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Applying an equity lens to liver health and research in Europe

  • Meritxell Ventura-Cots
    Affiliations
    Liver Unit, Vall d’Hebron University Hospital, Barcelona, Spain

    Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Campus Hospitalari, Barcelona, Spain

    Centro de Investigación Biomédica en Red de enfermedades digestivas y hepáticas (CIBERehd), Madrid, Spain
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  • Ramon Bataller
    Affiliations
    Center for Liver Diseases, Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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  • Jeffrey V. Lazarus
    Affiliations
    Barcelona Institute for Global Health (ISGlobal), Hospital Clínic, University of Barcelona, Barcelona, Spain

    Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain

    CUNY Graduate School of Public Health and Health Policy, NY, New York, USA
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  • Joan Benach
    Affiliations
    Research Group on Health Inequalities, Environment, and Employment Conditions (GREDS-EMCONET), Universitat Pompeu Fabra, Barcelona, Spain

    Johns Hopkins University-Universitat Pompeu Fabra Public Policy Center (UPF-BSM), Barcelona, Spain

    Ecological Humanities Research Group (GHECO), Universidad Autónoma de Madrid, Madrid, Spain
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  • Juan M. Pericàs
    Correspondence
    Corresponding author. Address: Liver Unit, Vall d’Hebron University Hospital, Vall d’Hebron Institut de Recerca (VHIR), Barcelona, Spain.
    Affiliations
    Liver Unit, Vall d’Hebron University Hospital, Barcelona, Spain

    Vall d’Hebron Institut de Recerca (VHIR), Vall d’Hebron Barcelona Campus Hospitalari, Barcelona, Spain

    Centro de Investigación Biomédica en Red de enfermedades digestivas y hepáticas (CIBERehd), Madrid, Spain

    Johns Hopkins University-Universitat Pompeu Fabra Public Policy Center (UPF-BSM), Barcelona, Spain
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Published:August 16, 2022DOI:https://doi.org/10.1016/j.jhep.2022.07.021

      Summary

      Liver disease is a major cause of premature death and disability in Europe. However, morbidity and mortality are not equally distributed in the population. In spite of this, there are few studies addressing the issue of health inequalities in Europe. In this Public Health Corner article, we compare the research conducted on health inequalities in Europe to other settings and highlight the main differences based upon an extensive review of the literature. We report that only 10.2% of studies were led by European institutions or conducted in European populations and that certain topics such as alcohol-related liver disease are largely overlooked. In addition, we discuss the relevance of including a health equity lens when conducting clinical, epidemiological and health systems’ research in liver disease and set out the basic requirements to tackle health inequalities in liver disease in Europe.

      The key importance of health inequalities research

      Why should liver disease scholars and practitioners be concerned about health inequalities?

      The high and growing prevalence of non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC), the high rates of late diagnosis and underdiagnosis of advanced liver disease, and the substantial impact of cirrhosis in lost working years in Europe, as recently highlighted by the European Association for the Study of the Liver (EASL)-Lancet Liver Commission,
      • Karlsen T.H.
      • Sheron N.
      • Zelber-Sagi S.
      • Carrieri P.
      • Dusheiko G.
      • Bugianesi E.
      • et al.
      The EASL-Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality.
      are well established. However, many researchers and practitioners often focus on one aspect of the impact of liver disease (e.g., clinical aspects), frequently neglecting the underlying causes of differences in the population.
      Such inequalities affect how we promote health, prevent or diagnose disease, care for, treat or even palliate many health conditions including liver disease. One clear example concerning liver disease is alcohol-related deaths, which have been steadily increasing in the US over the last decade as part of what has been called “deaths of despair” (drug overdose, alcohol-related disease and suicide).
      • Tilstra A.M.
      • Simon D.H.
      • Masters R.K.
      Trends in "deaths of despair" among working-aged White and Black Americans, 1990-2017.
      Alcohol-related deaths grew even more during the first 2 years of the COVID-19 pandemic.
      • White A.M.
      • Castle I.P.
      • Powell P.A.
      • Hingson R.W.
      • Koob G.F.
      Alcohol-related deaths during the COVID-19 pandemic.
      Tapper et al. recently provided another example of health inequalities with their study on ethnic disparities in rifaximin use and subspecialty referral for patients with hepatic encephalopathy.
      • Tapper E.B.
      • Essien U.R.
      • Zhao Z.
      • Ufere N.N.
      • Parikh N.D.
      Racial and ethnic disparities in rifaximin use and subspecialty referrals for patients with hepatic encephalopathy in the United States.
      In this Public Health Corner, we report on how research on health inequalities in liver disease has evolved during recent decades and how well-equipped Europe is to tackle this serious challenge.

      Origins of health inequalities research

      Although studies addressing differences in health and disease derive from the 17th century, widespread interest in social determinants of health and inequalities only peaked in the mid-19th century in Europe, with the work of Villermé in Paris, Virchow in Berlin, and Chadwik in Manchester.
      • Berkman L.F.
      • Kawachi I.
      A historical framework for social epidemiology: social determinants of population health.
      A major difference between scholars today is the more common use of the term “disparities” by North American scholars and “inequalities” or “inequities” by Europeans. Whereas “disparities” might be restricted to social or geographic variations, “inequality” and especially “equity” refer not only to simple differences in health outcomes and risk factors, but also to their underlying social causes and the unfair and avoidable unequal distribution of a certain risk factor, condition or disease among the social groups that make up a population. One example of disparity restricted to mere variations is that waiting lists for liver transplantation might differ according to the underlying liver disease. A more comprehensive and realistic approach will use the terms inequalities or inequities, since in addition to looking at the type of disease under analysis, it will also provide information on the mechanisms leading to such inequalities, such as the interactions between social determinants, and the intersection across axes of inequality (intersectional approach).
      • Holman D.
      • Salway S.
      • Bell A.
      • Beach B.
      • Adebajo A.
      • Ali N.
      • et al.
      Can intersectionality help with understanding and tackling health inequalities? Perspectives of professional stakeholders.
      The influential framework proposed by the World Health Organization Commission on Social Determinants of Health
      • Marmot M.
      • Friel S.
      • Bell R.
      • Houweling T.A.
      • Taylor S.
      Commission on Social Determinants of Health
      Closing the gap in a generation: health equity through action on the social determinants of health.
      served as the basis for inequalities’ research over the past 15 years (Fig. 1).
      Figure thumbnail gr1
      Fig. 1Conceptual framework to address social determinants of health and health inequalities inspired by the World Health Organization (WHO) Commission.
      Adapted from WHO, 2008.
      • Marmot M.
      • Friel S.
      • Bell R.
      • Houweling T.A.
      • Taylor S.
      Commission on Social Determinants of Health
      Closing the gap in a generation: health equity through action on the social determinants of health.
      In 2008, the WHO Commission on Social Determinants of Health presented a Conceptual Framework for Action on the Social Determinants of Health. Many earlier models followed a biomedical health paradigm, emphasising the importance of health care, lifestyles and biological factors. Instead, the Social Determinants of Health model shows how social, economic, and political factors influence a person's socioeconomic position which, in turn, plays a key role in determining health outcomes. A first element of the model is the socioeconomic political context, which refers to a series of collective political, economic and cultural collective factors, which are immeasurable at the individual level. These structural determinants reinforce social inequalities in society and can also define individual socioeconomic position (for example, social class, ethnicity/race, sex, age, or the territory where we live). In turn, these socioeconomic positions affect people’s specific intermediary determinants or “social determinants of health”, that is, the material circumstances in which we live, work and grow (for example, residential environment, employment and working conditions, income, housing), which affect the psychosocial factors (for example, stressful living circumstances or social isolation), and behaviours and biological factors (for example, nutrition, physical activity and alcohol consumption), which ultimately lead to poor and unequal health and well-being. All of these determinants exert some level of influence on another important determinant, namely the healthcare system itself.

      How do liver disease and inequality interact?

      Inequality is one of the main contributors to liver disease and a key player in conditions such as alcohol-related liver disease (ALD). Inequality plays a dual role impacting both the aetiologic agents that lead to the development of the disease as well as the access to proper medical and social resources (see Fig. 2). The impact of inequality on liver disease is not a direct one but rather the interaction of multiples factors that might act synergistically and have delayed and multi-layered effects on how liver disease is distributed across populations and how it affects some groups and individuals more severely than others (Table 1).
      Figure thumbnail gr2
      Fig. 2Interaction between alcohol consumption, alcohol-related liver disease and aetiological determinants including inequality factors.
      Table 1Examples of the impact of inequality in liver disease.
      TopicAxes of inequality/social determinants more frequently assessedExamplesPotential actions
      Chronic liver disease/cirrhosisSocioeconomic position, including education, type of employment and income, and geographical setting.In Barcelona (Spain), from 1992 to 2004, inequalities in cirrhosis mortality were observed in relationship to individual and area socioeconomic levels, with the highest death rates among those with lowest educational level and in socioeconomically deprived areas.
      • Dalmau-Bueno A.
      • García-Altés A.
      • Marí-Dell'olmo M.
      • Pérez K.
      • Espelt A.
      • Kunst A.E.
      • et al.
      Trends in socioeconomic inequalities in cirrhosis mortality in an urban area of Southern Europe: a multilevel approach.


      In Australia, manual workers were found to have consistently experienced cirrhosis mortality rates ≥2-folder higher than the rate experienced by non-manual workers.
      • Najman J.M.
      • Williams G.M.
      • Room R.
      Increasing socioeconomic inequalities in male cirrhosis of the liver mortality: Australia 1981-2002.


      In Denmark, 5-year survival was higher for married patients with cirrhosis than for those who never married or were divorced, but after adjustment only divorced patients had poorer survival than married patients (aHR 1.22; 95% CI 1.04-1.42). Five-year survival was lower for disability pensioners than for employed or unemployed patients (aHR 1.35; 95% CI 1.09-1.66).
      • Jepsen P.
      • Vilstrup H.
      • Andersen P.K.
      • Sørensen H.T.
      Socioeconomic status and survival of cirrhosis patients: a Danish nationwide cohort study.
      Local, national and regional databases systematically collecting information on chronic liver disease, including sociodemographic variables at the individual and area levels.

      Educational campaigns targeting specific populations at higher risk of cirrhosis from early ages.

      Implement reach out programmes for early diagnosis of liver disease in subpopulations at higher risk due to social determination, e.g. employment-related screening programmes of chronic liver disease and risk factors that are tailored according to occupational social class.
      Liver transplantationGeographic variability, MELD score, type of liver diseaseFollowing the introduction of the MELD score to the liver transplantation allocation system in 2002, race was no longer associated with receipt of a liver transplant or death on the waiting list, but disparities based on sex remain (i.e., women were less likely to be transplanted) in the US.
      • Moylan C.A.
      • Brady C.W.
      • Johnson J.L.
      • Smith A.D.
      • Tuttle-Newhall J.E.
      • Muir A.J.
      Disparities in liver transplantation before and after introduction of the MELD score.


      With US data from 2002 to 2016, Black patients were significantly more likely to undergo liver transplant due to acute liver failure than white patients (HR 1.20; 95% CI 1.08-1.30). There was no difference in wait-list removal because of death or clinical deterioration among racial/ethnic groups. Meanwhile, 1-year post-transplant survival was lowest in Black patients (79.6%) vs. White (82.8%), Hispanic (83.9%), and Asian (89.3%) patients (p = 0.02).
      • Nephew L.
      • Zia Z.
      • Ghabril M.
      • Orman E.
      • Lammert C.
      • Chalasani N.
      Black adult patients with acute liver failure are sicker and more likely to undergo liver transplantation than white patients.
      Studies needed on the impact of social determinants and inequalities of early transplantation for alcoholic hepatitis, as well as wait-list drop out and post-transplant outcomes of patients with morbid obesity and opioid use.

      Surveys and training programmes for healthcare professionals involved in liver transplantation regarding preconceptions on how sex, ethnicity, healthcare coverage, prior alcohol consumption, morbid obesity, etc. affect post-transplant outcomes. Debunk myths with quality data.
      Viral hepatitisAccess to treatment according to geographical setting, health systems and ethnicity and sexSocioeconomically marginalised individuals were significantly less likely (aOR 0.71; 95% CI 0.58-0.87) to receive direct-acting antivirals to treat hepatitis C in British Columbia (Canada).
      • Janjua N.Z.
      • Islam N.
      • Wong J.
      • Yoshida E.M.
      • Ramji A.
      • Samji H.
      • et al.
      Shift in disparities in hepatitis C treatment from interferon to DAA era: a population-based cohort study.


      Amongst 22,283 Chinese adults aged 18-59 years, the coverage rate of HBV vaccination and the completion rate were 20.2% and 16.0%, respectively in 2017. Amongst analysed factors, household income contributed the largest percentage to observed inequalities (52.17% for at least 1 dose and 52.03% for complete vaccinations).
      • Zhu D.
      • Guo N.
      • Wang J.
      • Nicholas S.
      • Wang Z.
      • Zhang G.
      • et al.
      Socioeconomic inequality in Hepatitis B vaccination of rural adults in China.
      Viral hepatitis elimination plans, either at the national level or focused on vulnerable populations (i.e., micro-elimination) should be designed with equity of access and outcomes as a pillar.

      Vulnerable populations (e.g., sub-Saharan migrants with chronic hepatitis B infection) should be systematically screened and actively engaged in treatment and follow-up.
      ALDSocioeconomic position, including education and income, and deprivation.Hospital admissions related to ALD significantly increased in England from 2002 to 2014, particularly concentrated in middle-aged males and deprived areas.
      • Green M.A.
      • Strong M.
      • Conway L.
      • Maheswaran R.
      Trends in alcohol-related admissions to hospital by age, sex and socioeconomic deprivation in England, 2002/03 to 2013/14.


      Danish citizens with the lowest education attainment presented 5-fold higher incidence of ALD.
      • Askgaard G.
      • Fleming K.M.
      • Crooks C.
      • Kraglund F.
      • Jensen C.B.
      • West J.
      • et al.
      Socioeconomic inequalities in the incidence of alcohol-related liver disease: a nationwide Danish study.


      The increase in liver-related mortality occurring at a global level between 1985 and 2015 was strongly associated with high levels of alcohol consumption as well as indicators of national wealth and government health expenditure on health.
      • Li W.
      • Kemos P.
      • Salciccioli J.D.
      • Marshall D.C.
      • Shalhoub J.
      • Alazawi W.
      Socioeconomic factors associated with liver-related mortality from 1985 to 2015 in 36 developed countries.
      Awareness campaigns on the harmful effects of alcohol consumption should be deployed from early ages in schools, particularly those located in socially deprived areas.

      Increase taxation on alcoholic products considering how social marketing has targeted segments of the population based on income, cultural aspects and type of employment, among other factors.

      Increase taxes or fine bars and restaurants that include alcoholic beverages in day-to-day menus served in blue collar areas
      Liver cancerAccess to treatment according to sex, ethnicity and socioeconomic statusA meta-analysis found that elderly, non-Caucasians and patients of low socioeconomic status had lower treatment rates for HCC than their counterparts in the US.
      • Tan D.
      • Yopp A.
      • Beg M.S.
      • Gopal P.
      • Singal A.G.
      Meta-analysis: underutilisation and disparities of treatment among patients with hepatocellular carcinoma in the United States.


      Hepatitis C-positive Black patients develop HCC at earlier stages of liver disease and present with a more aggressive phenotype.
      • Shaltiel T.
      • Zheng S.
      • Siderides C.
      • Gleeson E.M.
      • Carr J.
      • Pletcher E.R.
      • et al.
      Hepatitis C-positive Black patients develop hepatocellular carcinoma at earlier stages of liver disease and present with a more aggressive phenotype.
      Besides the underlying aetiology and stage of advanced liver disease, consider socioeconomic and cultural variables to design HCC surveillance strategies.

      Ensure that no patient is denied HCC treatment for reasons other than those related to the stage of the disease, including both medical treatment, locoregional techniques and liver transplantation.
      NAFLDSex, ethnicityMales were found to have a higher NAFLD prevalence in the US, while women have an overall higher burden of advanced liver disease and complications, whereas they are less likely to be transplanted once cirrhosis develops. In the US, the Hispanic population had the highest NAFLD prevalence and poorer outcomes, whereas Whites had fewer complications than other ethnicities. Patients with low socioeconomic status had higher NAFLD prevalence and a higher likelihood of progression and complications.
      • Talens M.
      • Tumas N.
      • Lazarus J.V.
      • Benach J.
      • Pericàs J.M.
      What do we know about inequalities in NAFLD distribution and outcomes? A scoping review.
      Educational programmes delivered at schools on the harms of a sedentary lifestyle on fat-rich sugar-rich diets, including a clear portrayal of obesity as a disease.

      Obesity should be tackled by community health programmes in which parents are engaged.

      The information provided to patients on the disease prognosis and related risk factors should avoid victim blaming while ensuring both individual and system-level resources are enacted regardless of education, sex, socioeconomic status or religious beliefs.

      Patient associations and investigators should ensure that the most affected populations are properly represented in clinical trial enrolment strategies.
      Autoimmune hepatitisEthnicity/race, sexIn a study conducted in the San Francisco area (US), Black (OR 9.6, 95% CI 1.8-178), Latino (OR 25.0, 95% CI 5.3-448), and Asian/Pacific Islander (OR 10.8, 95% CI 2.2-196) race/ethnicity were associated with increased odds of an AIH diagnosis compared to the White reference group.
      • Lee B.
      • Holt E.W.
      • Wong R.J.
      • Sewell J.L.
      • Somsouk M.
      • Khalili M.
      • et al.
      Race/ethnicity is an independent risk factor for autoimmune hepatitis among the San Francisco underserved.
      Further studies are needed on inequalities in AIH in areas other than some US states.

      Aspects such as treatment related-toxicity or response according to ethnicity or socioeconomic status require further exploration.
      AIH, autoimmune hepatitis; aHR, adjusted hazard ratio; ALD, alcohol-related liver disease; aOR, adjusted odds ratio; HCC, hepatocellular carcinoma; HR, hazard ratio; MELD, model for end-stage liver disease; NAFLD, non-alcoholic fatty liver disease; OR, odds ratio.

      What is the current status of health inequalities research in liver disease?

      Literature search

      We performed a literature search (details in the supplementary methods) including articles addressing health disparities/inequalities in liver disease from PubMed inception in 1966 to June 7, 2022. The initial search retrieved 474 entries, and after excluding 7 duplicate studies and 164 out-of-scope studies, a total of 303 studies were analysed.

      Summary of findings

      We found striking results (Fig. 3): first, no articles published before the 2000s were retrieved; second, relatively few articles addressing inequalities in liver disease were found; third, most articles have been published over the last 5 years; fourth, most articles adopted a reductionistic disparities approach where only simple quantitative differences are described; fifth, only 16.1% of the studies were carried out in non-US institutions, and amongst North American studies only 2.4% were from Canada; sixth, European studies represented 10.2% of overall publications (Fig. 4), and no collaborative studies between European and North American institutions were found; seventh, most of the studies that did not address either clinical aspects nor treatment access issues were carried out by general epidemiologists or scholars, rather than liver disease specialists; and lastly, only 7.6% of studies tackled ALD inequalities.
      Figure thumbnail gr3
      Fig. 3Studies on health inequalities in liver disease 2000-2022.
      Three hundred and three studies were categorised according to: (A) Region of origin and main topic addressed; (B) Year of publication and main liver topic addressed; (C) Type of research approach; and (D) Axes of inequality addressed. ∗ Socioeconomic position includes social class, income and education. CLD, chronic liver disease; HCC, hepatocellular carcinoma; LT, liver transplantation; NAFLD, non-alcoholic fatty liver disease.
      Figure thumbnail gr4
      Fig. 4Worldwide geographical distribution of liver health inequalities research by authors’ country of origin.

      Inequalities by liver disease

      Some examples of the impact of inequality on each type of liver disease are shown in Table 1. The main findings are summarised in Box 1.
      Disparities in liver health inequalities research: A snapshot.
      The most addressed liver disease topic in the studies retrieved from the literature search is liver transplantation (38% of overall articles), in particular the inequalities derived from the use of prioritisation rules and scores, such as the model for end-stage liver disease score, and variations in policies across US states, e.g. concerning organ allocation. In short, although many studies have investigated the frequency and impact of inequalities on liver transplantation, this is likely the clearest example of a topic that has been largely addressed from a “disparities” perspective, where the mechanisms of inequalities have often been overlooked. While a number of studies in the US have tackled relevant factors such as the organisation of healthcare systems, ethnicity, sex or geographically driven (e.g., urban-rural) disparities, few articles were found on other relevant fields of inequality concerning liver transplantation, such as early liver transplantation for alcoholic hepatitis, and transplantation for people who inject drugs or those living with morbid obesity. Unconscious and conscious bias might have contributed to the lack of attention to certain subpopulations. In the current scenario, with the increasing burden of non-alcoholic steatohepatitis as a leading cause of transplantation,
      • Younossi Z.M.
      • Stepanova M.
      • Ong J.
      • Trimble G.
      • AlQahtani S.
      • Younossi I.
      • et al.
      Nonalcoholic steatohepatitis is the most rapidly increasing indication for liver transplantation in the United States.
      the opioid crisis continuing to rage in the US,
      • Verna E.C.
      • Schluger A.
      • Brown Jr., R.S.
      Opioid epidemic and liver disease.
      and compelling evidence showing favourable outcomes of early liver transplantation for alcoholic hepatitis,
      • Louvet A.
      • Labreuche J.
      • Moreno C.
      • Vanlemmens C.
      • Moirand R.
      • Féray C.
      • et al.
      Early liver transplantation for severe alcohol-related hepatitis not responding to medical treatment: a prospective controlled study.
      these specific subpopulations receive little attention from an inequalities perspective. For instance, there is scarce data on sociocultural determinants and inequalities underlying denial of early liver transplantation for patients with ALD at high risk of alcohol recidivism. Thus, the role of socioeconomic factors, ethnicity, type of health coverage, migrant status or the existence of policies and programmes supporting alcohol cessation, social and employment reintegration on the likelihood of patients with alcoholic hepatitis being selected as candidates for early transplantation has not been adequately addressed. Similarly, social factors that contribute to the deleterious effects of opioids on outcomes after liver transplantation are largely unknown.
      • Braun H.J.
      • Schwab M.P.
      • Jin C.
      • Amara D.
      • Mehta N.J.
      • Grace T.R.
      • et al.
      Opioid use prior to liver transplant is associated with increased risk of death after transplant.
      Obesity is associated with both area-level determinants such as poverty, food insecurity, and lack of green spaces and public transportation, as well as individual level determinants (e.g., educational attainment, income and cultural aspects affecting diet and exercise).
      • Cockerham W.C.
      Theoretical approaches to research on the social determinants of obesity.
      Recent studies have shown that morbid obesity increases the likelihood of being delisted from the liver transplant waiting list.
      • Kaur N.
      • Emamaullee J.
      • Lian T.
      • Lo M.
      • Ender P.
      • Kahn J.
      • et al.
      Impact of morbid obesity on liver transplant candidacy and outcomes: national and regional trends.
      ,
      • Delacôte C.
      • Favre M.
      • El Amrani M.
      • Ningarhari M.
      • Lemaitre E.
      • Ntandja-Wandji L.C.
      • et al.
      Morbid obesity increases death and dropout from the liver transplantation waiting list: a prospective cohort study.
      Whether socioeconomic factors influence this finding should be investigated.
      Top viral hepatitis subjects are foremost access to hepatitis C treatment (direct-acting antiviral agents) and secondly hepatitis A and B vaccination. Studies addressing viral hepatitis cover a wide range of axes of inequality (from access to treatment to the impact of ethnic and geographical disparities) and approaches (from clinically oriented studies addressing the suitability of available treatments according to HCV genotype to public health approaches based on micro-elimination of HCV in vulnerable populations and national strategies against viral hepatitis).
      The topics that have recently experienced a greater boost in publications are NAFLD and HCC. In HCC, a strong emphasis on access to treatment prevailed, either medical, surgical and locoregional therapies, or liver transplantation.
      As for NAFLD, in a previous study
      • Talens M.
      • Tumas N.
      • Lazarus J.V.
      • Benach J.
      • Pericàs J.M.
      What do we know about inequalities in NAFLD distribution and outcomes? A scoping review.
      we found that very few studies investigating socioeconomic determinants of health and inequality on NAFLD had been published, almost all of them in the US, where Hispanic ethnicity has been associated with a higher prevalence of NAFLD and poorer outcomes and female sex has been associated with a lower chance of receiving a liver transplant once cirrhosis develops. Moreover, low socioeconomic status was associated with a higher NAFLD prevalence (4 articles) and a higher likelihood of progression and complications.
      Amongst the few articles focusing on ALD (n = 23, 7.6% of overall articles), virtually all were published from 2015 onwards. The dominant approach was epidemiological, mostly based on national databases analysing the incidence of alcohol-related deaths and hospital admissions.
      Further, very few studies were found on autoimmune hepatitis and other autoimmune/inflammatory liver diseases.

      Inequalities by type of research approach

      Health systems/services perspective studies were the most frequently found during the literature search, e.g., access to liver transplant, to hepatitis C treatment/cascade of care, to clinical trials in various diseases, or rifaximin in the case of the aforementioned study by Tapper et al.
      • Tapper E.B.
      • Essien U.R.
      • Zhao Z.
      • Ufere N.N.
      • Parikh N.D.
      Racial and ethnic disparities in rifaximin use and subspecialty referrals for patients with hepatic encephalopathy in the United States.
      Epidemiological studies were mainly focused on mortality or hospitalisation rates and relied on databases such as the National Health and Nutrition Examination Survey or United Network for Organ Sharing/Organ Procurement and Transplantation Network, while the rest were essentially based on prospective cohorts or meta-analyses. Clinically oriented studies fundamentally analysed aspects such as the impact of sex or ethnicity on the severity of clinical presentation or outcomes, or the response to treatment of a certain liver disease. Notably, studies on how policies or interventions impacted health inequalities in liver disease were relatively scarce and largely focused on HCV elimination or transplantation. There are almost no studies on the effect of policies such as food and beverage labelling, programmes to alleviate food insecurity or alcohol taxation on the inequalities observed in NAFLD, ALD and cirrhosis.

      Inequalities according to the studied axes of inequality and social determinants

      As for the analysed axes of inequality in the studies, race/ethnicity was the most frequently explored, followed by sex. Interestingly, a relatively low proportion of studies were based on the type of disease or associated characteristics, e.g., whether waiting lists are different for patients with HCC vs. cholangiocarcinoma, or if different HCV genotypes are more amenable to therapy. It is also worth mentioning that a good share of studies addressed more than one axis of inequality, e.g., the combination of sex, ethnicity and geographical setting was common.

      Potential reasons why Europe is lagging in the study of health inequalities in liver disease

      The few exceptions that prove the rule

      Except for some countries such as the United Kingdom
      • Green M.A.
      • Strong M.
      • Conway L.
      • Maheswaran R.
      Trends in alcohol-related admissions to hospital by age, sex and socioeconomic deprivation in England, 2002/03 to 2013/14.
      ,
      • Masson S.
      • Aldersley H.
      • Leithead J.A.
      • Day E.
      • Langford A.
      • Healy P.
      • et al.
      Liver transplantation for alcohol-related liver disease in the UK: revised UK Liver Advisory Group recommendations for referral.
      or Denmark,
      • Askgaard G.
      • Fleming K.M.
      • Crooks C.
      • Kraglund F.
      • Jensen C.B.
      • West J.
      • et al.
      Socioeconomic inequalities in the incidence of alcohol-related liver disease: a nationwide Danish study.
      or cities where there is a strong tradition of social epidemiology research such as Barcelona
      • Borrell C.
      • Palència L.
      • Bosakova L.
      • Gotsens M.
      • Morrison J.
      • Costa C.
      • et al.
      Socioeconomic inequalities in chronic liver diseases and cirrhosis mortality in European urban areas before and after the onset of the 2008 economic recession.
      ,
      • Dalmau-Bueno A.
      • García-Altés A.
      • Marí-Dell'olmo M.
      • Pérez K.
      • Espelt A.
      • Kunst A.E.
      • et al.
      Trends in socioeconomic inequalities in cirrhosis mortality in an urban area of Southern Europe: a multilevel approach.
      or Rotterdam,
      • Mackenbach J.P.
      • Kulhánová I.
      • Bopp M.
      • Borrell C.
      • Deboosere P.
      • Kovács K.
      • et al.
      Inequalities in alcohol-related mortality in 17 European countries: a retrospective analysis of mortality registers.
      it appears that Europe as a whole is overlooking the investigation of health inequality in liver disease. In addition, most studies are conducted by general epidemiologists who are not specifically devoted to liver disease analysis, while adopting an equity lens is a rarity amongst clinicians, i.e. it appears that the “virtuous coupling” between clinicians, epidemiologists, and other scholars with expertise in liver disease is unfortunately relatively rare.

      Some causes of the current situation

      This worrying situation is probably multicausal. One of the main reasons is possibly due to the lack of training, since education on health inequalities that provides adequate research capabilities is almost entirely limited to the Anglo-American sphere.
      • Cash-Gibson L.
      • Rojas-Gualdrón D.F.
      • Pericàs J.M.
      • Benach J.
      Inequalities in global health inequalities research: a 50-year bibliometric analysis (1966-2015).
      In addition, to the best of our knowledge, courses or workshops addressing health inequalities in liver disease are not currently offered. Another cause might be more systemic, e.g. in many European countries it was widely assumed following the emergence of the welfare state and universal healthcare that access to health services, educational attainment, social class, migration status or ethnicity would only have a marginal impact.

      The particularly worrying case of alcohol-related liver disease

      One perplexing scenario, which could be called the “European alcohol research paradox”, is why ALD is so poorly studied from an equity perspective, particularly in Europe where the median alcohol consumption is higher than in other continents, with 50% of end-stage liver disease being due to alcohol,
      • Karlsen T.H.
      • Sheron N.
      • Zelber-Sagi S.
      • Carrieri P.
      • Dusheiko G.
      • Bugianesi E.
      • et al.
      The EASL-Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality.
      and where approximately 20% of the global burden of liver disease due to alcohol is located?
      • Shield K.
      • Manthey J.
      • Rylett M.
      • Probst C.
      • Wettlaufer A.
      • Parry C.D.H.
      • et al.
      National, regional, and global burdens of disease from 2000 to 2016 attributable to alcohol use: a comparative risk assessment study.
      Is it due to stigma and prejudice? Or is it precisely because alcohol abuse is so common in European countries that it is normalised and therefore overlooked, and we end up ‘blaming the victim’ in cases of alcohol-related cirrhosis?
      • Giesbrecht N.
      A new resource for examining and responding to the contexts of alcohol-related harm.
      We tend to think that most clinicians and epidemiologists addressing ALD are well-informed on the impact of socioeconomic and cultural determinants of the disease, and how not only people with underlying mental health issues but also those with precarious jobs, economic insecurity, or an irregular migration status are more likely to develop alcohol abuse disorders from childhood.
      • Gauffin K.
      • Hemmingsson T.
      • Hjern A.
      The effect of childhood socioeconomic position on alcohol-related disorders later in life: a Swedish national cohort study.
      An important issue is that many liver disease specialists feel frustrated and powerless when liver-related alcohol disorders are diagnosed so late, in decompensated patients with severe alcohol dependency.
      • Shah N.D.
      • Ventura-Cots M.
      • Abraldes J.G.
      • Alboraie M.
      • Alfadhli A.
      • Argemi J.
      • et al.
      Alcohol-related liver disease is rarely detected at early stages compared with liver diseases of other etiologies worldwide.
      Moreover, national policies and healthcare pathways are barely capable of educating, promoting health related to alcohol consumption, diagnosing and referring, or providing psychological or addiction support from early ages and stages of the disease. Furthermore, media (traditional and new social networks) and advertising industries have a strong role in the promotion of alcohol consumption.
      • McCambridge J.
      • Mialon M.
      Alcohol industry involvement in science: a systematic review of the perspectives of the alcohol research community.
      ,
      • Curtis B.L.
      • Lookatch S.J.
      • Ramo D.E.
      • McKay J.R.
      • Feinn R.S.
      • Kranzler H.R.
      Meta-analysis of the association of alcohol-related social media use with alcohol consumption and alcohol-related problems in adolescents and young adults.

      Proposals for the future

      Tackling inequality requires population-wide appraisals

      Acquiring an equity lens is important not only to disentangle the various outcomes and potential underlying causes of a certain liver disease across groups, enabling the design and implementation of tailored interventions and policies, but also to apply such interventions in an equitable way. Actually, an intervention might end up increasing the inequalities it is supposed to mitigate if certain aspects such as social stratification are not considered.
      • Benach J.
      • Malmusi D.
      • Yasui Y.
      • Martínez J.M.
      A new typology of policies to tackle health inequalities and scenarios of impact based on Rose's population approach.
      Tackling the socioeconomic gradient in health across the entire spectrum of socioeconomic positions constitutes a population-wide goal. The aim here is levelling up health outcomes across the social gradient, with the greatest rate of health gain in the worst affected social stratum, the next greatest health gain in the next lowest social stratum and so on. However, potentially positive interventions might also have some downsides. Let us take as an example the simple case of two unequal social groups, the rich and the poor. A positive intervention could increase the average general health of both groups taken together. However, this improvement could be unequal and augment differences in the health of both groups. For instance, if an educational policy to decrease alcohol consumption among teenagers is targeted to what is considered to be an average middle-class urban individual, the decrease in alcohol consumption might be substantially higher in the city compared to rural settings, and amongst those relatively well educated and with fairly high household incomes compared to the children of blue collar families, thereby increasing the inequality gap between groups in spite of the average health improvement. Moreover, health promotion and prevention should also be built upon an equitable approach, including the evaluation strategies (a critical point that is often overlooked) put in place.
      • Hogeling L.
      • Lammers C.
      • Vaandrager L.
      • Koelen M.
      What works for vulnerable families? Interpretations of effective health promotion.
      A selection of critical points that need addressing through future actions is provided in Box 2.
      Critical points: What is to be done?AASLD, American Association for the Study of Liver Diseases; ALEH, Asociación Latinoamericana para el Estudio del Hígado (Latin American Association for the Study of the Liver); APASL, Asian Pacific Association for the Study of the Liver; EASL, European Association for the Study of the Liver; WHO, World Health Organization.

      Multi-level action and multidisciplinary teams: the haystack of future initiatives

      To effectively tackle liver health inequalities in Europe and elsewhere, actions should be taken at various levels and a wide range of stakeholders must be involved. From data collection and analysis to the design of public health interventions, from training of healthcare professionals to population-level awareness campaigns, from community health to clinical trial design, equity should be embedded and monitored through a multi-layered approach. To this aim, multidisciplinary teams involving clinicians, nurses, epidemiologists, public health specialists, sociologists and political scientists among other experts, should work together to generate the best possible evidence so that policymakers can take effective action.

      No improvement is possible without reliable data

      There is an urgent need for reliable data sources at the national level in order to accurately capture the burden of liver disease and to determine how it is distributed across subpopulations and groups. The current lack of availability of minimum quality data likely explains the observed differences across geographical settings in research activity regarding liver disease inequalities. Efforts to generate good estimates of the global impact and distribution of liver disease by aetiology are largely hampered by deficiencies in country-level data. For instance, in many countries death certification data collated by the World Health Organization are known to underreport liver-related deaths,
      • Karlsen T.H.
      • Sheron N.
      • Zelber-Sagi S.
      • Carrieri P.
      • Dusheiko G.
      • Bugianesi E.
      • et al.
      The EASL-Lancet Liver Commission: protecting the next generation of Europeans against liver disease complications and premature mortality.
      and Global Burden of Disease data do not have enough granularity to calculate accurate estimates by type of liver disease. Therefore, data collection through large epidemiological databases and prospective cohorts should be stimulated and funded.

      Inequalities in the drug development pipeline?

      That participants in clinical trials seldom represent the population that will eventually be treated with the compounds tested has been reported in detail for a long while,
      • Vitale C.
      • Fini M.
      • Spoletini I.
      • Lainscak M.
      • Seferovic P.
      • Rosano G.M.
      Under-representation of elderly and women in clinical trials.
      but it has not been a subject of broad interest until recent years. Moreover, while bias based on sex and ethnicity have been widely documented in areas such as cardiovascular disease, little attention has been paid in liver disease. Recently, Burra, Zanetto and Germani warned that the “sex gap in clinical trials” in hepatology, although increasingly recognised, threatens equitable access to safe and effective drugs for both sexes in areas such as NAFLD.
      • Burra P.
      • Zanetto A.
      • Germani G.
      Sex bias in clinical trials in gastroenterology and hepatology.
      Robertson and colleagues recently reported that amongst clinical trials on weight management in adults living with severe obesity, which is tightly related to NAFLD, only 6.1% trials reported adapting recruitment to appeal to underserved groups, 10.0% reported culturally adapting their trial materials, over half of the trials reported participants' race or ethnicity, and one-fifth reported socioeconomic status.
      • Robertson C.
      • Aceves-Martins M.
      • Cruickshank M.
      • Imamura M.
      • Avenell A.
      Does weight management research for adults with severe obesity represent them? Analysis of systematic review data.
      Remarkably, both in liver disease and other areas, there are relevant axes of inequality other than sex, age and ethnicity that are rarely discussed when analysing equal representation in clinical trials, e.g. religion, education, socioeconomic status or type of health insurance. In countries such as the US, an individual from a low socioeconomic background with poor healthcare coverage might be more likely to participate in certain clinical trials because this might allow them to benefit from health provision temporarily. On the other hand, they might not be able to access the treatment tested once it has been commercialised. This and other related aspects of drug development are key but nonetheless often overlooked.

      A global joint commission on liver health equity?

      A good starting point would be the creation of a Joint Commission on Liver Health Equity including representatives from EASL, AASLD (American Association for the Study of Liver Diseases), APASL (Asian Pacific Association for the Study of the Liver) and ALEH (Latin American Association for the Study of the Liver) that comprehensively analyses the current situation and provides guidance for the coming years. Such a global initiative should help to raise awareness and boost data collection and research. However, given the particularities of liver disease and its associated inequalities according to each region, in order to be effective, initiatives will likely need to be tailored to smaller geographic areas, for instance EASL leading at the European level in coordination with national scientific societies. Moreover, EASL should play a leading role in designing educational materials and a specific research training itinerary in health inequalities for scholars, healthcare providers and policymakers working in the field of liver disease. For instance, EASL might consider launching a specific training course and a “Liver Equality Research Award”. In the mid-term, health inequalities, which are currently almost exclusively taught in public health venues, should be included in the curricula of life and health sciences’ degrees.

      Pending work in academic settings

      In addition to the fundamental work of raising awareness and providing educational tools, health inequalities as a sub-discipline should be included in scientific conferences and workshops. Similarly, scientific journals could incorporate an “equality corner” or in some way encourage research and highlight the relevance of health inequalities to the hepatology community. Specific aspects that might be incorporated into a researcher’s routine include the systematic collection of dimensions, indicators, and variables that would enable inequalities in the design of clinical and epidemiological studies to be addressed in a comprehensive way, e.g. the recent international consensus on advancing the global public health agenda for NAFLD, in the section on “Policy strategies and a societal approach” included the following recommendation: “The NAFLD prevention agenda should include the creation of healthier, more equitable and sustainable societies as one of its core goals. One way to do that should be to emphasize the Sustainable Development Goals’ targets that are relevant to preventing and treating NAFLD”.
      • Lazarus J.V.
      • Mark H.E.
      • Anstee Q.M.
      • Arab J.P.
      • Batterham R.L.
      • Castera L.
      • et al.
      Advancing the global public health agenda for NAFLD: a consensus statement.
      Journals, institutional review boards, and research councils evaluating projects should ensure that at least some of their reviewers have specific training in health inequalities research and provide meaningful feedback in this regard, with specific emphasis on how potential policies and interventions derived from research findings might be implemented and evaluated.

      Health equity, also in artificial intelligence/machine learning and big data

      Of emergent importance is that an equity lens be applied to the burgeoning fields of big data and artificial intelligence/machine learning (AI/ML). In hepatology, despite the advances towards clinically useful applications derived from AI/ML, there is a risk that biases and health inequities can be introduced or exacerbated by these technologies. As stated in a recent review, if left unrecognised in the set up and application of such technologies, certain biases and overlooked inequalities could generate or worsen systematic racial, ethnic and sex disparities when deployed on a large scale.
      • Uche-Anya E.
      • Anyane-Yeboa A.
      • Berzin T.M.
      • Ghassemi M.
      • May F.P.
      Artificial intelligence in gastroenterology and hepatology: how to advance clinical practice while ensuring health equity.
      In brief, the main reasons are two-fold: first, the “rule of big numbers” might stress the relevance of clinical and analytical findings while neglecting socio-epidemiological variables; and secondly, the latter could be wrongly interpreted. For example, a certain ethnicity could be interpreted as being associated with poorer outcomes according to an AI algorithm that analysed data from millions of individuals of a particular country. However, if data on socioeconomics or healthcare access were not available, this might hide that the actual cause of a poor prognosis is the inability to pay for healthcare due to economic deprivation, which could potentially be disproportionally concentrated in a certain ethnicity, e.g. African Americans. This of course could have potential implications for policy design.

      Not without the patients and their communities

      Equally important is the involvement of patients and their communities, including representatives such as ELPA (European Liver Patients Association), Liver Patients International and other patient advocacy groups, which might provide critical insight on how stigma and inequalities are perceived by the population and vulnerable groups, and how they should be tackled. Moreover, they can help to advocate so that political parties and European institutions such as the European Commission increase funding in research projects on liver health equality with the goal of supporting public health and health system interventions aimed at reducing liver health inequalities. Policymakers should also be engaged in this important endeavour and be asked to provide “health-in-all-policies” responses, e.g. Health Department action on its own would not be enough to tackle ALD, but Education, Consumer Affairs, Treasury, and Labour departments should also be involved.

      Conclusions

      In summary, the first steps on the path to giving equality the place it deserves in the liver disease community largely depend on researchers and practitioners. To achieve this goal, Europe should increase its awareness of health inequalities in the liver arena, perform high quality research that addresses health inequalities and guide and inspire health policymakers and society as a whole to close this gap so that all of our communities are effectively protected from liver diseases.

      Abbreviations

      AI/ML, artificial intelligence/machine learning; ALD, alcohol-related liver disease; EASL, European Association for the study of the Liver; NAFLD, non-alcoholic fatty liver disease.

      Financial support

      No funding was received for the present work.

      Authors’ contributions

      All the authors listed in the contributors’ affiliations meet the ICMJE Authorship Criteria, that is, they substantially contributed to conception and design, acquisition of data, drafting of the article, critical revision, and final approval of the manuscript.

      Data availability statement

      The databases built upon the literature search strategy as well as the articles excluded and the reasons for exclusion will be made available upon request.

      Conflict of interest

      JMP reports having received consulting fees from Boehringer Ingelheim, MSD and Novo Nordisk, speaking fees from Gilead and Novo Nordisk, and travel expenses from Gilead, Rubió, Pfizer, Astellas, MSD, CUBICIN, and Novo Nordisk outside of the submitted work. He has received educational and research support from Gilead, Pfizer, Astellas, Accelerate, Novartis, Abbvie, ViiV, and MSD, as well as funds from European Commission/EFPIA IMI2 853966-2, IMI2 777377, H2020 847989, and ISCIII PI19/01898; JVL reports grants and speaker fees from AbbVie, Gilead Sciences and MSD and speaker fees from Genfit, Intercept and ViiV, outside of the submitted work; MVC is a recipient of the Juan Rodés grant JR19/00015; RB is a recipient of NIAAA grants U01AA021908 and U01AA020 and NIDDK P30DK120531821.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Acknowledgements

      We want to thank Dr Ramiro Manzano for his support in the design of the literature search strategy. JVL acknowledges support to ISGlobal from the Spanish Ministry of Science, Innovation and Universities through the “Centro de Excelencia Severo Ochoa 2019–2023” Programme (CEX2018-000806-S) and from the Government of Catalonia through the CERCA Programme. JB gratefully acknowledges the financial support by ICREA under the ICREA Academia programme.

      Supplementary data

      The following are the supplementary data to this article:

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