents only a very small proportion of liver-related-deaths in Europe, when analysing it as the primary cause of death, although it is unlikely that these codes represent the current understanding on NAFLD or NASH.
      Figure thumbnail gr7
      Fig. 7Time trends in age-standardised mortality from NAFLD/NASH – both genders by region. (A) Northern, (B) Eastern, (C) Southern, (D) Western Europe.

      World Health Organization Regional Office for Europe. European Detailed Mortality Database. 23 August 2016.

      In fact, the attributed codes do not enable recognition of NASH-related cirrhosis. Also, in the presence of other concomitant diagnosis such as alcohol or viral hepatitis these are recorded as the first cause of disease. Furthermore, the major cause of death in patients with NAFLD/NASH is cardiovascular.
      • Ekstedt M.
      • Hagstrom H.
      • Nasr P.
      • Fredrikson M.
      • Stal P.
      • Kechagias S.
      • et al.
      Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up.
      NAFLD coded as the cause of death is only starting to appear in Ireland, Luxembourg, Hungary and the UK, countries where obesity is high (>23%).
      It is difficult to ascertain the true prevalence of NAFLD, which is often diagnosed at a pre-cirrhotic stage, since the GBD

      Global burden of disease project, Institute for Health Metrics and Evaluation. Global Health Data Exchange. Available from: http://ghdx.healthdata.org/.

      database does not discriminate it. However, one meta-analysis, combining data from 2000 to 2015, pointed out an estimated prevalence of NAFLD in Europe of 23.71% (95% CI 16.12 to 33.45%).
      • Younossi Z.M.
      • Koenig A.B.
      • Abdelatif D.
      • Fazel Y.
      • Henry L.
      • Wymer M.
      Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes.
      Again, NAFLD/NASH-related cirrhosis is not discriminated in data from the ELTR.

      European Liver and Intestine Transplant Association. European Liver Transplant Registry 2017. Available from: www.eltr.eu.

      Since many cases of “cryptogenic cirrhosis” and “other cirrhosis” may be burned-out NASH, this would represent a percentage of up to 11.9% (8,427/71,007) of liver transplantations for cirrhosis from 1988 to 2016.
      Given the drawbacks in obtaining reliable data on NAFLD/NASH prevalence, data may be mostly inferred from the prevalence of obesity and diabetes. There is evidence that for every 1 unit increase in BMI, the odds of NAFLD increase by 13% to 38% and per 1 cm increase in waist circumference, they increase by 3% to 10%.
      • Pang Q.
      • Zhang J.-Y.
      • Song S.-D.
      • Qu K.
      • Xu X.-S.
      • Liu S.-S.
      • et al.
      Central obesity and nonalcoholic fatty liver disease risk after adjusting for body mass index.
      It is also of note that excess body-weight is a significant co-factor for the progression of liver disease from all aetiologies.
      • Berzigotti A.
      • Garcia-Tsao G.
      • Bosch J.
      • Grace N.D.
      • Burroughs A.K.
      • Morillas R.
      • et al.
      Obesity is an independent risk factor for clinical decompensation in patients with cirrhosis.

       Trends in obesity and type 2 diabetes in Europe

      An upwards shift in population BMI has been observed in males and females across all regions in Europe. The majority of the data collected came from self-reported sources (only four countries had measured data), which are likely to be under-reported and therefore underestimate obesity prevalence.
      • Visscher T.L.
      • Viet A.
      • Kroesbergen H.
      • Seidell J.C.
      Underreporting of BMI in adults and its effect on obesity prevalence estimations in the period 1998 to 2001.
      • Gosse M.
      How accurate is self-reported BMI?.
      Nevertheless, the increase in obesity for countries in all regions is matched by the increase in NAFLD mortality, with a slight delay in peaks of obesity and peaks of NAFLD.
      Regarding prevalence of obesity (BMI >30 kg/m2), a large variation among countries is observed, ranging from below 10% of the total adult population in Norway, Italy and Switzerland, to above 25% in Uzbekistan and the UK (Fig. 8).
      Figure thumbnail gr8
      Fig. 8Prevalence of obesity (BMI >30 kg/m2) in females and males in the most recent year available. Estimates come from measured BMI, all other data points used self-reported. Note: Uzbekistan estimates come from surveys in separate years and so are presented separately.
      Time trends from 2007 in the prevalence of adult type 2 diabetes in countries, by region, are shown (Fig. 9). Northern European countries showed a trend towards increasing prevalence of type 2 diabetes in adults, with some country exceptions. Similarly, for Eastern Europe, prevalence decreased between 2011 and 2013 in all countries apart from Slovenia and the Czech Republic, but all countries have experienced a recent increase between 2013 and 2015. In Southern Europe, prevalence was increasing for the majority of countries. Diabetes prevalence levels have generally remained stable in Western European countries, except for Germany where a sharp decrease followed by an increase was seen.
      Figure thumbnail gr9
      Fig. 9Age-standardised national prevalence of type 2 diabetes in adults (both genders) aged 20–79 years over time by region. (A) Northern, (B) Eastern, (C) Southern, (D) Western Europe. Estimation methodology was revised in 2011.

      International Diabetes Federation. IDF Diabetes Atlas.

      There are also large differences in the prevalence of type 2 diabetes across Europe. In 2015, <4% of the total population in European countries had type 2 diabetes, while in countries such as Serbia more than 10% of individuals were diagnosed with the condition (Fig. 10).
      Figure thumbnail gr10
      Fig. 10Map of the age-adjusted prevalence of type 2 diabetes in adults, both genders (2015).

      International Diabetes Federation. IDF Diabetes Atlas.

       Policies and interventions aimed at reducing obesity and diabetes

       Interventions to reduce obesity

      Obesity is a major risk factor for NAFLD and liver cancer, so interventions that prevent or reduce obesity will have an important impact on the subsequent incidence of liver disease.
      Given that obesity is a major risk factor for NAFLD and liver cancer, interventions that prevent or reduce obesity will have important impacts on subsequent incidence of obesity-related liver diseases. Obesity is a complex problem requiring multi-level and multi-sectorial action.
      • Huang T.T.
      • Drewnowski A.
      • Kumanyika S.K.
      • Glass T.A.
      A systems-oriented multilevel framework for addressing obesity in the 21st century.

      Government Office for Science. Tackling obesities: future choices – obesity system atlas. 2007.

      We summarised work by the WHO,

      World Health Organization. Population-based approaches to childhood obesity prevention. 2012.

      Harvard university,

      Harvard T.H. Chan School of Public Health. Childhood obesity intervention cost effectiveness study (CHOICES). Available from: www.choicesproject.org/.

      the Heart Foundation Australia

      National Heart Foundation of Australia Effectiveness of food reformulation as a strategy to improve population health. Rapid Review of the Evidence. 2012.

      and the UK National Institute for Health and Care Excellence (NICE).

      National Institute for Health and Care Excellence. NICE guidance diet, nutrition and obesity. Available from: www.nice.org.uk/guidance/lifestyle-and-wellbeing/diet-nutrition-and-obesity.

      These reviews assess the effectiveness and cost-effectiveness of a range of interventions to reduce childhood and/or adult obesity as well as other systematic reviews found in the academic literature.

       Policy/population-level approaches

       Marketing of unhealthy foods and non-alcoholic beverages to children

      Marketing of food predominantly promotes the purchase of high fat, salt, and sugary foods,
      • Cairns G.
      • Angus K.
      • Hastings G.
      • Caraher M.
      Systematic reviews of the evidence on the nature, extent and effects of food marketing to children. A retrospective summary.
      given their long shelf life and cheap production.
      • Stuckler D.
      • McKee M.
      • Ebrahim S.
      • Basu S.
      Manufacturing epidemics: the role of global producers in increased consumption of unhealthy commodities including processed foods, alcohol, and tobacco.
      In their review, the WHO concluded that the impact of limiting food and beverage advertising on television may be one of the most cost-effective public health approaches to reduce the prevalence of childhood obesity
      Council on Communications and Media
      Policy statement – children, adolescents, and the media.
      • Haby M.
      • Vos T.
      • Carter R.
      • Moodie M.
      • Markwick A.
      • Magnus A.
      • et al.
      A new approach to assessing the health benefit from obesity interventions in children and adolescents: the assessing cost-effectiveness in obesity project.
      and related NCDs.

      World Health Organization. Scaling up action against NCDs: How much will it cost? Geneva; 2011.

      The WHO framework for implementing the set of recommendations on the marketing of foods and non-alcoholic beverages to children provides guidance on how to implement these recommendations.

      World Health Organization. A framework for implementing the set of recommendations on the marketing of foods and non-alcoholic beverages to children. 2012.

       Nutritional labelling – provision of nutritional information, in a standardised format, on foods sold

      Evidence suggests that nutritional labelling enables consumers to make healthier food choices.

      World Health Organization. Global status report on noncommunicable diseases 2010. Geneva; 2011.

      Nutritional labelling that guides a consumer’s understanding, in particular ‘traffic light labelling’ was cited by the WHO as a promising measure to tackle obesity. This labelling system uses colours (green, amber and red) to indicate the relative levels (low, medium or high) of fat, saturated fat, sugar and salt in the product. The labelling of calories on menus in fast food restaurants has also been identified as a promising obesity prevention measure.
      • Sacks G.
      • Swinburn B.
      • Lawrence M.
      Obesity Policy Action framework and analysis grids for a comprehensive policy approach to reducing obesity.

       Food taxes and subsidies

      There is strong evidence that price influences consumer patterns. Experimental studies have indicated that increasing price reduces purchase and subsequent energy intake.
      • Epstein L.H.
      • Dearing K.K.
      • Roba L.G.
      • Finkelstein E.
      The influence of taxes and subsidies on energy purchased in an experimental purchasing study.
      • Epstein L.H.
      • Handley E.A.
      • Dearing K.K.
      • Cho D.D.
      • Roemmich J.N.
      • Paluch R.A.
      • et al.
      Purchases of food in youth: influence of price and income.
      The WHO carried out a meta-review of 11 recent systematic reviews on the effectiveness of fiscal policies to reduce weight, improve diet and prevent NCDs.

      World Health Organization. Fiscal policies for diet and prevention of noncommunicable diseases: technical meeting report, 5–6 May 2015, Geneva, Switzerland. 2016.

      They concluded that the strongest evidence was for sugar-sweetened beverage (SSB) taxes, reducing consumption in the range of 20–50%. Fruit and vegetable subsidies increase consumption in the range of 10–30%, though evidence is mixed for their impact on BMI, net calorie intake and disease outcomes.
      The UK Health Forum, in collaboration with Cancer Research UK modelled a 20% tax on SSB in the UK, estimated to prevent 3.7 million cases of obesity and 25,498 cases of BMI-related disease over the next 10 years (2015–2025), and avoid £10 million in National Health Service costs in 2025 alone.

      Cancer Research UK, UK Health Forum. Short and sweet: why the government should introduce a sugary drinks tax. 2016.

       Food reformulation

      Food reformulation is the reduction of salt and calories from sugar and saturated fat in processed foods or the increase of beneficial nutrients such as fibre, fruit, vegetables, and whole grains. These adjustments may be effective in reducing calories consumed and potentially reducing (or halting) rising obesity. However, a slow decrease (or increase) in nutrients is required to successfully shift population tastes.
      • Webster J.
      Reformulating food products for health: context and key issues for moving forward in Europe.
      Several studies explored the effectiveness of food reformulation as a strategy to improve population health and found that besides providing health benefits, such reformulation programmes have been shown to be cost-effective.
      • Selmer R.M.
      • Kristiansen I.S.
      • Haglerød A.
      • Graff-Iversen S.
      • Larsen H.K.
      • Meyer H.E.
      • et al.
      Cost and health consequences of reducing the population intake of salt.
      • Joffres M.R.
      • Campbell N.R.
      • Manns B.
      • Tu K.
      Estimate of the benefits of a population-based reduction in dietary sodium additives on hypertension and its related health care costs in Canada.
      • Cobiac L.J.
      • Vos T.
      • Veerman J.L.
      Cost-effectiveness of interventions to reduce dietary salt intake.

       School-based interventions

      Interventions in schools were found to have mixed results, according to Amini et al.
      • Amini M.
      • Djazayery A.
      • Majdzadeh R.
      • Taghdisi M.-H.
      • Jazayeri S.
      Effect of school-based interventions to control childhood obesity: a review of reviews.
      in their review of eight reviews on the impact of school-based interventions to control or reduce obesity. While multi-component interventions in a school setting were found to be the most promising approach for preventing obesity (i.e. consisting of diet, activity, education/cognitive components), programmes that concentrate on single components (e.g. diet or physical activity) were sometimes effective in reducing adiposity measures.

       Individual and family-based interventions

      Both WHO and NICE recommend the use of multi-component lifestyle interventions, which typically include components such as diet, physical activity, and educational/cognitive.

      National Institute for Health and Care Excellence. Weight management: lifestyle services for overweight or obese adults – Public Health Guideline 2014. Available from: www.nice.org.uk/guidance/ph53.

      World Health Organization. Interventions on diet and physical activity: what works: summary report. Geneva; 2009.

      One meta-analysis examined the clinical effectiveness of different types of interventions: diet or exercise alone vs. combined behavioural weight management programmes (BWMP).
      • Johns D.J.
      • Hartmann-Boyce J.
      • Jebb S.A.
      • Aveyard P.
      Diet or exercise interventions vs. combined behavioral weight management programs: a systematic review and meta-analysis of direct comparisons.
      They found only a significantly greater weight-loss in the combined BWMPs (−1.72 kg, 95% CI −2.80 to −0.64) at 12 months. In relation to childhood obesity, NICE found strong evidence from eight randomised controlled trials that child/adolescent and parent weight management interventions result in significant decreases in BMI, and are more favourable than child-only programmes.

      National Institute for Health and Care Excellence. Weight management: lifestyle services for overweight or obese children and young people. Public health guideline [PH47]. 2013. Available from: https://www.nice.org.uk/guidance/ph47/chapter/9-The-evidence.

       Interventions to reduce type 2 diabetes and liver cancer

      Type 2 diabetes accounts for 90–95% of all diabetes cases,

      American Diabetes Association. Type 2. Available from: www.diabetes.org.

      and the majority of patients with type 2 diabetes are obese and/or have high abdominal body fat. According to the International Diabetes Federation, 80% of type 2 diabetes cases are preventable with a healthy diet and physical activity.
      • Tuomilehto J.
      • Lindström J.
      • Eriksson J.G.
      • Valle T.T.
      • Hämäläinen H.
      • Ilanne-Parikka P.
      • et al.
      Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance.
      The diabetes prevention programme (DPP)
      • Vickerman P.
      • Martin N.
      • Turner K.
      • Hickman M.
      Can needle and syringe programmes and opiate substitution therapy achieve substantial reductions in hepatitis C virus prevalence? Model projections for different epidemic settings.
      has been well evaluated and implemented in a number of countries. The initial randomised controlled trial
      Diabetes Prevention Program Research Group
      Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin.
      found that receiving a lifestyle intervention was more effective than metformin or placebo in decreasing the risk of developing type 2 diabetes (58% vs. 31% vs. 11).
      The role of metformin in diabetes has been investigated in relation to its impact on liver cancer mortality yielding mixed results, with some studies suggesting that metformin reduced the risk of liver cancer in type 2 diabetic patients
      • Hassan M.M.
      • Curley S.A.
      • Li D.
      • Kaseb A.
      • Davila M.
      • Abdalla E.K.
      • et al.
      Association of diabetes duration and diabetes treatment with the risk of hepatocellular carcinoma.
      • Donadon V.
      • Balbi M.
      • Ghersetti M.
      • Grazioli S.
      • Perciaccante A.
      • Della Valentina G.
      • et al.
      Antidiabetic therapy and increased risk of hepatocellular carcinoma in chronic liver disease.
      • Donadon V.
      • Balbi M.
      • Mas M.D.
      • Casarin P.
      • Zanette G.
      Metformin and reduced risk of hepatocellular carcinoma in diabetic patients with chronic liver disease.
      • Lee M.-S.
      • Hsu C.-C.
      • Wahlqvist M.L.
      • Tsai H.-N.
      • Chang Y.-H.
      • Huang Y.-C.
      Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals.
      while others
      • Ferrara A.
      • Lewis J.D.
      • Quesenberry C.P.
      • Peng T.
      • Strom B.L.
      • Van Den Eeden S.K.
      • et al.
      Cohort study of pioglitazone and cancer incidence in patients with diabetes.
      • Gandini S.
      • Puntoni M.
      • Heckman-Stoddard B.M.
      • Dunn B.K.
      • Ford L.
      • DeCensi A.
      • et al.
      Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders.
      • Stevens R.
      • Ali R.
      • Bankhead C.
      • Bethel M.
      • Cairns B.
      • Camisasca R.
      • et al.
      Cancer outcomes and all-cause mortality in adults allocated to metformin: systematic review and collaborative meta-analysis of randomised clinical trials.
      • Tsilidis K.K.
      • Capothanassi D.
      • Allen N.E.
      • Rizos E.C.
      • Lopez D.S.
      • van Veldhoven K.
      • et al.
      Metformin does not affect cancer risk: a cohort study in the UK Clinical Practice Research Datalink analyzed like an intention-to-treat trial.
      found no significant impact of metformin on the risk of liver cancer, as recently reviewed by Fujita et al. (2016).
      • Fujita K.
      • Iwama H.
      • Miyoshi H.
      • Tani J.
      • Oura K.
      • Tadokoro T.
      • et al.
      Diabetes mellitus and metformin in hepatocellular carcinoma.
      A recent meta-analysis, found diabetic metformin users have a 76% lower risk of hepatocellular carcinoma (HCC) than non-users.
      • Zhang H.
      • Gao C.
      • Fang L.
      • Zhao H.-C.
      • Yao S.-K.
      Metformin and reduced risk of hepatocellular carcinoma in diabetic patients: a meta-analysis.

       Interventions to reduce NAFLD

      Since obesity is a key risk factor for NAFLD, the aforementioned interventions, if successful, might be assumed to have an impact on the subsequent reduction in NAFLD. However, on a population basis, the impact of successful obesity interventions on reducing NAFLD prevalence will be a slow process. A study from Vreman et al.
      • Vreman R.A.
      • Goodell A.J.
      • Rodriguez L.A.
      • Porco T.C.
      • Lustig R.H.
      • Kahn J.G.
      Health and economic benefits of reducing sugar intake in the USA, including effects via non-alcoholic fatty liver disease: a microsimulation model.
      using a microsimulation model with Markov chains for NAFLD (including steatosis, NASH, cirrhosis and HCC) estimated that a 20% reduction in added sugar consumption is projected to annually avert 0.767 million (M) disability-adjusted life years (95% CI 0.757 M to 0.777 M) and a total of US$ 10.3 billion (B) (95% CI 10.2 B to 10.4 B).

      Viral hepatitis-related liver disease

      Overall estimates indicate that approximately 15 million people living in the EU are infected with HBV.

       Current prevalence of hepatitis B virus and historic trends

      Estimates of population hepatitis B virus (HBV) prevalence are limited by the lack of high-quality, representative nationwide prevalence estimates, especially in younger age groups.
      Two of the most comprehensive studies into national-level prevalence estimates of chronic HBV infection in the general European population provided inconsistent results.

      European Centre for Disease Prevention and Control. Systematic review on hepatitis B and C prevalence in the EU/EEA. Stockholm; 2016.

      • Schweitzer A.
      • Horn J.
      • Mikolajczyk R.T.
      • Krause G.
      • Ott J.J.
      Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013.
      However, both showed regional variation with higher rates in Eastern and Southern European countries compared to Northern and Western European countries.

      European Centre for Disease Prevention and Control. Systematic review on hepatitis B and C prevalence in the EU/EEA. Stockholm; 2016.

      • Schweitzer A.
      • Horn J.
      • Mikolajczyk R.T.
      • Krause G.
      • Ott J.J.
      Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013.

      World Health Organization. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2017 2017. Available from: http://www.who.int/immunization/diseases/hepatitisB/HBsAg_estimates_and_methods_final_V3.pdf?ua=1.

      These prevalence estimates in both reviews are likely to be an underestimation (in part due to inclusion of estimates among blood donors as a proxy for the general population in the absence of other evidence). These two datasets were compared to the modelled estimates of hepatitis B surface antigen (HBsAg) prevalence from the Polaris Observatory

      The Polaris Observatory Collaborators. The Global Prevalence, Cascade of Care, and Prophylaxes Coverage of Hepatitis B in 2016. Lancet Gastroenterol Hepatol (submitted).

      Polaris Observatory Collaborators
      Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study.
      and showed that HBsAg prevalence was fairly stable or slightly decreasing in Northern Europe between 2007 and 2017, with prevalence below 1.5%. Southern and Western Europe showed decreasing trends (<2% and 1% HBsAg prevalence, respectively), while Eastern Europe had stable or decreasing trends with less than 5% HBsAg prevalence (Uzbekistan had <10% prevalence in 2007 and <8% prevalence in 2017). Overall, estimates indicate that approximately 15 million people are living with HBV in the EU.
      A time-trend analysis of the WHO seroprevalence showed HBV prevalence decreasing globally, but trends varied between countries in Europe:
      • Ott J.J.
      • Horn J.
      • Krause G.
      • Mikolajczyk R.T.
      Time trends of chronic HBV infection over prior decades–a global analysis.
      HBsAg prevalence increased over time in Poland and Russia, potentially as a consequence of strong political and social changes since 1963, resulting in increased access to injectable drugs. Historically low endemicity countries, such as France, Germany and Spain, showed little reduction over time, while other countries have seen large annual reductions (>5% annual change), for instance the UK, Greece and Slovenia where trends mirror those of high income Eastern Mediterranean states. A fourth group of countries are those with medium to low endemicity, with a relative decrease of around 5% per year.
      Variation in HBV prevalence between countries can be partly explained by vaccination policies, although the majority of data shown is in adults, so it is not clear if there has been a shift in mean age at infection after the implementation of hepatitis B vaccination in some countries in the late 1990s. Other factors that could explain the changes include improvements in infection control (blood donation screening, medical settings prevention, health worker vaccination, awareness and health promotion around disease and transmission) and changes in hepatitis B case reporting. More focussed assessment of the prevalence of hepatitis B exists for specific risk groups, in particular PWID, may reveal differences in hepatitis B prevalence across European countries.

       Current prevalence of HCV and historic trends

      Estimates of HCV prevalence from representative anti-HCV surveys

      European Centre for Disease Prevention and Control. Systematic review on hepatitis B and C prevalence in the EU/EEA. Stockholm; 2016.

      were available for the general population for 13 countries in a recent ECDC review, ranging from 0.1% (Belgium, Ireland and the Netherlands) to 5.9% (Italy). A recent global estimation of HCV prevalence of 1.8% in Europe, suggests over 13 million estimated cases.
      • Petruzziello A.
      • Marigliano S.
      • Loquercio G.
      • Cozzolino A.
      • Cacciapuoti C.
      Global epidemiology of hepatitis C virus infection: an up-date of the distribution and circulation of hepatitis C virus genotypes.
      Overall, the Polaris estimates seem lower than previously published data. For the EU, approximately 3.2 million people have viraemic HCV infections.
      The European Union HCV Collaborators
      Hepatitis C virus prevalence and level of intervention required to achieve the WHO targets for elimination in the European Union by 2030: a modelling study.
      However, non-EU countries considered in the present report contribute an additional 6.0 million patients with viraemic hepatitis C.
      The Polaris Observatory HCV Collaborators
      Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study.

       Interpretation of hepatitis B and C data

      Interpretation of both hepatitis B and C data is difficult, as trends are likely a reflection of both testing and screening practices. The mix of acute and chronic cases, the lack of availability of good quality, timely and nationally-representative, general-population level data are limitations to the use of hepatitis B and C incidence and prevalence data. The lack of gender and age-stratified data makes it difficult to evaluate the impact of hepatitis B vaccination policies and practices. Surveillance systems are heterogeneous, coverage varies, and several case definitions are used for both hepatitis B and C. More robust prevalence estimates are needed for the general population in countries and in specific risk groups.

       HBV and HCV-related liver disease burden

      The 2017 WHO Global hepatitis report

      World Health Organization. Global Hepatitis Report 2017. Geneva; 2017.

      states that HBV and HCV infections account for 96% of the global mortality from hepatitis-related end-stage liver disease.
      Although the majority of prevalent cases of cirrhosis and other chronic liver diseases are accounted for by alcohol use and HBV and HCV infections in the GBD,

      Global burden of disease project, Institute for Health Metrics and Evaluation. Global Health Data Exchange. Available from: http://ghdx.healthdata.org/.

      countries vary in the relative contributions of these aetiologies. Thus, in many Western countries (such as Ireland, Germany and Portugal), where alcohol is the most important risk factor, viral hepatitis B and C combined contribute to a lesser extent, while a smaller proportion of cirrhosis and liver disease cases are due to other undefined causes. In Central European countries however, viral hepatitis and alcohol contribute approximately equally to the burden of liver disease. Viral hepatitis is the main determinant of disease for all ages and genders when considering countries further east. In Eastern Europe, HCV generally accounts for a greater proportion of liver disease cases than HBV, however in Kazakhstan and Uzbekistan hepatitis B accounts for more cases than hepatitis C (see HEPAHEALTH report).
      The GBD

      Global burden of disease project, Institute for Health Metrics and Evaluation. Global Health Data Exchange. Available from: http://ghdx.healthdata.org/.

      shows a north-south gradient in the modelled data of HCC – with the highest rates being reported for Italy (see main HEPAHEALTH report). Viral hepatitis was the predominant aetiology, followed by alcohol use, with the exception of Sweden, where non-viral, non-alcohol-related aetiologies accounted for the majority of HCC cases. HCC cases associated with HBV infection were more prevalent in Eastern European countries, whereas HCV was more frequent in Western European and Mediterranean countries.
      Viral hepatitis mortality seems to play a minor role in overall liver-related mortality. Alcohol is the most important determining factor in most countries, with the exception of Italy, where viral hepatitis predominates. However, a significant proportion of deaths due to unknown factors or HCC, raise the question about the completeness of death certificates. A recent linkage study from Switzerland estimated under-reporting of HCV infection in up to 45% of death certificates among deaths from HCV-related complications,
      • Keiser O.
      • Giudici F.
      • Mullhaupt B.
      • Junker C.
      • Dufour J.F.
      • Moradpour D.
      • et al.
      Trends in hepatitis C-related mortality in Switzerland.
      while a US study reported even higher rates of under-reporting.
      • Mahajan R.
      • Xing J.
      • Liu S.J.
      • Ly K.N.
      • Moorman A.C.
      • Rupp L.
      • et al.
      Mortality among persons in care with hepatitis C virus infection: the Chronic Hepatitis Cohort Study (CHeCS), 2006–2010.
      Viral hepatitis leads to HCC, and this might instead be the cause of death recorded, among other complications such as sepsis, encephalopathy or digestive bleeding.

       Historic trends of HBV- and HCV-related morbidity and mortality

      While the increase in prevalence of end-stage liver disease in Northern and Eastern Europe seems significantly driven by increased alcohol use, time trends observed in Western and Southern European countries underline a major role of HBV and HCV infections. HBV and HCV, together with alcohol, account for a major proportion of liver cancers in Northern and Western European countries. The modest increase observed in Russia is driven mostly by alcohol use (the other aetiologies remaining almost unmodified over time), while the HCC increases in Southern Europe were largely due to increases in liver disease caused by hepatitis B and especially hepatitis C.
      As a significant cause of mortality, viral hepatitis remains a high priority throughout Europe.
      Regarding mortality, viral hepatitis remains a high priority throughout Europe. Increases were observed in most Northern European countries, Hungary, Italy, Croatia, and Portugal (see main HEPAHEALTH report), whereas in the remaining countries (such as France and Germany), rates have remained stable or even decreased slightly over time. This is possibly related to the high antiviral treatment uptake reported for those countries.
      • Wedemeyer H.
      • Duberg A.S.
      • Buti M.
      • Rosenberg W.M.
      • Frankova S.
      • Esmat G.
      • et al.
      Strategies to manage hepatitis C virus (HCV) disease burden.

       Interventions for the prevention and treatment of chronic viral hepatitis B and C

      The global burden of viral hepatitis has been highlighted by the WHO with activities such as the publication of the first guidelines for the prevention, care and treatment of persons living with chronic hepatitis B infection

      World Health Organization. Guidelines for the Prevention Care and Treatment of Persons with Chronic Hepatitis B Infection: World Health Organization; 2015.

      and guidelines on the screening, care and treatment of persons infected with hepatitis C

      World Health Organization. Fiscal policies for diet and prevention of noncommunicable diseases: technical meeting report, 5–6 May 2015, Geneva, Switzerland. 2016.

      (to be updated in 2018), as well as the World Health Assembly (WHA)’s endorsement of the Global Health Sector Strategy on viral hepatitis 2016–2021.

      World Health Organization. Draft global health sector strategies. Viral hepatitis, 2016–2021. Report by the Secretariat. Geneva; 2016.

      This strategy aims at reducing new HBV and HCV infections by 90% and mortality by 65%. The baseline situation detailed in the WHO report
      • Nayagam S.
      • Thursz M.
      • Sicuri E.
      • Conteh L.
      • Wiktor S.
      • Low-Beer D.
      • et al.
      Requirements for global elimination of hepatitis B: a modelling study.
      and elsewhere
      The European Union HCV Collaborators
      Hepatitis C virus prevalence and level of intervention required to achieve the WHO targets for elimination in the European Union by 2030: a modelling study.
      shows how the European region is well positioned to easily reach most of its goals, with the notable exception of effective testing strategies and treatment, where more aggressive policies are needed.

       Prevention through vaccination

      HBV vaccination of newborns or adults at high risk is effective in preventing long-term chronic HBV infection,
      • Poorolajal J.
      • Mahmoodi M.
      • Majdzadeh R.
      • Nasseri-Moghaddam S.
      • Haghdoost A.
      • Fotouhi A.
      Long-term protection provided by hepatitis B vaccine and need for booster dose: a meta-analysis.
      and cost-effective regardless of endemicity.

      Chaiyakunapruk N et al. Hepatitis B vaccination: an updated systematic review of economic evaluations in low and middle income countries. 2017.

      • La Torre G.
      • Mannocci A.
      • Saulle R.
      • Colamesta V.
      • Meggiolaro A.
      • Mipatrini D.
      • et al.
      Economic evaluation of HBV vaccination: a systematic review of recent publications (2000–2013).
      As of August 2017, all countries in the HEPAHEALTH project include hepatitis B vaccination as part of their vaccination schedule, with the UK being the last EU country to introduce it.
      An effective HCV vaccine is not currently available. Despite HCV vaccine development efforts being hampered by several immune evasion strategies,
      • Drummer H.E.
      Challenges to the development of vaccines to hepatitis C virus that elicit neutralizing antibodies.
      several vaccines are currently being developed, and a few are in human studies.
      • Houghton M.
      Hepatitis C: the next 25 years.
      • Swadling L.
      • Capone S.
      • Antrobus R.D.
      • Brown A.
      • Richardson R.
      • Newell E.W.
      • et al.
      A human vaccine strategy based on chimpanzee adenoviral and MVA vectors that primes, boosts, and sustains functional HCV-specific T cell memory.
      The current costs of direct-acting antivirals (DAAs), compared to traditional vaccination costs, make HCV vaccination a much cheaper transmission control strategy: a recent modelling study in the UK
      • Stone J.
      • Martin N.K.
      • Hickman M.
      • Hellard M.
      • Scott N.
      • McBryde E.
      • et al.
      The potential impact of a hepatitis c vaccine for people who inject drugs: is a vaccine needed in the age of direct-acting antivirals?.
      estimated that even low efficacy HCV vaccines would have considerable impact on prevalence and incidence among PWID over 40 years. They found that similar reductions in prevalence or incidence could be achieved with 4–16 or 2–11 times fewer HCV treatments, respectively.

       Improvement in access to testing and diagnosis of hepatitis B and C

      The cost-effectiveness of screening the general population for viral hepatitis is a matter of debate, and affected primarily by the high cost of DAAs (in the case of HCV) and the rate of referral (notoriously poor for both viruses). A 2013 systematic review of the cost-effectiveness of HBV and/or HCV screening included 29 publications with varying eligible populations and implementation of screening.
      • Hahné S.J.
      • Veldhuijzen I.K.
      • Wiessing L.
      • Lim T.-A.
      • Salminen M.
      • van de Laar M.
      Infection with hepatitis B and C virus in Europe: a systematic review of prevalence and cost-effectiveness of screening.
      Overall, HBsAg screening of the baby-boomer generation, universal HBsAg antenatal screening, HBsAg screening of migrants, HCV screening and treatment of the general population and in PWID were found to be cost-effective. There was limited evidence on the effectiveness of HCV antenatal screening, or screening of migrants, prisoners, men having sex with men (MSM), or sexual health clinic attendees in the UK. Strategies to increase the cost-effectiveness of screening for viral hepatitis include: targeting birth cohorts,
      • Brouard C.
      • Le Strat Y.
      • Larsen C.
      • Jauffret-Roustide M.
      • Lot F.
      • Pillonel J.
      The undiagnosed chronically-infected HCV population in France. Implications for expanded testing recommendations in 2014.
      • Bruggmann P.
      • Negro F.
      • Bihl F.
      • Blach S.
      • Lavanchy D.
      • Müllhaupt B.
      • et al.
      Birth cohort distribution and screening for viraemic hepatitis C virus infections in Switzerland.
      • McGarry L.J.
      • Pawar V.S.
      • Panchmatia H.R.
      • Rubin J.L.
      • Davis G.L.
      • Younossi Z.M.
      • et al.
      Economic model of a birth cohort screening program for hepatitis C virus.
      • Rein D.B.
      • Smith B.D.
      • Wittenborn J.S.
      • Lesesne S.B.
      • Wagner L.D.
      • Roblin D.W.
      • et al.
      The cost-effectiveness of birth-cohort screening for hepatitis C antibody in US primary care settings.
      or using point-of-care assays followed by nucleic acid testing performed reflexively.
      • Chapko M.K.
      • Dufour D.R.
      • Hatia R.I.
      • Drobeniuc J.
      • Ward J.W.
      • Teo C.G.
      Cost-effectiveness of strategies for testing current hepatitis C virus infection.
      • Sehr M.A.
      • Joshi K.D.
      • Fontanesi J.M.
      • Wong R.J.
      • Bitmead R.R.
      • Gish R.G.
      Markov modeling in hepatitis B screening and linkage to care.
      In countries where a high prevalence of infection is associated with widespread use of low-cost generic DAAs, these hurdles are easily overcome, allowing for generalised screening.
      • Kim D.D.
      • Hutton D.W.
      • Raouf A.A.
      • Salama M.
      • Hablas A.
      • Seifeldin I.A.
      • et al.
      Cost-effectiveness model for hepatitis C screening and treatment: implications for Egypt and other countries with high prevalence.
      No consensus currently exists as to the optimal screening strategy. Data on access to and uptake of DAAs was only available for a selection of European countries.

      ABPI Viral Hepatitis Initiative. Access and Uptake of Direct Acting Antiviral Medicines in the UK and selected European countries based on data from IMS Health report for ABPI VHI: Hepatitis C Treatment in Europe, AXDoF162070 2017. Available from: http://www.abpi.org.uk/our-work/library/medical-disease/Documents/Access_and_Uptake_of_Direct_Acting_Antiviral_Medicines.pdf.

      There are persisting, significant variations in access of patients to DAAs across European countries: by January 2017, Portugal, Belgium and Germany have now treated over a quarter of their patients estimated to be infected. By contrast, the trend in the UK has been one of slower and lower levels of access.

       Harm reduction

      Among PWID, sharing needles/syringes and other paraphernalia is the main risk factor for HCV infection. Needle syringe exchange programmes (NSP) provide clean syringes and needles to prevent onward transmission. They operate through fixed sites, outreach, peer PWID networks, vending machines and pharmacies, and include opioid substitution therapy (OST), psychosocial approaches and residential rehabilitation. In a systematic review,
      • Platt L.
      • Minozzi S.
      • Reed J.
      • Vickerman P.
      • Hagan H.
      • French C.
      • et al.
      Needle syringe programmes and opioid substitution therapy for preventing hepatitis C transmission in people who inject drugs.
      OST reduced HCV incidence by between 32% and 73% in European countries, with little variation due to study design considerations and by 74% (95% CI 11–93), when combined with high coverage of NSP. This confirmed findings of large protective effects of NSP and OST on injecting risk behaviours associated with blood-borne viral transmission.
      • Turner K.M.
      • Hutchinson S.
      • Vickerman P.
      • Hope V.
      • Craine N.
      • Palmateer N.
      • et al.
      The impact of needle and syringe provision and opiate substitution therapy on the incidence of hepatitis C virus in injecting drug users: pooling of UK evidence.
      However, another systematic review found limited evidence of an effect.
      • Davis S.M.
      • Daily S.
      • Kristjansson A.L.
      • Kelley G.A.
      • Zullig K.
      • Baus A.
      • et al.
      Needle exchange programs for the prevention of hepatitis C virus infection in people who inject drugs: a systematic review with meta-analysis.
      A modelling study predicted that scaling up OST and NSP combined with antiviral therapy, i.e. by applying the concept of treatment as prevention would reduce incidence and prevalence of HCV among PWID.
      • Vickerman P.
      • Martin N.
      • Turner K.
      • Hickman M.
      Can needle and syringe programmes and opiate substitution therapy achieve substantial reductions in hepatitis C virus prevalence? Model projections for different epidemic settings.
      • Martin N.K.
      • Vickerman P.
      • Hickman M.
      Mathematical modelling of hepatitis C treatment for injecting drug users.
      Variation in findings may be due to limitations intrinsic to NSP programmes: the need for a large number of syringes per user per year, the increased survival of HCV in injection paraphernalia compared to other blood-borne pathogens, and the fact that HCV infections often occur early in the injection career, before injectors get into contact with appropriate services.
      • Castro-Sanchez A.
      • Shkedy Z.
      • Hens N.
      • Aerts M.
      • Geskus R.
      • Prins M.
      • et al.
      Estimating the force of infection for HCV in injecting drug users using interval-censored data.
      • Pouget E.R.
      • Hagan H.
      • Des Jarlais D.C.
      Meta-analysis of hepatitis C seroconversion in relation to shared syringes and drug preparation equipment.
      A modelling study has predicted that significantly reducing both incidence and prevalence of HCV among PWID could only be achieved by scaling up OST and NSP combined with antiviral therapy, i.e. by applying the concept of treatment as prevention,
      • Vickerman P.
      • Martin N.
      • Turner K.
      • Hickman M.
      Can needle and syringe programmes and opiate substitution therapy achieve substantial reductions in hepatitis C virus prevalence? Model projections for different epidemic settings.
      • Martin N.K.
      • Vickerman P.
      • Hickman M.
      Mathematical modelling of hepatitis C treatment for injecting drug users.
      given that a sustained virological response (SVR) is tantamount to clearance in the vast majority of people, even among high-risk populations. Although sexual transmission of HCV is infrequent among monogamous, serodiscordant couples,
      • Terrault N.A.
      • Dodge J.L.
      • Murphy E.L.
      • Tavis J.E.
      • Kiss A.
      • Levin T.
      • et al.
      Sexual transmission of hepatitis C virus among monogamous heterosexual couples: the HCV partners study.
      a high transmission rate has been recently reported among MSM engaged in high-risk sexual practices.
      • Wandeler G.
      • Gsponer T.
      • Bregenzer A.
      • Günthard H.F.
      • Clerc O.
      • Calmy A.
      • et al.
      Hepatitis C virus infections in the Swiss HIV Cohort Study: a rapidly evolving epidemic.
      Risk factors for transmission of HCV among MSM are coinfection with HIV
      • Wandeler G.
      • Gsponer T.
      • Bregenzer A.
      • Günthard H.F.
      • Clerc O.
      • Calmy A.
      • et al.
      Hepatitis C virus infections in the Swiss HIV Cohort Study: a rapidly evolving epidemic.
      and sexualised drug use (“chemsex”).
      • Pufall E.
      • Kall M.
      • Shahmanesh M.
      • Nardone A.
      • Gilson R.
      • Delpech V.
      • et al.
      Sexualized drug use (‘chemsex’) and high-risk sexual behaviours in HIV-positive men who have sex with men.
      HIV-negative MSM may become infected with HCV if engaged in high-risk sexual practices.
      • Charre C.
      • Cotte L.
      • Kramer R.
      • Miailhes P.
      • Godinot M.
      • Koffi J.
      • et al.
      Hepatitis C virus spread from HIV-positive to HIV-negative men who have sex with men.
      Strategies aimed to eliminate HCV in HIV-positive MSM should include aggressive awareness campaigns to promote the correct and consistent use of condoms, and, possibly, the implementation of a treatment as a prevention approach.
      • Scott N.
      • Stoové M.
      • Wilson D.P.
      • Keiser O.
      • El-Hayek C.
      • Doyle J.
      • et al.
      Eliminating hepatitis C virus as a public health threat among HIV-positive men who have sex with men: a multi-modelling approach to understand differences in sexual risk behaviour.
      However, a modelling study has pointed out how reducing high-risk sexual behaviour would be the most effective intervention for controlling the HCV epidemic among MSM, independent of treatment interventions.

       Achieving the WHO targets in Europe for HBV and HCV

      A simulation model of the global HBV epidemic was recently developed,
      • Nayagam S.
      • Thursz M.
      • Sicuri E.
      • Conteh L.
      • Wiktor S.
      • Low-Beer D.
      • et al.
      Requirements for global elimination of hepatitis B: a modelling study.
      Western European countries would be capable of reducing HBV-related mortality below a threshold of 50 deaths per 100,000 by the early 2020s with comparatively small interventions (essentially increasing the treatment uptake to 80%), while Central and Eastern Europe may reach the same goal before 2030.
      For HCV, another modelling study estimated the level of intervention required to achieve WHO targets of 65% reduction in liver-related deaths, a 90% reduction of new viral hepatitis infections, and 90% of patients with viral hepatitis infections being diagnosed by 2030.
      The European Union HCV Collaborators
      Hepatitis C virus prevalence and level of intervention required to achieve the WHO targets for elimination in the European Union by 2030: a modelling study.
      Their model suggests that to achieve the WHO targets, treatment would need to increase from 150,000 patients annually using DAAs at 95% SVR in 2015 to 187,000 in 2025, with expansion of treatment age to 15–74 years old, and treatment of all fibrosis stages. Screening should also be expanded from 88,800 new cases annually in 2015 to 180,000 by 2025. EASL clinical practice guidelines currently recommend that all patients with HCV infection should be considered for treatment.
      European Association for the Study of the Liver
      EASL Recommendations on Treatment of Hepatitis C 2018.

      Discussion and interpretation

       Liver disease epidemiology is changing and can be changed

      Historical experience illustrates how rapidly trends in liver disease mortality can change in response to population-level factors.
      Evidence gathered across this study presents liver disease as a complex, diverse and important disease in Europe. Very significant shifts in liver mortality have occurred since 1970. There have been up to fourfold decreases in Southern European countries as a result of decreased wine consumption. In other countries there have been increases in liver mortality of equal magnitude. Experience from earlier in the 20th century illustrates how rapidly liver mortality can change in response to the factors that influence behaviour at a population level, despite the fact that it takes between 10 and 50 years of progressive fibrosis to develop cirrhosis, liver failure and HCC. The rationing of alcohol during warfare, prohibition in the US or Gorbachov’s 1980s policy in the Soviet Union led to dramatic changes in liver mortality within a few years, with the maximum changes occurring within five years.
      • Terris M.
      Epidemiology of cirrhosis of the liver: national mortality data.
      • Nemtsov A.V.
      Alcohol-related human losses in Russia in the 1980s and 1990s.
      The explanation for this paradox probably lies in the fact that much of the mortality from alcohol-related liver disease is a result of acute-on-chronic liver failure related to recent drinking.
      HBV and HCV are important drivers of liver disease, and may be the most important driver in certain countries. Rising prevalence of obesity throughout the vast majority of Europe is likely to further shift the distribution of the burden of liver disease, and in some countries, is already a significant cause of cirrhosis and HCC. These risk factors are synergistic, for example a BMI greater than 35 kg/m2 doubles the hepatotoxicity of alcohol.
      • Hart C.L.
      • Morrison D.S.
      • Batty G.D.
      • Mitchell R.J.
      • Davey S.G.
      Effect of body mass index and alcohol consumption on liver disease: analysis of data from two prospective cohort studies.
      • Liu B.
      • Balkwill A.
      • Reeves G.
      • Beral V.
      Body mass index and risk of liver cirrhosis in middle aged UK women: prospective study.
      Similarly an alcohol intake of more than 17.5 cl per week can increase the mortality of hepatitis C by 2.5 times.
      • Younossi Z.
      • Zheng L.
      • Stepanova M.
      • Venkatesan C.
      • Mir H.
      Moderate, excessive or heavy alcohol consumption: each is significantly associated with increased mortality in patients with chronic hepatitis C.
      Therefore, it is probably unhelpful to think of liver disease within independent disease silos, but to consider liver disease at a population level as the outcome of a multifactorial process, with an important role for health inequality.
      • Mackenbach J.P.
      • Kulhanova I.
      • Bopp M.
      • Borrell C.
      • Deboosere P.
      • Kovacs K.
      • et al.
      Inequalities in alcohol-related mortality in 17 European countries: a retrospective analysis of mortality registers.

       Strategies for reducing the risk factor for liver disease exist

      Several strands of evidence, from empirical, epidemiological and modelling work have shown the potential for reducing the principal risk factors for liver disease within a population. These strategies will vary in administrative cost and impact, depending on the risk factor in question, a country’s epidemiology and the context in which they are implemented, but they can be broadly categorised into population and individual-level approaches.
      For alcohol the most effective and cost-effective intervention is to increase the price of alcohol.
      • Burton R.
      • Henn C.
      • Lavoie D.
      • O'Connor R.
      • Perkins C.
      • Sweeney K.
      • et al.
      A rapid evidence review of the effectiveness and cost-effectiveness of alcohol control policies: an English perspective.
      Organisation for Economic Co-operation and Development
      Tackling harmful alcohol use: economics and public health policy.
      This measure has the additional advantage that it increases treasury revenues, thus increasing the capacity of health systems to tackle the adverse impacts of alcohol misuse. There is a wealth of evidence that alcohol marketing has a deleterious impact on young people.
      • Jernigan D.
      • Noel J.
      • Landon J.
      • Thornton N.
      • Lobstein T.
      Alcohol marketing and youth alcohol consumption: a systematic review of longitudinal studies published since 2008.
      Modelling studies suggest that marketing regulations would be effective and cost-effective.
      • Anderson P.
      • Chisholm D.
      • Fuhr D.C.
      Effectiveness and cost-effectiveness of policies and programmes to reduce the harm caused by alcohol.
      Evidence from natural experiments is ever increasing, with the French Loi Evin as an excellent example of practical and effective regulation of alcohol marketing.
      • Anderson P.
      • Chisholm D.
      • Fuhr D.C.
      Effectiveness and cost-effectiveness of policies and programmes to reduce the harm caused by alcohol.
      India and Russia have banned alcohol advertising, joined most recently by Lithuania. Policies regulating the availability, the marketing of alcohol and the drink environment and availability of alcohol have been identified, as well as screening and brief interventions and alcohol treatment.
      Several policy options have been examined with the aim of reducing obesity and diabetes, with recommendations including adjusting the food environment through regulation of marketing to children, improvement of nutritional labelling and reformulation, fiscal measures, such as the (now defunct) Danish tax on saturated fat,
      • Vallgårda S.
      • Holm L.
      • Jensen J.D.
      The Danish tax on saturated fat: why it did not survive.
      the UK’s upcoming levy on SSBs
      • Briggs A.D.
      • Mytton O.T.
      • Kehlbacher A.
      • Tiffin R.
      • Elhussein A.
      • Rayner M.
      • et al.
      Health impact assessment of the UK soft drinks industry levy: a comparative risk assessment modelling study.
      or Hungary’s 2011 “chips tax” on food high in salt, sugar or caffeine,
      • Bíró A.
      Did the junk food tax make the Hungarians eat healthier?.
      as well as subsidies to dissuade consumption of harmful commodities or persuade consumption of healthy commodities. Individual-level interventions to increase physical activity, or reduce obesity through behavioural lifestyle interventions were also noted as likely to reduce obesity rates in specific population groups.
      The European region is uniquely positioned to achieve the WHO target of elimination of viral hepatitis as a public health threat by 2030.
      • Duffell E.F.
      • Hedrich D.
      • Mardh O.
      • Mozalevskis A.
      Towards elimination of hepatitis B and C in European Union and European Economic Area countries: monitoring the World Health Organization’s global health sector strategy core indicators and scaling up key interventions.
      Vaccination against HBV, DAAs for HCV, increased testing for both HCV and HBV and harm reduction through needle-exchange and OST are likely to reduce the burden of viral hepatitis infection in both general and high-risk population groups. Commitment to integrated action of multiple interventions across the spectrum of the varied epidemiological, demographic and socio-political landscape of Europe is key to any successful elimination of hepatitis. Indeed, screening for hepatitis C in the general population in the US was estimated to be cost-effective and reducing HCV-related morbidity and mortality, but the authors noted that this effectiveness would be contingent on improved rates of referral, treatment, and cure.
      • Coffin P.O.
      • Scott J.D.
      • Golden M.R.
      • Sullivan S.D.
      Cost-effectiveness and population outcomes of general population screening for hepatitis C.
      Extending screening for other chronic diseases to reduce late diagnosis is also likely to have a large impact on mortality, as screening helps to identify patients at genetic risk of alcoholic or other liver diseases; can prompt behaviour change (abstinence, weight control) and form the basis for further screening programmes to prevent life-threatening complications.

       Challenges and potential limitations

      One of the factors that can enhance the effort to reduce liver disease is the relevant, timely, standardised data collection for programmatic monitoring and evaluation. The data used for this study was extracted from standardised databases, in order to increase comparability between countries and across time for historical trends. This reduced the granularity of the data available, as definitions and categorisation of diseases available in international databases (i.e. WHO and GBD) were far broader than clinical classifications traditionally used. Nevertheless, using this standardised data avoided the complications arising from countries’ different use of terminology, diagnosis, data recording and reporting practices, which creates uncertainty when comparing national-level data, or historical data. While the European-level perspective of the project included a large number of countries, not all countries were included because of time and resource limitations. Thus, data and trends in some Eastern and Central Asian countries were not explored. Although the reviews focussed on upstream drivers of liver diseases, infection with hepatitis virus, obesity and harmful alcohol use, this review did not cover other rarer origins of liver disease (i.e. genetics, drug use) in any detail. However, the focus on determinants that can be modified or reduced through health policies provides some concrete options for national and international policy makers to tackle the rising burden of liver disease in Europe.
      While previous reports and analyses also described the burden of liver disease in Europe, we did not restrict the focus to one risk factor, and included historical trend data in order to provide more information on the context in which policies need to be implemented for different countries. The international focus also allows situations between countries to be compared, but can help policy makers identify evidence and experience from culturally, politically and epidemiologically similar European neighbours. The initial review describing the burden of the liver disease across Europe, coupled with trends in risk factors, serve to illustrate the magnitude of the problem, and hopefully, identify liver disease as an important priority for European policy makers, clinicians and health researchers.
      Even for a developed region such as Europe we have noted throughout that epidemiological data on the burden of liver disease is in many areas of insufficient quality, comparability and relevance.
      Therefore, this work serves as a call to action on surveillance and data collection of analysis on liver disease, highlighting that further work is needed in collecting, harmonising, defining and reporting data. While no specific Europe wide guidelines exist on the collection of liver disease surveillance data, any plan to enhance surveillance of liver disease in Europe should incorporate elements of continuity (data collection should be ongoing); practicality (implementation should be feasible, but also should be useful for onwards action); uniformity (standardisation of notifications, and reporting practices within and across countries); and should be timely to allow prompt programmatic action. Based on mortality data reported to international organisations, more work needs to be done to clarify and codify the aetiology and causes of death. One prime example of this is in NAFLD/NASH, which is under-represented in the causes of death and in the proportion of prevalent cases of liver disease, in part because of historical coding and data collection. Future efforts to elaborate ICD-10 and other codes for liver disease should consider the current picture of the disease.

      Conclusions

      The progressing and increasing profile of liver disease in Europe is a concerning issue. The uncertainties in the sources of data do not detract from the overall picture of liver disease as a growing public health problem across Europe. This study highlights that the governance and public health tools to reverse this trend exist. These tools should be implemented and integrated to have a timely and significant impact on liver disease morbidity and mortality. The time for action is now.

      Financial support

      This work was supported by EASL funding.

      Conflict of interest

      Helena Cortez-Pinto received lecture and advisory board fees from Intercept, Genfit, and Gilead. Francesco Negro received a research grant from Gilead and AbbVie , and is advising Gilead, AbbVie, and Merck. Jeffrey Lazarus declares speaker fees and research grants from AbbVie, Gilead Sciences and MSD, outside of this study. The other authors declare no conflict of interest.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contributions

      Laura Pimpin was responsible for the overall management of the project, analysed data, designed and consolidated the scope, led the review of the literature, conducted qualitative interviews, and drafted the final report. Helena Cortez-Pinto advised on the HEPAHEALTH project and drafted the obesity/type 2 diabetes and liver disease section of the manuscript. Francesco Negro advised on the HEPAHEALTH project and drafted the viral hepatitis section of the manuscript. Emily Corbould collected, collated and analysed data, participated in the review of the literature and contributed to the write-up of the report. Jeffrey V Lazarus advised on the HEPAHEALTH project and revised the full manuscript. Laura Webber advised on the design of the project, conducted qualitative interviews, participated in the review of the literature and contributed to the write-up of the report. Nick Sheron advised on the HEPAHEALTH project and drafted the introduction, Alcohol and liver disease, and discussion sections of the manuscript.

      Acknowledgements

      Fiona Godfrey (EASL) for her invaluable help in coordinating this work. Jennifer Saxton, Jessica Flood and Holly Prudden (UKHF) for their work collecting, collating and analysing data and participation in the review of the literature. Center for Disease Analysis (CDA) Foundation for preparation of Polaris Observatory data.

      Supplementary data

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