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The global burden of cirrhosis: A review of disability-adjusted life-years lost and unmet needs

  • Peter Jepsen
    Correspondence
    Corresponding author. Address: Department of Hepatology and Gastroenterology, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, DK-8200, Aarhus N, Denmark. Tel.: +45 2425 2944.
    Affiliations
    Department of Hepatology and Gastroenterology, Aarhus University Hospital, Aarhus, Denmark

    Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
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  • Zobair M. Younossi
    Affiliations
    Betty and Guy Beatty Center for Integrated Research, Inova Health System, Falls Church, VA, USA

    Department of Medicine, Center for Liver Diseases, Inova Fairfax Hospital, Falls Church, VA, USA
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      Summary

      Cirrhosis is a burden on the individual and on public health. The World Health Organization’s metric of public health burden is the disability-adjusted life-year (DALY), the sum of years of life lost due to premature death and years of life lived with disability. The more DALYs attributable to a disease, the greater its burden on public health. Cirrhosis was responsible for 26.8% fewer DALYs in 2019 than in 1990, which is positive, but the reduction in DALYs across the spectrum of diseases in and outside the liver was 34.4%. Hepatitis C (26% of DALYs), alcohol (24%), and hepatitis B (23%) contribute almost equally to the global burden of cirrhosis. The contribution from non-alcoholic fatty liver disease (8%) is small but increasing. There is substantial global variation in the burden and causes of cirrhosis. We find that the poorest countries carry the greatest burden of cirrhosis, and that this burden is primarily caused by cirrhosis from hepatitis B infection. Interventions targeting hepatitis B infection are known, but not fully implemented. In more affluent countries, alcohol and hepatitis C are the dominant causes of cirrhosis, but non-alcoholic fatty liver will likely become a dominant cause of cirrhosis in parallel with the increasing prevalence of obesity. We also argue that the World Health Organization underestimates the public health burden associated with cirrhosis because it assigns zero disability to compensated cirrhosis and considers decompensated cirrhosis as only mildly disabling.

      Keywords

      Introduction

      Cirrhosis is the final stage of liver fibrosis, which itself results from a perpetuated wound-healing process after a liver injury that can lead to a wide range of chronic diseases involving the liver.
      • Schuppan D.
      • Afdhal N.H.
      Liver cirrhosis.
      The most prevalent chronic liver diseases are chronic viral hepatitis (from hepatitis B or C infection), alcohol-related liver disease, and non-alcoholic fatty liver disease (NAFLD).
      Cirrhosis negatively impacts on patient-reported outcomes and health-related quality of life.
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      Development of a disease specific questionnaire to measure health related quality of life in patients with chronic liver disease.
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      Factors associated with poor health-related quality of life of patients with cirrhosis.
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      Quality of life in cirrhosis.
      The impact of cirrhosis on quality of life can add to the existing impairment of quality of life related to viraemia in patients with hepatitis C.
      • Younossi Z.M.
      • Stepanova M.
      • Afdhal N.
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      Improvement of health-related quality of life and work productivity in chronic hepatitis C patients with early and advanced fibrosis treated with ledipasvir and sofosbuvir.
      ,
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      • Hunt S.
      The patient's journey with chronic hepatitis C from interferon plus ribavirin to interferon- and ribavirin-free regimens: a study of health-related quality of life.
      Conversely, effective treatment of hepatitis C can lead to significant gains in patients’ quality of life, especially for patients with decompensated cirrhosis. In addition, there is evolving evidence indicating that quality of life is significantly impaired in patients with NAFLD in the form of non-alcoholic steatohepatitis.
      • Younossi Z.M.
      • Stepanova M.
      • Lawitz E.J.
      • Reddy K.R.
      • Wai-Sun Wong V.
      • Mangia A.
      • et al.
      Patients with nonalcoholic steatohepatitis experience severe impairment of health-related quality of life.
      Cirrhosis can have economic consequences in the form of health expenditures and job losses. A United States study found that patients with chronic liver disease were less likely to be employed than comparable people without chronic liver disease (44.7% vs. 69.6%), that they had lost work due to disability, and that they had greater healthcare expenses.
      • Stepanova M.
      • De Avila L.
      • Afendy M.
      • Younossi I.
      • Pham H.
      • Cable R.
      • et al.
      Direct and indirect economic burden of chronic liver disease in the United States.
      Caregivers of patients with cirrhosis also have lower quality of life than population controls.
      • Nguyen D.L.
      • Chao D.
      • Ma G.
      • Morgan T.
      Quality of life and factors predictive of burden among primary caregivers of chronic liver disease patients.
      Clinicians caring for patients with cirrhosis will recognise the negative impact of cirrhosis on individuals and families. This review will focus on cirrhosis as a burden on public health, but – as we shall return to – we may be underestimating the impact of cirrhosis on public health by underestimating its impact on individual health.

      The Global Burden of Disease

      At the population-level, burden of disease is primarily measured in terms of mortality and morbidity, and financial burden is also important because resources are limited. The World Health Organization (WHO) uses the Global Burden of Disease studies to measure the burden of diseases and injuries, and it now regularly measures the burden of more than 100 diseases in various populations. Data for 2019 were made available in October 2020 and can be accessed through this website: http://www.healthdata.org/gbd/2019. Most of the data presented in this review were downloaded from http://ghdx.healthdata.org/gbd-results-tool.
      GBD 2019 Diseases and Injuries Collaborators
      Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease study 2019.
      The Global Burden of Disease study centres on the disability-adjusted life-year (DALY), which is a method of weighing a disease according to its impact on mortality and morbidity. The DALY will also be our focal point, preferred over metrics such as incidence rate, mortality rate, prevalence, or healthcare expenditures (Box 1). The DALY is the sum of years of life lost due to premature death (YLL) and years of life lived with disability (YLD). One DALY represents the loss of 1 life-year of full health. Thus, the more DALYs attributable to a disease, the greater its burden on public health.
      Glossary of terms.
      DALY
      Disability-adjusted life-year. One DALY represents 1 life-year of full health lost. DALY = YLL+ YLD.
      YLL
      Years of life lost to premature death. For cirrhosis, the product of the number of deaths from cirrhosis in the population times the population’s life expectancy at the age of death.
      YLD
      Years of life lived with disability. For cirrhosis, the product of the cirrhosis prevalence in the population times the disability weight for cirrhosis.
      QALY
      Quality-adjusted life-year. One QALY represents 1 life-year of full health gained.
      Incidence rate
      New cases, e.g. new cases of cirrhosis, divided by the population’s total observation time. The population’s total observation time within a given calendar year may be approximated as the number of people in the population at the beginning of the year.
      Mortality rate
      Deaths in the population, e.g. deaths from cirrhosis, divided by the population’s total observation time. The population’s total observation time within a given calendar year may be approximated as the number of people in the population at the beginning of the year.
      Healthcare expenditure
      Money spent on healthcare, e.g. spent on cirrhosis, often expressed as a proportion of a country’s gross domestic product.
      The YLL is the product of the number of deaths from cirrhosis in the population times the population’s life expectancy at the age of death. Thus, many deaths and deaths at an early age in an otherwise long-living population give higher YLL. The YLD is the product of the cirrhosis prevalence in the population times the disability weight for cirrhosis. Cirrhosis prevalence, in turn, is the number of incident patients with cirrhosis times the survival time with cirrhosis. Thus, a high disease incidence, long survival time, and severe disability give higher YLD. The disability weight is on a scale from 0 (no disability) to 1 (dead).
      The disability-adjusted life-year (DALY) is the sum of years of life lost due to premature death and years of life lived with disability. More DALYs equal greater burden on public health.
      Disability weights are based on valuation by a representative population sample and cover 8 domains of health: mobility, selfcare, pain and discomfort, cognition, interpersonal activities, vision, sleep and energy, and affect.

      World Health Organization. The Global Burden of Disease concept. Accessed 19 July 2020. Available from: https://www.who.int/quantifying_ehimpacts/publications/en/9241546204chap3.pdf.

      The WHO’s most recent disability weight for decompensated cirrhosis was 0.178, increasing to 0.300 if accompanied by severe anaemia,
      GBD 2019 Diseases and Injuries Collaborators
      Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease study 2019.
      so decompensated cirrhosis was similar in disability to “profound hearing loss” (0.204) and “severe back pain without leg pain” (0.272). For compensated cirrhosis the disability weight was 0, meaning that compensated cirrhosis is believed to have no impact on health or ability.
      GBD 2019 Diseases and Injuries Collaborators
      Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease study 2019.
      ,
      GBD 2017 Cirrhosis Collaborators
      The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017.
      The combination of a high early-age mortality and a low disability weight mean that the DALY for cirrhosis is virtually identical to the YLL; the YLD is nearly zero.
      The DALY is in many respects similar to the QALY, the quality-adjusted life-year. The QALY is a measure of life expectancy corrected for disability, and it can be used to compare interventions by balancing quantity of life and quality of life. QALYs are often linked with the costs associated with an intervention in a cost-utility analysis.
      • Thompson Coon J.
      • Rogers G.
      • Hewson P.
      • Wright D.
      • Anderson R.
      • Jackson S.
      • et al.
      Surveillance of cirrhosis for hepatocellular carcinoma: a cost-utility analysis.
      A source of confusion is that 1 QALY represents 1 life-year of full health gained, while 1 DALY represents 1 life-year of full health lost.

      The burden of cirrhosis

      In the most recent GBD study, from 2019, cirrhosis was responsible for 560.4 age-standardised DALYs per 100,000 population globally. By comparison, chronic obstructive pulmonary disease was responsible for 926.1 age-standardised DALYs per 100,000 population,
      GBD 2017 DALYs and HALE Collaborators
      Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017.
      skin and subcutaneous diseases for 559.4, depressive disorders for 577.8, dementia for 338.6, liver cancer for 151.1, and inflammatory bowel disease for 20.2.
      GBD 2017 DALYs and HALE Collaborators
      Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017.
      Note that deaths from hepatocellular carcinoma do not count as deaths from cirrhosis in the Global Burden of Disease studies, although most of these cancers develop in patients with cirrhosis.
      GBD 2017 Cirrhosis Collaborators
      The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017.
      The 560.4 age-standardised DALYs per 100,000 population attributable to cirrhosis in 2019 was a 26.8% reduction since 1990.
      GBD 2019 Diseases and Injuries Collaborators
      Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease study 2019.
      ,
      GBD 2017 DALYs and HALE Collaborators
      Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017.
      During that period, cirrhosis moved from being the 15th-leading cause of DALYs lost globally to being the 16th-leading cause, and the reduction in age-standardised DALY rate across all diseases was 34.4%. Only 3 diseases saw substantial increases in age-standardised DALY rates: HIV/AIDS (58.5% increase), musculoskeletal disorders except rheumatoid arthritis (30.7% increase), and diabetes (24.4% increase).
      GBD 2019 Diseases and Injuries Collaborators
      Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease study 2019.
      For women, cirrhosis was the 20th-leading contributor of DALYs in 2019, between dementia and lung cancer, after being the 19th-leading cause in 2010. The top 5 contributors are neonatal disorders, ischaemic heart disease, stroke, lower respiratory tract infections, and diarrhoeal diseases. For men, cirrhosis was the 9th-leading contributor of DALYs in 2019, up from 12th in 2010. The top 5 are ischaemic heart disease, neonatal disorders, stroke, road injuries, and lower respiratory tract infections.
      GBD 2019 Diseases and Injuries Collaborators
      Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease study 2019.

      Variation in the burden of cirrhosis

      The burden of cirrhosis is not evenly distributed across the world. It varies by gender and age, by region, and by sociodemographic index. It also varies in response to the variation in prevalence of chronic liver diseases that cause cirrhosis, i.e. hepatitis B and C infection, alcohol-related liver disease, and NAFLD.

      Gender and age

      The age-standardised DALY rate for cirrhosis was 783.3 per 100,000 for men and 344.0 per 100,000 for women in 2019, meaning that men were responsible for 69% of the total burden of cirrhosis. This proportion was unchanged since 1990. The DALY rate for men peaked at age 60–64 years in 2019, as it did in 1990, and between 1990 and 2019 the DALY rate in childhood decreased more than it did in other age groups. Specifically, it fell from 202 to 105 per 100,000 (a 48% decline) for boys aged <5 years compared with 2,942 to 2,168 per 100,000 (a 26% decline) for men aged 60–64 years. Among women, the DALY rate peaked at age 70–74 years in 1990 and at age 75–79 in 2019, and relative changes during the 30-year period were similar to those seen among men (Fig. 1). Note that we generally present age-standardised rates to account for regional differences in age distribution.
      Cirrhosis is a major burden on the public health, almost exclusively due to premature deaths. In their analyses, the WHO likely underestimates the disability associated with cirrhosis.
      Figure thumbnail gr1
      Fig. 1DALYs lost to cirrhosis per 100,000 population by gender, age, and calendar year. DALYs, disability-adjusted life-years.

      Regional variation

      In 2019, the countries with the highest age-standardised DALY rates for cirrhosis were Egypt (2,410 per 100,000 population), Cambodia (1,983 per 100,000), Turkmenistan (1,872 per 100,000), and Mongolia (1,866 per 100,000). However, the proportion of DALYs attributable to cirrhosis better reflects the burden of cirrhosis relative to other health burdens. In 2019, this proportion was 1.8% globally, up from 1.3% in 1990 and 1.7% in 2010.
      GBD 2019 Diseases and Injuries Collaborators
      Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease study 2019.
      The 3 countries with the highest proportions were Moldova (6.0% of all DALYs in 2019 were lost to cirrhosis), Turkmenistan (5.8%), and Egypt (5.8%), and the 3 with the lowest proportions were Mozambique (0.5%), New Zealand (0.6%), and Iceland (0.6%). For comparison, the proportion was 1.1% in China, 1.4% in the United Kingdom, 1.4% in Italy, 1.7% in the United States, and 2.7% in Russia (Fig. 2).
      Figure thumbnail gr2
      Fig. 2Proportion of DALYs attributable to cirrhosis in 2019. This illustration is downloaded from the Global Burden of Disease website, https://vizhub.healthdata.org/gbd-compare/. DALYs, disability-adjusted life-years.
      The proportion of DALYs attributable to cirrhosis in 2019 was low in Africa, but with a regional spike in Egypt. In other regions, spikes were found in Mexico and Cambodia (Fig. 2). In Egypt, 5.8% of all DALYs were attributable to cirrhosis, with hepatitis C (43% of cirrhosis DALYs) and hepatitis B (26% of cirrhosis DALYs) responsible for the majority of DALYs attributable to cirrhosis. In Mexico, by contrast, alcohol (36% of cirrhosis DALYs) and hepatitis C (28%) were the main culprits behind the 4.1% of DALYs lost to cirrhosis. In Cambodia, as in Egypt, it was hepatitis C (30%) and hepatitis B (23%) that were responsible for most of the 5.3% of DALYs lost to cirrhosis.
      Within Europe the proportion of DALYs attributable to cirrhosis in 2019 ranges from 0.6% in Iceland and Norway to 3.8% in Romania. The epidemiology of cirrhosis within Europe (and a handful of countries outside Europe) was studied extensively in EASL’s 2018 HEPAHEALTH project.
      • Pimpin L.
      • Cortez-Pinto H.
      • Negro F.
      • Corbould E.
      • Lazarus J.V.
      • Webber L.
      • et al.
      Burden of liver disease in Europe: epidemiology and analysis of risk factors to identify prevention policies.
      ,

      European Association for the Study of the Liver. HEPAHEALTH project report. Accessed 19 July 2020. Available from: https://easl.eu/publication/hepahealth-project-report/.

      It combined data on cirrhosis prevalence from the Global Burden of Disease database with mortality data from WHO’s European Detailed Mortality and Health for All databases, and added knowledge from local experts when data were insufficient.
      • Pimpin L.
      • Cortez-Pinto H.
      • Negro F.
      • Corbould E.
      • Lazarus J.V.
      • Webber L.
      • et al.
      Burden of liver disease in Europe: epidemiology and analysis of risk factors to identify prevention policies.
      The HEPAHEALTH project examined the mortality rate from cirrhosis across Europe. The mortality rate from cirrhosis is different from the DALY rate from cirrhosis, but the 2 measures are strongly correlated because the DALY for cirrhosis depends almost exclusively on mortality, not on morbidity, as explained above (Spearman rho = 0.94, Fig. 3).
      Figure thumbnail gr3
      Fig. 3Association between 195 countries’ DALY rate from cirrhosis and mortality rate from cirrhosis. Both rates are crude rates per 100,000 population. DALY, disability-adjusted life-year.
      The HEPAHEALTH report divided Europe into 4 groups based on their time-trend in age-adjusted mortality from cirrhosis in 1970–2016 (Fig. 4): decreasing, stable low, increasing, and stable high. Countries with a decreasing trend were Western and Southern European countries, while the stable low countries were scattered across Europe. The countries with a worrying, increasing trend were the United Kingdom, Romania, Hungary, Bulgaria, Lithuania, Latvia, Estonia, Kazakhstan, and Finland, and they now have the same high mortality from cirrhosis as the 2 countries with a stable high mortality: Slovakia and Uzbekistan. The HEPAHEALTH report stated that “alcoholic liver disease is the largest burden and highest priority in the North of Europe, while viral hepatitis is the highest priority in the East and South”.

      European Association for the Study of the Liver. HEPAHEALTH project report. Accessed 19 July 2020. Available from: https://easl.eu/publication/hepahealth-project-report/.

      Figure thumbnail gr4
      Fig. 4Time trends in age-adjusted mortality from cirrhosis, 1970–2016. From the HEPAHEALTH project report, available at https://easl.eu/publication/hepahealth-project-report/. We apologise for the missing Albanian sea border.

      Sociodemographic index

      The Global Burden of Disease study assigns a sociodemographic index to all countries based on income per capita, average educational attainment, and births per woman of fertile age. The sociodemographic index is scaled from 0 (lowest income, fewest years of schooling, and highest fertility) to 1 (highest income, most years of schooling, and lowest fertility).
      GBD 2017 DALYs and HALE Collaborators
      Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017.
      The sociodemographic index correlates with the age-standardised DALY rate for cirrhosis, meaning that the burden of cirrhosis is lower in more affluent countries (Fig. 5). The 5 countries with the lowest sociodemographic index are Somalia, Niger, Chad, Burkina Faso, and Mali; the 5 with the highest sociodemographic index are Switzerland, Norway, Germany, Luxembourg, and Andorra. Countries with a sociodemographic index around 0.5 include Bangladesh (0.483), Cameroon (0.490), Honduras (0.496), Mauritania (0.496), Zambia (0.505), Kenya (0.508), Sudan (0.515), and Nicaragua (0.517).
      Figure thumbnail gr5
      Fig. 5Association between the sociodemographic index and the age-standardised DALY rate for cirrhosis in 2019. Each of the 195 countries in the Global Burden of Disease dataset is represented by a circle, and the black line is a lowess smoother to facilitate the visual interpretation. The sociodemographic index is based on income per capita, average educational attainment, and births per woman of fertile age, and more affluent countries have a higher index. DALYs, disability-adjusted life-years.

      Aetiology of cirrhosis

      Although there are many risk factors for cirrhosis, clinical tradition emphasises certain risk factors as aetiologies of cirrhosis. The 2019 Global Burden of Disease study estimated the breakdown of DALYs by aetiology. Of the 560.4 total age-standardised DALYs per 100,000 population attributable to cirrhosis, they estimated that 129.9 (23%) DALYs per 100,000 were due to hepatitis B, 146.3 (26%) were due to hepatitis C, 133.3 (24%) were due to alcohol use, 43.7 (8%) were due to NAFLD, and 107.3 (19%) were due to other causes.
      GBD 2017 DALYs and HALE Collaborators
      Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017.
      The largest decrease from 2010 to 2019 was by 23% (hepatitis B), the smallest by 1% (NAFLD).
      GBD 2017 DALYs and HALE Collaborators
      Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017.
      These trends indicate that, within cirrhosis, the contribution from NAFLD-cirrhosis is increasing. There is substantial regional variation, and there is substantial variation in time trends in the prevalence of these aetiologies.
      Hepatitis C (26% of DALYs), alcohol (24%), and hepatitis B (23%) contribute almost equally to the global burden of cirrhosis. The contribution from non-alcoholic fatty liver disease (8%) is small but increasing.

      Hepatitis B

      The 2016 prevalence of hepatitis B infection (defined as positive HBsAg) in the general population has been estimated at 3.9% globally, with regional estimates of 0.4% in the Pan-American region, 1.6% in Europe, 2.2% in the Eastern Mediterranean region, 3.5% in South-East Asia region, 5.7% in the Western Pacific region, and 7.2% in Africa.
      The Polaris Observatory Collaborators
      Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study.
      The prevalence is decreasing in most countries, but increasing in some countries in all regions.
      • Ott J.J.
      • Horn J.
      • Krause G.
      • Mikolajczyk R.T.
      Time trends of chronic HBV infection over prior decades - a global analysis.
      More than 80% of patients with hepatitis B infection come from just 21 countries, and 57% come from China, India, Nigeria, Indonesia, or the Philippines.
      The Polaris Observatory Collaborators
      Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study.
      There is a strong correlation between sociodemographic index and burden from cirrhosis due to hepatitis B, with the heaviest burden on the poorer regions (Fig. 6).
      Figure thumbnail gr6
      Fig. 6Association between age-standardised DALYs per 100,000 and sociodemographic index for cirrhosis from hepatitis B, hepatitis C, harmful alcohol consumption, and NAFLD. The lines are lowess smoothing plots of the actual age-standardised DALY rates, one for each aetiology for each of the 195 countries in the Global Burden of Disease dataset. The sociodemographic index is based on income per capita, average educational attainment, and births per woman of fertile age, and more affluent countries have a higher index. DALY(s), disability-adjusted life-year(s); NAFLD, non-alcoholic fatty liver disease.

      Hepatitis C

      The 2015 global prevalence of viraemic HCV infection was estimated at 1.0%, with the highest regional prevalence in Central Asia (3.6%), Eastern Europe (3.3%), and central sub-Saharan Africa (2.1%).
      The Polaris Observatory HCV Collaborators
      Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study.
      With the introduction of direct-acting antivirals to treat hepatitis C infection, prevalence is going down,
      • Razavi H.
      Global epidemiology of viral hepatitis.
      and elimination has become the target.

      World Health Organization. Global health sector strategy on viral hepatitis 2016-2021. Accessed 30 July 2020. Available from: https://www.who.int/hepatitis/strategy2016-2021/ghss-hep/en/.

      The poorest and the wealthiest countries have the lowest burden from cirrhosis due to hepatitis C (Fig. 6).

      Alcohol

      The per capita alcohol consumption is 6.4 litres globally, up from 5.5 litres in 2005. The Middle East and Northern Africa have the lowest alcohol consumption, whereas consumption is highest in the European region.
      • Mellinger J.L.
      Epidemiology of alcohol use and alcoholic liver disease.
      Per capita consumption in Europe decreased from 12.1 litres in 2000 to 9.8 litres in 2016, but within Europe consumption has increased in the East and gone down in the South, and the pattern of drinking has generally shifted to earlier, heavier drinking.
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      • Webber L.
      • et al.
      Burden of liver disease in Europe: epidemiology and analysis of risk factors to identify prevention policies.
      The United Kingdom has received much attention for its increasing burden from alcohol, and efforts to counteract this,
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      • Negro F.
      • Corbould E.
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      • Webber L.
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      Burden of liver disease in Europe: epidemiology and analysis of risk factors to identify prevention policies.
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      Addressing liver disease in the UK: a blueprint for attaining excellence in health care and reducing premature mortality from lifestyle issues of excess consumption of alcohol, obesity, and viral hepatitis.
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      Incidence and prevalence of cirrhosis in the United Kingdom, 1992-2001: a general population-based study.
      while alcohol consumption has also increased in the Western Pacific and Southeast Asia regions.
      • Mellinger J.L.
      Epidemiology of alcohol use and alcoholic liver disease.
      In the United States, too, alcohol consumption has increased and shifted towards heavier drinking.
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      Epidemiology of DSM-5 alcohol use disorder: results from the national epidemiologic survey on alcohol and related conditions III.
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      Prevalence of 12-month alcohol use, high-risk drinking, and DSM-IV alcohol use disorder in the United States, 2001-2002 to 2012-2013: results from the national epidemiologic survey on alcohol and related conditions.
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      This has not increased the prevalence of alcoholic liver disease, which was stable at 8.1% to 8.8% of the total population between 2001 and 2016, but patients were more severely ill in later years. Thus, the prevalence of stage 3 or 4 fibrosis increased from 2.2% to 6.6%, and the prevalence of complications of cirrhosis grew in these patients as well.
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      There is a strong correlation between sociodemographic index and the proportion of alcohol drinkers. In the quintile of countries with the highest (the most favourable) sociodemographic index, 72% of women and 83% of men were current drinkers in 2016, compared with 9% of women and 20% of men in the quintile of countries with low-to-middle sociodemographic index.
      GBD 2016 Alcohol Collaborators
      Alcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease study 2016.
      This does not translate into an increasing age-standardised DALY rate from alcohol-related cirrhosis with increasing sociodemographic index, but it may explain why alcohol is the dominant aetiology of cirrhosis in affluent countries (Fig. 6).

      Non-alcoholic fatty liver disease

      Although NAFLD can occur in lean people, its prevalence correlates strongly with the prevalence of obesity and type 2 diabetes. NAFLD has a prevalence of 32% in the Middle East, 31% in South America, 27% in Asia, 24% in the United States, 23% in Europe, and 14% in Africa.
      • Younossi Z.
      • Anstee Q.M.
      • Marietti M.
      • Hardy T.
      • Henry L.
      • Eslam M.
      • et al.
      Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention.
      • Younossi Z.M.
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      Global epidemiology of nonalcoholic fatty liver disease - meta-analytic assessment of prevalence, incidence, and outcomes.
      • Younossi Z.M.
      Non-alcoholic fatty liver disease - a global public health perspective.
      The prevalence of cirrhosis among these patients is unclear, but the prevalence of NAFLD is increasing and will continue to do so. A modelling study predicted changes in the prevalence of NAFLD from 2016 to 2030 for 8 countries: China, Japan, United States, France, Germany, Italy, Spain, and United Kingdom.
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      The study predicted that the prevalence of NAFLD will increase in all countries, and the largest increase will come in China. Moreover, the number of patients with cirrhosis due to NAFLD will also increase in all countries, with the largest increase (156%) in France.

      Cirrhosis severity

      Compensated cirrhosis is associated with lower mortality and morbidity than decompensated cirrhosis. Studies have found that patients with alcohol-related cirrhosis have typically already decompensated when they are diagnosed with cirrhosis, whereas this is atypical for patients with cirrhosis from hepatitis B or C.
      • Dam Fialla A.
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      • Touborg Lassen A.
      Incidence, etiology and mortality of cirrhosis: a population-based cohort study.
      ,
      • Ratib S.
      • Fleming K.M.
      • Crooks C.J.
      • Aithal G.P.
      • West J.
      1 and 5 year survival estimates for people with cirrhosis of the liver in England, 1998-2009: a large population study.
      As a result, the prevalence of compensated cirrhosis is low in areas where alcohol is the most common aetiology of cirrhosis, if only diagnosed patients are counted. This will likely change with more widespread screening for liver disease in the community, e.g. with transient elastography.
      In the 2017 Global Burden of Disease study, the prevalence of compensated and decompensated cirrhosis was “modeled on the basis of hospital data and claims data”, and all hospitalised patients were assumed to be decompensated.
      GBD 2017 Cirrhosis Collaborators
      The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017.
      ,

      European Association for the Study of the Liver. HEPAHEALTH project report. Accessed 19 July 2020. Available from: https://easl.eu/publication/hepahealth-project-report/.

      The modelling gave age-standardised prevalence estimates indicating that, as a global average, 8.7% of patients with cirrhosis have decompensated cirrhosis, and there is little geographic variation.
      GBD 2017 Cirrhosis Collaborators
      The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017.
      Thus, the prevalence of cirrhosis is mainly attributable to compensated cirrhosis, but the vast majority of DALYs result from decompensated cirrhosis; this is because the disability attributed to compensated cirrhosis is zero, and the mortality from compensated cirrhosis is much lower than the mortality from decompensated cirrhosis.
      Cirrhosis was responsible for 26.8% fewer DALYs in 2019 than in 1990, but this was less than the 34.4% decline for all causes combined.

      The financial burden of cirrhosis

      The financial burden on societies depends on the prevalence of cirrhosis and the costs per patient with cirrhosis. The age-standardised prevalence of compensated cirrhosis increased from 1,355 per 100,000 population in 1990 to 1,395 per 100,000 in 2017. Concurrently, the age-standardised prevalence of decompensated cirrhosis increased from 111 to 133 per 100,000.
      GBD 2017 Cirrhosis Collaborators
      The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017.
      The prevalence is the product of cirrhosis incidence and survival time for patients with cirrhosis, and because they are both increasing,
      GBD 2017 Cirrhosis Collaborators
      The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017.
      ,
      • Deleuran T.
      • Vilstrup H.
      • Jepsen P.
      Decreasing mortality among Danish alcoholic cirrhosis patients: a nationwide cohort study.
      • Schmidt M.L.
      • Barritt A.S.
      • Orman E.S.
      • Hayashi P.H.
      Decreasing mortality among patients hospitalized with cirrhosis in the United States from 2002 through 2010.
      • McPhail M.J.W.
      • Parrott F.
      • Wendon J.A.
      • Harrison D.A.
      • Rowan K.A.
      • Bernal W.
      Incidence and outcomes for patients with cirrhosis admitted to the United Kingdom critical care units.
      • Majumdar A.
      • Bailey M.
      • Kemp W.M.
      • Bellomo R.
      • Roberts S.K.
      • Pilcher D.
      Declining mortality in critically ill patients with cirrhosis in Australia and New Zealand between 2000 and 2015.
      we can expect cirrhosis prevalence to continue its increase until we manage to curb the incidence. It is likely that we will see different time trends for different cirrhosis aetiologies. The prevalence of cirrhosis from hepatitis B and hepatitis C will decrease owing to the global efforts to eliminate them,

      World Health Organization. Global health sector strategy on viral hepatitis 2016-2021. Accessed 30 July 2020. Available from: https://www.who.int/hepatitis/strategy2016-2021/ghss-hep/en/.

      but the prevalence of cirrhosis from NAFLD will increase.
      A United States study found that the hospitalisation costs attributable to cirrhosis grew by 30% between 2008 and 2014. Costs attributable to compensated cirrhosis grew by 24%, while costs attributable to decompensated cirrhosis grew by 36%. The total costs attributable to decompensated cirrhosis were 63% higher than those for compensated cirrhosis.
      • Desai A.P.
      • Mohan P.
      • Nokes B.
      • Sheth D.
      • Knapp S.
      • Boustani M.
      • et al.
      Increasing economic burden in hospitalized patients with cirrhosis: analysis of a national database.
      It is overly simplistic to claim that the financial burden of cirrhosis will grow if the prevalence of cirrhosis continues to grow; patients with cirrhosis may require less treatment than today, or treatment may be cheaper. For example, when patients with cirrhosis from hepatitis C are treated with direct-acting antivirals, the prevalence of compensated cirrhosis goes up because patients live longer, but the total costs can go down because society does not have to pay to treat decompensated cirrhosis. More realistically, though, the total costs after introduction of a treatment do go up, but because patients live longer and better those costs are considered acceptable.
      • McEwan P.
      • Bennett H.
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      • Webster S.
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      • et al.
      The cost-effectiveness of daclatasvir-based regimens for the treatment of hepatitis C virus genotypes 1 and 4 in the UK.
      With respect to cirrhosis from NAFLD, the financial burden will almost certainly continue to increase until effective treatments emerge.
      • Allen A.M.
      • Van Houten H.K.
      • Sangaralingham L.R.
      • Talwalkar J.A.
      • McCoy R.G.
      Healthcare cost and utilization in nonalcoholic fatty liver disease: real-world data from a large U.S. Claims database.
      ,
      • Younossi Z.M.
      • Blissett D.
      • Blissett R.
      • Henry L.
      • Stepanova M.
      • Younossi Y.
      • et al.
      The economic and clinical burden of nonalcoholic fatty liver disease in the United States and Europe.

      How can we reduce the burden of cirrhosis?

      We can reduce the burden of cirrhosis by reducing the incidence of cirrhosis, by improving the quantity or quality of life for patients with cirrhosis, or by reducing the costs of treating cirrhosis. Many societies are willing to accept increased costs (or reduced income) to achieve one or more of the other goals.
      The burden of cirrhosis can be reduced by primary prevention, which involves societal measures to prevent development of cirrhosis. Examples of such efforts include minimum-pricing of alcohol,
      • Pimpin L.
      • Cortez-Pinto H.
      • Negro F.
      • Corbould E.
      • Lazarus J.V.
      • Webber L.
      • et al.
      Burden of liver disease in Europe: epidemiology and analysis of risk factors to identify prevention policies.
      ,
      • O'Donnell A.
      • Anderson P.
      • Jane-Llopis E.
      • Manthey J.
      • Kaner E.
      • Rehm J.
      Immediate impact of minimum unit pricing on alcohol purchases in Scotland: controlled interrupted time series analysis for 2015-18.
      • 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.

      World Health Organization. Alcohol policy impact case study: The effects of alcohol control measures on mortality and life expectancy in the Russian Federation. Accessed 30 July 2020. Available from: https://www.euro.who.int/en/publications/abstracts/alcohol-policy-impact-case-study-the-effects-of-alcohol-control-measures-on-mortality-and-life-expectancy-in-the-russian-federation-2019.

      vaccination for hepatitis B, and food labelling to prevent obesity.
      • Pimpin L.
      • Cortez-Pinto H.
      • Negro F.
      • Corbould E.
      • Lazarus J.V.
      • Webber L.
      • et al.
      Burden of liver disease in Europe: epidemiology and analysis of risk factors to identify prevention policies.
      Thus, primary prevention is in the domain of politicians. Secondary prevention means early detection of cirrhosis before it causes symptoms. Such efforts include transient elastography or similar testing of at-risk patients, e.g. patients with hazardous alcohol consumption,
      • 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).
      patients with known or suspected chronic viral hepatitis, and patients with type 2 diabetes and other features of the metabolic syndrome.
      • Pimpin L.
      • Cortez-Pinto H.
      • Negro F.
      • Corbould E.
      • Lazarus J.V.
      • Webber L.
      • et al.
      Burden of liver disease in Europe: epidemiology and analysis of risk factors to identify prevention policies.
      Finally, tertiary prevention involves reducing the incidence or impact of complications of cirrhosis – e.g. ascites, variceal bleeding, hepatic encephalopathy, hepatocellular carcinoma, and death – following diagnosis.

      Unmet needs

      Although the global number of DALYs attributable to cirrhosis per 100,000 population is decreasing, it is not decreasing as fast as for other diseases, hence the proportion of all DALYs that can be attributed to cirrhosis is going up.
      GBD 2019 Diseases and Injuries Collaborators
      Global burden of 369 diseases and injuries in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease study 2019.
      This observation suggests that we should do more to reduce the burden of cirrhosis, and indeed we can do more.
      With respect to hepatitis B, many interventions are known to be effective but are not implemented.
      • Palayew A.
      • Razavi H.
      • Hutchinson S.J.
      • Cooke G.S.
      • Lazarus J.V.
      Do the most heavily burdened countries have the right policies to eliminate viral hepatitis B and C?.
      Only 13% of children born to HBsAg-positive mothers receive hepatitis B immunoglobulin and timely birth-dose and follow-up vaccination;
      The Polaris Observatory Collaborators
      Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study.
      only around 10% of the 292 million people believed to be infected are diagnosed;
      The Polaris Observatory Collaborators
      Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study.
      and only around 5% of the 94 million people eligible for treatment are treated.
      The Polaris Observatory Collaborators
      Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study.
      The WHO aims to diagnose 90% of people infected with hepatitis B by 2030, and to treat 80% of those eligible for treatment.

      World Health Organization. Global health sector strategy on viral hepatitis 2016-2021. Accessed 30 July 2020. Available from: https://www.who.int/hepatitis/strategy2016-2021/ghss-hep/en/.

      This will require large increases in screening and treatment in most countries; the greatest improvements so far have been in infant vaccination.
      The Polaris Observatory Collaborators
      Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: a modelling study.
      With respect to hepatitis C, primary prevention includes measures to reduce transmission such as screening of blood products and access to sterile needles; another major step is to find and treat patients who are already infected.
      • Palayew A.
      • Razavi H.
      • Hutchinson S.J.
      • Cooke G.S.
      • Lazarus J.V.
      Do the most heavily burdened countries have the right policies to eliminate viral hepatitis B and C?.
      The WHO has a goal to reduce new viral hepatitis infections by 90% and deaths from hepatitis C by 65% by 2030.

      World Health Organization. Global health sector strategy on viral hepatitis 2016-2021. Accessed 30 July 2020. Available from: https://www.who.int/hepatitis/strategy2016-2021/ghss-hep/en/.

      This goal has been met in many areas, but not all.
      Alcohol consumption can be reduced by increasing alcohol taxation and by reducing access to alcohol, but such policies may be unpopular and opposed by the alcohol industry. Thus, whereas no one opposes primary prevention of viral hepatitis infection, this is quite different for alcohol, resulting in an occasional unmet need of the political will to take effective steps.
      • 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.
      ,
      • Williams R.
      • Aithal G.
      • Alexander G.J.
      • Allison M.
      • Armstrong I.
      • Aspinall R.
      • et al.
      Unacceptable failures: the final report of the Lancet commission into liver disease in the UK.
      With respect to secondary prevention, there is still no evidence from randomised trials that screening for alcohol-related liver disease reduces the burden of cirrhosis, but there is weaker evidence that it does.
      • 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).
      ,
      • Eyles C.
      • Moore M.
      • Sheron N.
      • Roderick P.
      • O'Brien W.
      • Leydon G.M.
      Acceptability of screening for early detection of liver disease in hazardous/harmful drinkers in primary care.
      ,
      • Burton R.
      • Sheron N.
      Missed opportunities for intervention in alcohol-related liver disease in the UK.
      Moreover, it may be difficult to have the at-risk population referred from the primary care physician to the screening examination; treatment of alcohol use disorder is too often considered futile, and there is an unmet need for better treatments, particularly ones that can be offered to patients with liver disease.
      • Addolorato G.
      • Mirijello A.
      • Barrio P.
      • Gual A.
      Treatment of alcohol use disorders in patients with alcoholic liver disease.
      There is substantial global variation in the burden and causes of cirrhosis. Generally, the burden is lower in more affluent countries owing primarily to their smaller burden of hepatitis B.
      Primary prevention of NAFLD includes policy actions to reduce obesity, e.g. through taxation of fat content or restriction on marketing of fatty foods.
      • Williams R.
      • Aithal G.
      • Alexander G.J.
      • Allison M.
      • Armstrong I.
      • Aspinall R.
      • et al.
      Unacceptable failures: the final report of the Lancet commission into liver disease in the UK.
      This can be supplemented with information campaigns promoting physical exercise and a diet low in fat and fructose. Secondary prevention, screening patients for fatty liver disease, may be successful in preventing cirrhosis, but due to the sheer volume of obese patients the question is who to screen.

      Areas of controversy

      There is controversy over many primary, secondary, and tertiary interventions to reduce the burden of cirrhosis because of the lack of evidence from randomised trials, but we will highlight a couple of controversies that are relevant for future studies on the burden of cirrhosis.

      Does the DALY concept underestimate the burden of cirrhosis?

      The DALY is the sum of years of healthy life lost plus years lived with disability. For cirrhosis, the years lived with disability contribute virtually nothing to the DALY because the disability weight of decompensated cirrhosis is very small, and compensated cirrhosis does not count as disability at all.
      GBD 2017 Cirrhosis Collaborators
      The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017.
      As stated in the introduction, that conclusion is at odds with research findings and clinical experience.
      The disability weights are based on surveys of the general public, and respondents were asked which of 2 individuals they would consider to be healthier.
      • Salomon J.A.
      • Haagsma J.A.
      • Davis A.
      • de Noordhout C.M.
      • Polinder S.
      • Havelaar A.H.
      • et al.
      Disability weights for the global burden of disease 2013 study.
      For that purpose, patients with decompensated cirrhosis were described to the layperson as “a person with a swollen belly and swollen legs. The person feels weakness, fatigue, and loss of appetite”.
      GBD 2017 Disease and Injury Incidence and Prevalence Collaborators
      Global, regional, and national incidence, prevalence, and years lived with disability for 354 diseases and injuries for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017.
      The disability weight is higher for ‘severe low back pain without leg pain’ (0.272 vs. 0.178 for decompensated cirrhosis), which is described like this: “This person has severe back pain, which causes difficulty dressing, sitting, standing, walking, and lifting things. The person sleeps poorly and feels worried.” Compare now with the markedly lower disability weight of 0.054 for ‘moderate low back pain’: “This person has severe back pain, which causes difficulty dressing, sitting, standing, walking, and lifting things.” For a clinical hepatologist it is difficult to accept that the disability associated with decompensated cirrhosis is midway between moderate and severe low back pain, and many of our patients certainly have to deal with worry and poor sleep, e.g. due to pruritus and muscle cramps.
      • Marchesini G.
      • Bianchi G.
      • Amodio P.
      • Salerno F.
      • Merli M.
      • Panella C.
      • et al.
      Factors associated with poor health-related quality of life of patients with cirrhosis.
      Higher, more realistic, disability weights would increase the burden of cirrhosis in the Global Burden of Disease studies. With the 2019 study, the Global Burden of Disease investigators have stratified the disability weight for decompensated cirrhosis according to the severity of anaemia, so that patients with decompensated cirrhosis and severe anaemia have a disability weight of 0.178 for decompensated cirrhosis plus 0.122 for severe anaemia for a total of 0.300. Less severe anaemia adds 0.003 (mild anaemia) or 0.042 (moderate anaemia) to the 0.178 for decompensated cirrhosis. This principle might be expanded, so that alcohol-related cirrhosis is given a disability weight that is the sum of the disability weight for cirrhosis and the disability weight for alcohol use disorder, which ranges from 0.123 (very mild), over 0.235 (mild), and 0.373 (moderate), to 0.570 (severe). Another possibility is to consider health-state utilities instead of disability weights. A recent United States study developed health-state utilities for cirrhosis with 2 different methods, both ranging from 0 to 1, with 1 representing optimal health:
      • Foster C.
      • Baki J.
      • Nikirk S.
      • Williams S.
      • Parikh N.D.
      • Tapper E.B.
      Comprehensive health-state utilities in contemporary patients with cirrhosis.
      with the standard gamble method, health-utilities ranged from 0.85 in Child-Pugh A (compensated) to 0.78 in Child-Pugh C (decompensated), whereas with the visual-analogue scale method they ranged from 0.70 in Child-Pugh A to 0.55 in Child-Pugh C.
      The Global Burden of Disease studies do not attribute deaths from hepatocellular carcinoma to cirrhosis although the majority of hepatocellular carcinomas develop in patients with cirrhosis.
      GBD 2017 Cirrhosis Collaborators
      The global, regional, and national burden of cirrhosis by cause in 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease study 2017.
      Thus, a substantial proportion of the 151.1 age-standardised DALYs per 100,000 population lost to liver cancer might have been added to the 560.4 DALYs per 100,000 lost to cirrhosis.

      Will a change of names make it more difficult to study cirrhosis?

      NAFLD was introduced as a separate cause of cirrhosis in the 2017 Global Burden of Disease study. Recently, an international consensus panel proposed a name change to metabolic dysfunction-associated fatty liver disease (MAFLD) and a different set of diagnostic criteria.
      • Eslam M.
      • Newsome P.N.
      • Sarin S.K.
      • Anstee Q.M.
      • Targher G.
      • Romero-Gomez M.
      • et al.
      A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement.
      ,
      • Eslam M.
      • Sanyal A.J.
      • George J.
      • International Consensus P.
      MAFLD: a consensus-driven proposed nomenclature for metabolic associated fatty liver disease.
      The proposal also included a definition of ‘dual aetiology fatty liver disease’ covering fatty liver disease that meets the criteria for MAFLD plus the criteria for another liver disease, e.g. alcohol-related liver disease or viral hepatitis.
      • Eslam M.
      • Newsome P.N.
      • Sarin S.K.
      • Anstee Q.M.
      • Targher G.
      • Romero-Gomez M.
      • et al.
      A new definition for metabolic dysfunction-associated fatty liver disease: an international expert consensus statement.
      Because of the high prevalence of MAFLD, such a change will have a profound impact on epidemiologic studies of cirrhosis. Patients with MAFLD have been found to be older and have more severe metabolic comorbidities than patients with NAFLD,
      • Lin S.
      • Huang J.
      • Wang M.
      • Kumar R.
      • Liu Y.
      • Liu S.
      • et al.
      Comparison of MAFLD and NAFLD diagnostic criteria in real world.
      and what we currently describe as alcohol-related cirrhosis or cirrhosis due to viral hepatitis may come to be categorised as dual aetiology cirrhosis. Such changes will disrupt studies of time trends, including the analyses of DALYs attributable to various cirrhosis aetiologies in the Global Burden of Disease studies. Other arguments against the proposed name change have been put forward, chiefly concerns that it will stunt ongoing development of drugs to treat NAFLD, require new regulatory pathways, and sever ties to neighbouring disciplines, e.g. endocrinology.
      • Younossi Z.M.
      • Rinella M.E.
      • Sanyal A.
      • Harrison S.A.
      • Brunt E.
      • Goodman Z.
      • et al.
      From NAFLD to MAFLD: implications of a premature change in terminology.
      In the long run, the idea of naming a disease according to the presence or absence of 1 causal risk factor is untenable, but that it is what we do when we speak of “alcohol-related cirrhosis”, “cirrhosis from hepatitis C”, or “cirrhosis from non-alcoholic fatty liver disease”. Our understanding of the causes of cirrhosis and their interaction will evolve, and we will need new names for new ‘types of cirrhosis’ again. The field will need to discuss naming conventions for multi-cause cirrhosis.

      Abbreviations

      DALY(s), disability-adjusted life-year(s); MAFLD, metabolic dysfunction-associated fatty liver disease; NAFLD, non-alcoholic fatty liver disease; QALY(s), quality-adjusted life-year(s); WHO, World Health Organization; YLD, years of life lived with disability; YLL, years of life lost due to premature death.

      Financial support

      PJ was supported by a grant from the Novo Nordisk Foundation (NNF18OC0054612). The funding organization was not involved in the conception, the writing, or the decision to submit the manuscript for publication.

      Authors’ contributions

      Peter Jepsen drafted the manuscript. Both authors revised and edited the manuscript for content.

      Conflict of interest

      ZMY has served as consultant and or received research funds from Intercept, NovoNordisk, Gilead, BMS, Abbott, Siemens, Terns, Merck, Madrigal and Axcella. PJ reports grants from Novo Nordisk Foundation, during the conduct of the study.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Appendix A. Supplementary data

      The following is/are the supplementary data related to this article:

      Transparency declaration

      This article is published as part of a supplement entitled New Concepts and Perspectives in Decompensated Cirrhosis. Publication of the supplement was supported financially by CSL Behring. The sponsor had no involvement in content development, the decision to submit the manuscript or in the acceptance of the manuscript for publication.

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