NAFLD vs. MAFLD – It is not the name but the disease that decides the outcome in fatty liver

Abstract

Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United StatesJournal of HepatologyVol. 75Issue 6PreviewRecently, international experts proposed redefining non-alcoholic fatty liver disease (NAFLD) as metabolic dysfunction-associated fatty liver disease (MAFLD), based on modified criteria. It is suspected that outcomes such as mortality may differ for these clinical entities. We studied the impact of MAFLD and NAFLD on all-cause and cause-specific mortality in US adults. Full-Text PDF Reply to: “NAFLD vs. MAFLD – It is not the name but the disease that decides the outcome in fatty liver”Journal of HepatologyVol. 76Issue 2PreviewWe thank De and their colleagues1 for their interest in our study. We respectfully submit that their input does not influence our major conclusion. In addition, the main objective of our work was to provide supporting data linking metabolic dysfunction-associated fatty liver disease (MAFLD) to all-cause mortality and not to propose a change in terminology from non-alcoholic fatty liver disease (NAFLD) to MAFLD. Full-Text PDF We read with great interest the study by Kim et al. who analysed the NHANES III (National Health and Nutrition Examination Survey) cohort and provided interesting insights into the prognostic outcomes of metabolic dysfunction-associated fatty liver disease (MAFLD) and non-alcoholic fatty liver disease (NAFLD).[1]Kim D. Konyn P. Sandhu K.K. Dennis B.B. Cheung A.C. Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol. 2021; 75 (S0168-8278(21)01964-4): 1284-1291https://doi.org/10.1016/j.jhep.2021.07.035Google ScholarIt is intriguing to note that out of 13,856 patients in the NHANES III cohort with ultrasound assessment of hepatic steatosis, 1,193 (8.6%) patients were excluded because of missing laboratory variables like triglycerides, HDL and high sensitivity-C-reactive protein (hs-CRP).[1]Kim D. Konyn P. Sandhu K.K. Dennis B.B. Cheung A.C. Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol. 2021; 75 (S0168-8278(21)01964-4): 1284-1291https://doi.org/10.1016/j.jhep.2021.07.035Google Scholar An additional 4,875 (35.2%) patients were further excluded as they did not fast for 8 hours or did not have fasting levels of glucose or insulin.[1]Kim D. Konyn P. Sandhu K.K. Dennis B.B. Cheung A.C. Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol. 2021; 75 (S0168-8278(21)01964-4): 1284-1291https://doi.org/10.1016/j.jhep.2021.07.035Google Scholar As per MAFLD criteria, the definition of metabolic-dysfunction in non-diabetic patients with normal BMI requires a battery of investigations, some of which like hs-CRP and HOMA-IR are not routinely ordered in patients being evaluated for hepatic steatosis in clinical practice.[2]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: 202-209https://doi.org/10.1016/j.jhep.2020.03.039Google Scholar To address this issue, we retrospectively reviewed data on 1,040 patients with NAFLD (mean age 40.9 ± 11.3 years, 604 (58%) males) managed prospectively in a real-life fashion over the last 10 years at our institute for the presence of MAFLD. Asian cut-offs for BMI and waist circumference were used for defining overweight and central obesity. Nine-hundred and sixteen (88%) patients had BMI ≥23 kg/m2 and/or type 2 diabetes mellitus (T2DM) and qualified as having MAFLD. Of the remaining 124 (12%) non-diabetic lean patients, hs-CRP was not available in any patient while HOMA-IR was available in only 7 (5.6%) patients. Despite the unavailability of these parameters, ≥2 of 7 criteria for metabolic-dysfunction were present in 48 of these 124 (38.7%) patients who were labelled as lean MAFLD. However, in the absence of HOMA-IR and hs-CRP levels, it was not possible to determine if the remaining 76 (61.3%) lean, non-diabetic patients with underlying NAFLD had MAFLD (Fig. 1). Our observations suggest the poor applicability of MAFLD criteria in real-life clinical practice. Indeed, a substantial number of such non-diabetic, lean patients with hepatic steatosis may not be evaluable using current MAFLD criteria in the real world due to the lack of all laboratory parameters.The authors reported that MAFLD was associated with increased all-cause mortality after adjusting for metabolic risk factors, while NAFLD was not.[1]Kim D. Konyn P. Sandhu K.K. Dennis B.B. Cheung A.C. Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol. 2021; 75 (S0168-8278(21)01964-4): 1284-1291https://doi.org/10.1016/j.jhep.2021.07.035Google Scholar Further, the adjusted increase in mortality appeared to be predominantly due to an increase in cancer mortality rather than cardiovascular mortality. Unfortunately, the data on liver related mortality was not available.It is important to note that all patients with MAFLD (+)/NAFLD (-) had a second etiology for liver disease.[1]Kim D. Konyn P. Sandhu K.K. Dennis B.B. Cheung A.C. Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol. 2021; 75 (S0168-8278(21)01964-4): 1284-1291https://doi.org/10.1016/j.jhep.2021.07.035Google Scholar The proportion of patients with significant alcohol consumption or chronic viral hepatitis has not been mentioned. Both alcohol and chronic viral hepatitis are pro-oncogenic and have been associated with a number of malignancies.[3]GBD 2016 Alcohol CollaboratorsAlcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet. 2018; 392: 1015-1035https://doi.org/10.1016/S0140-6736(18)31310-2Google Scholar,[4]Song C. Lv J. Liu Y. Chen J.G. Ge Z. Zhu J. et al.China Kadoorie Biobank Collaborative GroupAssociations between hepatitis B virus infection and risk of all cancer types.JAMA Netw Open. 2019; 2e195718https://doi.org/10.1001/jamanetworkopen.2019.5718Google Scholar While the authors have adjusted their calculations for traditional risk factors and metabolic co-morbidities, they have not adjusted for significant alcohol consumption or viral hepatitis. This makes us wonder if the presence of other concomitant etiology may have contributed to the excess all-cause and cancer-related mortality in MAFLD. The presence of a second etiology may also explain why the weighted prevalence of advanced fibrosis (9.22%) in the group of patients with MAFLD (+)/NAFLD (-) was substantially higher than those with MAFLD (+)/NAFLD (+) (2.61%) and MAFLD (-)/NAFLD (+) (0.47%), respectively. Hence, data on liver-related mortality are required for further granular understanding of the differences between MAFLD and NAFLD.The etymological debate on MAFLD vs. NAFLD revolves around the etiology of liver disease and should be driven primarily by pathophysiological concerns rather than prognostic endpoints.[5]Duseja A. Taneja S. Changing nomenclature from nonalcoholic fatty liver disease to metabolic dysfunction-associated fatty liver disease - not only premature but also confusing.J Clin Exp Hepatol. 2021; 11: 278-279https://doi.org/10.1016/j.jceh.2020.08.002Google Scholar Different subtypes or stages of a particular disease may have varying prognosis but should be categorised under a single etiology. Putative pathophysiological drivers in lean patients with MAFLD (-)/NAFLD (+) like gut microbiota and genetics also play a role in MAFLD (+)/NAFLD (+).[6]Aron-Wisnewsky J. Vigliotti C. Witjes J. Le P. Holleboom A.G. Verheij J. et al.Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders.Nat Rev Gastroenterol Hepatol. 2020; 17: 279-297https://doi.org/10.1038/s41575-020-0269-9Google Scholar,[7]Eslam M. George J. Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology.Nat Rev Gastroenterol Hepatol. 2020 Jan; 17: 40-52https://doi.org/10.1038/s41575-019-0212-0Google Scholar It should also be noted that patients with lean NAFLD are usually younger than those with the classical NAFLD phenotype who also qualify as MAFLD.[8]Younes R. Govaere O. Petta S. Miele L. Tiniakos D. Burt A. et al.Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach?.Gut. 2021; (Epub ahead of print)https://doi.org/10.1136/gutjnl-2020-322564Google Scholar,[9]Young S. Tariq R. Provenza J. Satapathy S.K. Faisal K. Choudhry A. et al.Prevalence and profile of nonalcoholic fatty liver disease in lean adults: systematic review and meta-analysis.Hepatol Commun. 2020; 4: 953-972https://doi.org/10.1002/hep4.1519Google Scholar In the present study too, patients with MAFLD (-)/NAFLD (+) were almost a decade younger (35.0 ± 0.9 years) than those with MAFLD (+)/NAFLD (+) (47.2 ± 0.6 years).[1]Kim D. Konyn P. Sandhu K.K. Dennis B.B. Cheung A.C. Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol. 2021; 75 (S0168-8278(21)01964-4): 1284-1291https://doi.org/10.1016/j.jhep.2021.07.035Google Scholar It is plausible that the subtle metabolic derangements in these young patients with MAFLD (-)/NAFLD (+) are not yet severe enough to be clinically discernible but will become so with the passage of time. Indeed, in a community-based study, patients with MAFLD (-)/NAFLD (+) had a significantly higher risk of developing new onset diabetes mellitus compared to controls with an adjusted relative risk of 2.2.[10]Niriella M.A. Ediriweera D.S. Kasturiratne A. De Silva S.T. Dassanayaka A.S. De Silva A.P. et al.Outcomes of NAFLD and MAFLD: results from a community-based, prospective cohort study.PLoS One. 2021; 16e0245762https://doi.org/10.1371/journal.pone.0245762Google ScholarIn conclusion, the debate on the nomenclature of NAFLD vs. MAFLD is far from over. It is not the name but the disease that decides the outcome of patients with fatty liver disease.AbbreviationsNAFLD, Non-alcoholic fatty liver disease; MAFLD, Metabolic dysfunction-associated fatty liver disease; NASH, Non-alcoholic steatohepatitis; T2DM, Type 2 diabetes mellitus; HDL, High density lipoprotein; hs-CRP, High sensitivity-C-reactive protein (hs-CRP); HOMA-IR, Homeostasis model assessment insulin resistance; BMI, Body mass index.Financial supportThe authors received no financial support to produce this manuscript.Authors’ contributionsAr De: manuscript writing, data analysis and critical revision, NA- writing, MM: data curation and analysis, PS: data curation and analysis, AD: data curation and critical revision We read with great interest the study by Kim et al. who analysed the NHANES III (National Health and Nutrition Examination Survey) cohort and provided interesting insights into the prognostic outcomes of metabolic dysfunction-associated fatty liver disease (MAFLD) and non-alcoholic fatty liver disease (NAFLD).[1]Kim D. Konyn P. Sandhu K.K. Dennis B.B. Cheung A.C. Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol. 2021; 75 (S0168-8278(21)01964-4): 1284-1291https://doi.org/10.1016/j.jhep.2021.07.035Google Scholar It is intriguing to note that out of 13,856 patients in the NHANES III cohort with ultrasound assessment of hepatic steatosis, 1,193 (8.6%) patients were excluded because of missing laboratory variables like triglycerides, HDL and high sensitivity-C-reactive protein (hs-CRP).[1]Kim D. Konyn P. Sandhu K.K. Dennis B.B. Cheung A.C. Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol. 2021; 75 (S0168-8278(21)01964-4): 1284-1291https://doi.org/10.1016/j.jhep.2021.07.035Google Scholar An additional 4,875 (35.2%) patients were further excluded as they did not fast for 8 hours or did not have fasting levels of glucose or insulin.[1]Kim D. Konyn P. Sandhu K.K. Dennis B.B. Cheung A.C. Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol. 2021; 75 (S0168-8278(21)01964-4): 1284-1291https://doi.org/10.1016/j.jhep.2021.07.035Google Scholar As per MAFLD criteria, the definition of metabolic-dysfunction in non-diabetic patients with normal BMI requires a battery of investigations, some of which like hs-CRP and HOMA-IR are not routinely ordered in patients being evaluated for hepatic steatosis in clinical practice.[2]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: 202-209https://doi.org/10.1016/j.jhep.2020.03.039Google Scholar To address this issue, we retrospectively reviewed data on 1,040 patients with NAFLD (mean age 40.9 ± 11.3 years, 604 (58%) males) managed prospectively in a real-life fashion over the last 10 years at our institute for the presence of MAFLD. Asian cut-offs for BMI and waist circumference were used for defining overweight and central obesity. Nine-hundred and sixteen (88%) patients had BMI ≥23 kg/m2 and/or type 2 diabetes mellitus (T2DM) and qualified as having MAFLD. Of the remaining 124 (12%) non-diabetic lean patients, hs-CRP was not available in any patient while HOMA-IR was available in only 7 (5.6%) patients. Despite the unavailability of these parameters, ≥2 of 7 criteria for metabolic-dysfunction were present in 48 of these 124 (38.7%) patients who were labelled as lean MAFLD. However, in the absence of HOMA-IR and hs-CRP levels, it was not possible to determine if the remaining 76 (61.3%) lean, non-diabetic patients with underlying NAFLD had MAFLD (Fig. 1). Our observations suggest the poor applicability of MAFLD criteria in real-life clinical practice. Indeed, a substantial number of such non-diabetic, lean patients with hepatic steatosis may not be evaluable using current MAFLD criteria in the real world due to the lack of all laboratory parameters. The authors reported that MAFLD was associated with increased all-cause mortality after adjusting for metabolic risk factors, while NAFLD was not.[1]Kim D. Konyn P. Sandhu K.K. Dennis B.B. Cheung A.C. Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol. 2021; 75 (S0168-8278(21)01964-4): 1284-1291https://doi.org/10.1016/j.jhep.2021.07.035Google Scholar Further, the adjusted increase in mortality appeared to be predominantly due to an increase in cancer mortality rather than cardiovascular mortality. Unfortunately, the data on liver related mortality was not available. It is important to note that all patients with MAFLD (+)/NAFLD (-) had a second etiology for liver disease.[1]Kim D. Konyn P. Sandhu K.K. Dennis B.B. Cheung A.C. Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol. 2021; 75 (S0168-8278(21)01964-4): 1284-1291https://doi.org/10.1016/j.jhep.2021.07.035Google Scholar The proportion of patients with significant alcohol consumption or chronic viral hepatitis has not been mentioned. Both alcohol and chronic viral hepatitis are pro-oncogenic and have been associated with a number of malignancies.[3]GBD 2016 Alcohol CollaboratorsAlcohol use and burden for 195 countries and territories, 1990-2016: a systematic analysis for the Global Burden of Disease Study 2016.Lancet. 2018; 392: 1015-1035https://doi.org/10.1016/S0140-6736(18)31310-2Google Scholar,[4]Song C. Lv J. Liu Y. Chen J.G. Ge Z. Zhu J. et al.China Kadoorie Biobank Collaborative GroupAssociations between hepatitis B virus infection and risk of all cancer types.JAMA Netw Open. 2019; 2e195718https://doi.org/10.1001/jamanetworkopen.2019.5718Google Scholar While the authors have adjusted their calculations for traditional risk factors and metabolic co-morbidities, they have not adjusted for significant alcohol consumption or viral hepatitis. This makes us wonder if the presence of other concomitant etiology may have contributed to the excess all-cause and cancer-related mortality in MAFLD. The presence of a second etiology may also explain why the weighted prevalence of advanced fibrosis (9.22%) in the group of patients with MAFLD (+)/NAFLD (-) was substantially higher than those with MAFLD (+)/NAFLD (+) (2.61%) and MAFLD (-)/NAFLD (+) (0.47%), respectively. Hence, data on liver-related mortality are required for further granular understanding of the differences between MAFLD and NAFLD. The etymological debate on MAFLD vs. NAFLD revolves around the etiology of liver disease and should be driven primarily by pathophysiological concerns rather than prognostic endpoints.[5]Duseja A. Taneja S. Changing nomenclature from nonalcoholic fatty liver disease to metabolic dysfunction-associated fatty liver disease - not only premature but also confusing.J Clin Exp Hepatol. 2021; 11: 278-279https://doi.org/10.1016/j.jceh.2020.08.002Google Scholar Different subtypes or stages of a particular disease may have varying prognosis but should be categorised under a single etiology. Putative pathophysiological drivers in lean patients with MAFLD (-)/NAFLD (+) like gut microbiota and genetics also play a role in MAFLD (+)/NAFLD (+).[6]Aron-Wisnewsky J. Vigliotti C. Witjes J. Le P. Holleboom A.G. Verheij J. et al.Gut microbiota and human NAFLD: disentangling microbial signatures from metabolic disorders.Nat Rev Gastroenterol Hepatol. 2020; 17: 279-297https://doi.org/10.1038/s41575-020-0269-9Google Scholar,[7]Eslam M. George J. Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology.Nat Rev Gastroenterol Hepatol. 2020 Jan; 17: 40-52https://doi.org/10.1038/s41575-019-0212-0Google Scholar It should also be noted that patients with lean NAFLD are usually younger than those with the classical NAFLD phenotype who also qualify as MAFLD.[8]Younes R. Govaere O. Petta S. Miele L. Tiniakos D. Burt A. et al.Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach?.Gut. 2021; (Epub ahead of print)https://doi.org/10.1136/gutjnl-2020-322564Google Scholar,[9]Young S. Tariq R. Provenza J. Satapathy S.K. Faisal K. Choudhry A. et al.Prevalence and profile of nonalcoholic fatty liver disease in lean adults: systematic review and meta-analysis.Hepatol Commun. 2020; 4: 953-972https://doi.org/10.1002/hep4.1519Google Scholar In the present study too, patients with MAFLD (-)/NAFLD (+) were almost a decade younger (35.0 ± 0.9 years) than those with MAFLD (+)/NAFLD (+) (47.2 ± 0.6 years).[1]Kim D. Konyn P. Sandhu K.K. Dennis B.B. Cheung A.C. Ahmed A. Metabolic dysfunction-associated fatty liver disease is associated with increased all-cause mortality in the United States.J Hepatol. 2021; 75 (S0168-8278(21)01964-4): 1284-1291https://doi.org/10.1016/j.jhep.2021.07.035Google Scholar It is plausible that the subtle metabolic derangements in these young patients with MAFLD (-)/NAFLD (+) are not yet severe enough to be clinically discernible but will become so with the passage of time. Indeed, in a community-based study, patients with MAFLD (-)/NAFLD (+) had a significantly higher risk of developing new onset diabetes mellitus compared to controls with an adjusted relative risk of 2.2.[10]Niriella M.A. Ediriweera D.S. Kasturiratne A. De Silva S.T. Dassanayaka A.S. De Silva A.P. et al.Outcomes of NAFLD and MAFLD: results from a community-based, prospective cohort study.PLoS One. 2021; 16e0245762https://doi.org/10.1371/journal.pone.0245762Google Scholar In conclusion, the debate on the nomenclature of NAFLD vs. MAFLD is far from over. It is not the name but the disease that decides the outcome of patients with fatty liver disease. AbbreviationsNAFLD, Non-alcoholic fatty liver disease; MAFLD, Metabolic dysfunction-associated fatty liver disease; NASH, Non-alcoholic steatohepatitis; T2DM, Type 2 diabetes mellitus; HDL, High density lipoprotein; hs-CRP, High sensitivity-C-reactive protein (hs-CRP); HOMA-IR, Homeostasis model assessment insulin resistance; BMI, Body mass index. AbbreviationsNAFLD, Non-alcoholic fatty liver disease; MAFLD, Metabolic dysfunction-associated fatty liver disease; NASH, Non-alcoholic steatohepatitis; T2DM, Type 2 diabetes mellitus; HDL, High density lipoprotein; hs-CRP, High sensitivity-C-reactive protein (hs-CRP); HOMA-IR, Homeostasis model assessment insulin resistance; BMI, Body mass index. NAFLD, Non-alcoholic fatty liver disease; MAFLD, Metabolic dysfunction-associated fatty liver disease; NASH, Non-alcoholic steatohepatitis; T2DM, Type 2 diabetes mellitus; HDL, High density lipoprotein; hs-CRP, High sensitivity-C-reactive protein (hs-CRP); HOMA-IR, Homeostasis model assessment insulin resistance; BMI, Body mass index. Financial supportThe authors received no financial support to produce this manuscript. The authors received no financial support to produce this manuscript. Authors’ contributionsAr De: manuscript writing, data analysis and critical revision, NA- writing, MM: data curation and analysis, PS: data curation and analysis, AD: data curation and critical revision Ar De: manuscript writing, data analysis and critical revision, NA- writing, MM: data curation and analysis, PS: data curation and analysis, AD: data curation and critical revision The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. Supplementary dataThe following are the supplementary data to this article: Download .pdf (.22 MB) Help with pdf files Multimedia component 1 The following are the supplementary data to this article: Download .pdf (.22 MB) Help with pdf files Multimedia component 1