“Dual aetiology fatty liver disease”: A recently proposed term associated with potential pitfalls
2020; Elsevier BV; Volume: 74; Issue: 4 Linguagem: Inglês
10.1016/j.jhep.2020.11.004
ISSN1600-0641
AutoresChristophe Moreno, Nick Sheron, Dina Tiniakos, Carolin Lackner, Philippe Mathurin,
Tópico(s)Alcohol Consumption and Health Effects
ResumoWe read with interest the manuscript entitled “A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement”, by Mohammed Eslam, Philip N Newsome and colleagues.[1]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.J Hepatol. 2020; 73: 202-209Abstract Full Text Full Text PDF PubMed Scopus (669) Google Scholar We agree that the proposed term metabolic dysfunction-associated fatty liver disease (MAFLD) is an interesting alternative to describe liver disease associated with an underlying systemic metabolic dysfunction. However, the authors suggest that in a patient satisfying criteria for MAFLD but with another risk factor, the term “dual-aetiology fatty liver disease” should be used. We disagree and fear that this term will affect the comprehensiveness of the disease’s established natural history, prevent prioritization of therapeutic management according to the main driver of liver-related morbidity and mortality, interfere with the epidemiological analysis of liver-related events, and decrease the relevance and impact of public health policies. In terms of natural history, the proposed term “dual aetiology fatty liver” obscures the fact that disease progression is mainly driven by the other risk factor whether this be viral hepatitis, autoimmune liver disease or an alcohol use disorder. For example, in patients with metabolic risk factors and harmful alcohol use, the natural history reveals that disease progression resembles the more severe course of alcohol-related liver disease and is very different from the comparatively slow disease progression observed in NAFLD alone. With regard to concomitant alcohol abuse and metabolic risk factors, several studies have established the huge discrepancy in the natural history of ALD and NAFLD. A study compared the long-term prognosis of 106 patients with biopsy-proven alcohol-related fatty liver and 109 patients with biopsy-proven NAFLD over a period of 9 and 16 years, respectively.[2]Dam-Larsen S. Franzmann M. Andersen I.B. Christoffersen P. Jensen L.B. Sorensen T.I.A. et al.Long term prognosis of fatty liver: risk of chronic liver disease and death.Gut. 2004; 53: 750-755Crossref PubMed Scopus (407) Google Scholar Incidence of cirrhosis was 20.7% (n = 22) in the alcohol-related fatty liver group and 0.9% (n = 1) in the NAFLD group. Twenty deaths were liver-related in the ALD group while only one was attributable to cirrhosis in the NAFLD group. Overall survival of the ALD group was significantly lower than in the NAFLD group, which was not different to the estimated survival of the general population. The dissociation of the aetiologies NALFD and ALD is essential to better understand the risk of liver-related mortality, which is low in patients with NAFLD and conversely high in patients with ALD. Long-term prognosis is remarkably different in patients with biopsy-proven NAFLD than in patients with biopsy-proven ALD in terms of rates and causes of mortality. Long-term follow-up of 3,453 patients with biopsy-proven ALD showed that 5-year cumulative mortality was 40.9% in patients with ALD compared with 5.8% in the matched reference population.[3]Hagström H. Thiele M. Roelstraete B. Söderling J. Ludvigsson J.F. Mortality in biopsy-proven alcohol-related liver disease: a population-based nationwide cohort study of 3453 patients.Gut. 2020 Mar 27; (gutjnl-2019-320446)https://doi.org/10.1136/gutjnl-2019-320446Crossref Scopus (16) Google Scholar Among the 3,453 patients with biopsy-proven ALD, the risk of death gradually increased from 27.5% in those with normal liver, 27.2% in those with steatosis, 34.2% in those with steatohepatitis to 46.7% in those with cirrhosis. Liver-related deaths accounted for 43% of total deaths and were significantly increased in all ALD subgroups compared with their respective reference individuals, except for those with normal liver on biopsy. In contrast, longitudinal follow-up of 619 patients with biopsy-proven NAFLD showed that hepatic mortality is drastically lower and only represents 9.2% of total deaths.[4]Angulo P. Kleiner D.E. Dam-Larsen S. Adams L.A. Bjornsson E.S. Charatcharoenwitthaya P. et al.Gastroenterology. 2015; 149: 389-397Abstract Full Text Full Text PDF PubMed Scopus (1393) Google Scholar The overall 5-year mortality was less than 5% in patients with NAFLD without fibrosis and around 10% in those with fibrosis, meaning that 5-year liver-related mortality is close to 0% in patients with biopsy-proven NAFLD without fibrosis and around 1% in those with fibrosis. Even at the more advanced stage of liver disease, disease progression remains different between ALD and NAFLD. In patients with newly diagnosed cirrhosis, patients with alcohol-related cirrhosis were younger, 45% of them were less than 40 years old compared to 22% of patients with NAFLD cirrhosis. NAFLD was associated with lower incidence rates of ascites, variceal bleeding and overall liver decompensation.[5]Orman E.S. Roberts A. Ghabril M. Nephew L. Desai A.P. Patidar K. et al.Trends in characteristics, mortality, and other outcomes of patients with newly diagnosed cirrhosis.JAMA Netw Open. 2019; 2e196412Crossref PubMed Scopus (17) Google Scholar All of these data show that harmful alcohol use leads to drastically faster disease progression than metabolic risk factors alone. The authors are right to point out that obesity and metabolic syndrome are risk factors for disease progression in individuals with harmful alcohol use (>2 drinks/day for women and >3/day for men).[6]Raynard B. Balian A. Fallik D. Capron F. Bedossa P. Chaput J.C. et al.Risk factors of fibrosis in alcohol-induced liver disease.Hepatology. 2002; 35: 635-638Crossref PubMed Scopus (309) Google Scholar,[7]Naveau S. Giraud V. Borotto E. Aubert A. Capron F. Chaput J.C. Excess weight risk factor for alcoholic liver disease.Hepatology. 1997; 25: 108-111Crossref PubMed Scopus (513) Google Scholar The interplay between ALD and NAFLD is complex as both conditions share common pathogenic pathways and are influenced by a number of the same genetic variants. Furthermore, histological features of both entities show broad overlap. There is a lot of evidence for additive/synergistic effects between ALD and obesity. In the UK prospective Million Women Cohort study[8]Liu B. Balkwill A. Reeves G. Beral V. Million Women Study CollaboratorsBody mass index and risk of liver cirrhosis in middle aged UK women: prospective study.BMJ. 2010; 340: c912Crossref PubMed Scopus (138) Google Scholar (1,230,662 women; 6.2-years of follow-up), the relative risk of cirrhosis in individuals with BMI>30 and >150 g/week alcohol use was 6.53, in individuals with BMI>30 and 150 g/week alcohol use the relative risk was 3.44 compared with individuals with normal BMI and 101 g/day in men and >61 g/day in women) to low risk (1-40g/day in men and 1-20g/day in women) and abstinence. A reduction of alcohol consumption of more than 2 levels (according to WHO classification) has been endorsed by health agencies, such as the European Medicines Agency, as a relevant surrogate endpoint to improve morbidity and mortality.[11]Falk D.E. O'Malley S.S. Witkiewitz K. Anton R.F. Litten R.Z. Slater M. et al.Evaluation of drinking risk levels as outcomes in alcohol pharmacotherapy trials: a secondary analysis of 3 randomized clinical trials.JAMA Psychiatry. 2019; 76: 374-381Crossref PubMed Scopus (44) Google Scholar,[12]Mathurin P. Lucey M.R. Liver transplantation in patients with alcohol-related liver disease: current status and future directions.Lancet Gastroenterol Hepatol. 2020; 5: 507-514Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar The proposed term “dual aetiology fatty liver” does not reflect this important information and is misleading regarding the behavioural interventions needed to improve health outcomes. Disease nomenclature needs to relate to the therapeutic strategy. As such, identifying the main pathogenetic pathways driving outcomes is warranted to define and prioritize therapeutic management. In obese people with autoimmune hepatitis the liver prognosis is driven by the autoimmune disease and not by steatosis. Steroids and immunosuppressive regimens are the recommended therapy regardless of the presence of steatosis. The same issue occurs in other settings such as severe alcoholic hepatitis (AH) or reactivation of HBV infection in patients with risk factors of metabolic syndrome. In these cases, the short-term outcome is related to the alcohol-induced or viral-related injury. For patients with severe AH, corticosteroids are the first-line treatment, and in the case of HBV reactivation, nucleos(t)ide analogues are the treatment of choice. In these patients, the presence of obesity and/or diabetes is a contributing factor to disease severity but not the main mechanism driving liver outcome. In all these different examples the term “dual-aetiology fatty liver” does not reflect the underlying pathogenesis and can obscure and mislead therapeutic strategy. We agree with the authors that physicians must identify and treat all risk factors in patients with chronic liver disease. However, the multiple risk factors of liver injury require prioritisation and obesity is frequently the least important factor. As illustrated in the context of chronic hepatitis C, sustained virological response (SVR) has been clearly demonstrated to be associated with an important decrease in liver-related morbidity and mortality in different large patient cohorts treated with direct acting antivirals.[13]Carrat F. Fontaine H. Dorival C. Simony M. Diallo A. Hezode C. et al.Clinical outcomes in patients with chronic hepatitis C after direct-acting antiviral treatment: a prospective cohort study.Lancet. 2019; 393: 1453-1464Abstract Full Text Full Text PDF PubMed Scopus (250) Google Scholar Although metabolic features confer a higher risk of hepatocellular carcinoma in patients following SVR, this risk no longer compares with that observed in the absence of viral eradication.[14]Nahon P. Layese R. Bourcier V. Cagnot C. Marcellin P. Guyader D. et al.Incidence of hepatocellular carcinoma after direct antiviral therapy for HCV in patients with cirrhosis included in surveillance programs.Gastroenterology. 2018; 155: 1436-1450Abstract Full Text Full Text PDF PubMed Scopus (111) Google Scholar The term “dual aetiology fatty liver” reduces the significance of viral disease to that of a steatotic process whereas scientific data on natural history, and disease progression after viral eradication are not in accordance with such a classification. The proposed term “dual aetiology fatty liver disease” will complicate and confuse epidemiological data analysis. As an example, the analysis of the global burden of cirrhosis from the Global Burden of Disease Study[15]GBD 2017 Cirrhosis CollaboratorsThe 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.Lancet Gastroenterol Hepatol. 2020; 5: 245-266Abstract Full Text Full Text PDF PubMed Scopus (246) Google Scholar revealed that in 2017 cirrhosis accounted for 1.32 million deaths worldwide: alcohol was recorded as a contributing factor in 48% of these deaths, whereas it was recorded as a causative factor in 332,268 deaths, with cirrhosis classified as alcohol-related cirrhosis. When considering the proposed term “dual aetiology fatty liver disease”, patients satisfying metabolic criteria would no longer be recorded as having ALD and would be excluded from the data. This is vitally important for health policy. The most effective government strategies identified by the WHO to reduce alcohol-related liver mortality include increased pricing and taxation of alcoholic beverages, restriction of the hours of lower “happy hour” pricing of alcohol, implementation of alcohol advertising bans and endorsing a minimum unit price.[16]Sheron N. Alcohol and liver disease in Europe-simple measures have the potential to prevent tens of thousands of premature deaths.J Hepatol. 2016; 64: 957-967Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar,[17]Hydes T. Gilmore W. Sheron N. Gilmore I. Treating alcohol-related liver disease from a public health perspective.J Hepatol. 2019; 70: 223-236Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar The effectiveness of these public health strategies has been demonstrated using robust endpoints: decreased alcohol consumption per capita, decreased alcohol-related morbidity and mortality, including liver-related events. Using the umbrella term “dual aetiology fatty liver disease” risks impairing the accurate evaluation of public health policies. Moreover, such a term will separate individuals exposed to alcohol consumption into 2 categories according to weight (ALD for individuals with normal weight and “dual aetiology fatty liver disease” for overweight or obese individuals). The concern is that the public health policies will no longer target those classified as having “dual aetiology fatty liver” even though this subgroup is at the highest risk of alcohol-induced liver injury. Obesity and alcohol misuse are both very significant global health concerns requiring urgent evidence-based action. However, in individuals with ALD, viral or autoimmune hepatitis the exclusion of these aetiological factors from the diagnosis creates very significant concerns, for the patient and their understanding of the disease, for clinicians prioritising therapy, for epidemiologists creating and analysing data and for health policymakers. The term “dual aetiology fatty liver disease” is a well meant but simplistic solution with a serious downside. In our view, redefining nomenclature of diseases requires a consensus supported by different scientific societies and experts from different fields. We urgently ask for a taskforce including not only experts in MAFLD or ALD, but also epidemiologists, addiction specialists and endocrinologists. This is, in our view, the only scientific way to modify nomenclature of diseases without creating confusion in the liver community. The authors received no financial support to produce this manuscript. Christophe Moreno: drafting of the manuscript; critical revision of the manuscript for important intellectual content; Nick Sheron: critical revision of the manuscript for important intellectual content; Dina Tiniakos: critical revision of the manuscript for important intellectual content; Carolin Lackner: critical revision of the manuscript for important intellectual content; Philippe Mathurin: drafting of the manuscript; critical revision of the manuscript for important intellectual content. Christophe Moreno was paid as consultant for Abbvie, Astellas, Bayer, Gilead Sciences, Norgine, Novartis; Nick Sheron: Clinical adviser to Public Health England. Other advisory work: Alcohol Health Alliance UK, UK Department of Health, Home Office, British Liver Trust, European Public Health Alliance, European Society for the Study of Liver Disease, British Society for the Study of Liver Disease. Consultancy work and travelling expenses from pharmaceutical companies: Norgine and Kyowa Kirin Limited, Gilead; Dina Tiniakos: nothing to declare; Carolin Lackner was paid as consultant for Allergan, Verily, Histoindex, Dr. Falk Pharma GmbH, Galmed Research and Development Ltd; Philippe Mathurin was paid as consultant for Sanofi, Gilead Sciences, Novo Nordisk, Intercept, Generon. Please refer to the accompanying ICMJE disclosure forms for further details. The following is/are the supplementary data to this article: Download .pdf (.27 MB) Help with pdf files Multimedia component 1 A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statementJournal of HepatologyVol. 73Issue 1PreviewThe exclusion of other chronic liver diseases including “excess” alcohol intake has until now been necessary to establish a diagnosis of metabolic dysfunction-associated fatty liver disease (MAFLD). However, given our current understanding of the pathogenesis of MAFLD and its rising prevalence, “positive criteria” to diagnose the disease are required. In this work, a panel of international experts from 22 countries propose a new definition for the diagnosis of MAFLD that is both comprehensive and simple, and is independent of other liver diseases. Full-Text PDF MAFLD: A holistic view to redefining fatty liver diseaseJournal of HepatologyVol. 74Issue 4PreviewWe thank Poniachik et al.,1 and Moreno et al.,2 for their interest in our work3,4 and acknowledging its multiple positive attributes. As they indicate, this includes the adoption of metabolic dysfunction-associated fatty liver disease (MAFLD) as an apt term reflecting the undisputed role of metabolic dysfunction in pathogenesis, and diagnostic criteria based on specific inclusions and not the absence of other diseases. The authors suggest that the consensus helps physicians to identify and treat all risk factors in those with chronic liver disease and through this, enables holistic care, clinical research and the development of public health prevention policies. Full-Text PDF
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