Reply
Authors: Linda Henry, James M. Paik, Zobair M. Younossi
Journal: Hepatology (2022)

We thank Fouad et al. and Attia et al. for their interest in our study about outcomes of NAFLD and MAFLD.[1–3] Because both letters raised similar concerns, we combined our responses. We believe there may be confusion about the MAFLD definition, which is “based on histological (biopsy), imaging or blood biomarker evidence of fat accumulation in the liver (hepatic steatosis) in addition to one of the following three criteria, namely overweight/obesity, presence of type 2 diabetes mellitus (T2DM), or evidence of metabolic dysregulation as defined by the presence of at least two metabolic risk abnormalities regardless of other liver diseases or alcohol consumption (not limited to ≤60 g).”[4] This is important because the assertion is about “superiority” of MAFLD over NAFLD due to metabolic dysfunction rather than “moderate alcohol consumption.”[2] To support their point, the authors refer to a study in which investigators defined MAFLD by excluding alcohol use ≥60 g/day, which is inconsistent with the original definition.[2,4] Although current evidence about the causality of alcohol and obesity is mixed,[5] it remains important to account for the confounding effect of alcohol‐associated liver disease (ALD) on MAFLD liver mortality. In fact, in our multivariable analysis, ALD strongly predicted liver‐specific mortality.[1] Furthermore, by using the National Health and Nutrition Examination Survey (NHANES) and the long‐term mortality data, our results are not only generalizable but in line with recently published studies using correct NHANES analytic methods.[6,7] The authors also voiced concerns on the lack of association of insulin resistance (IR) with liver mortality among MAFLD.[1,2] IR was associated with all‐cause mortality among MAFLD, suggesting its impact may be on nonliver mortality. Alternatively, ALD is such strong driver of liver mortality among MAFLD that it dilutes the impact of IR.[5] Central obesity (not overweight/obesity) was a significant risk factor for all‐cause mortality for MAFLD+ and NAFLD+.[1] The associations of central obesity and IR with NAFLD outcomes are not new findings, having been consistently documented over decades.[8] The authors questioned the use of moderate to severe steatosis by ultrasound to define fatty liver disease (FLD). This grade of steatosis is the most reliable FLD definition when using NHANES.[7] Furthermore, we applied the same threshold to both NAFLD and MAFLD negating any outcome differences. Attia et al. also declared the “superiority” of MAFLD over NAFLD as evidenced by “numerous studies and meta‐analyses,” but this assertion was not supported by their references.[3] They refer to a study reporting higher rates of fibrosis in MAFLD compared to NAFLD. Again, the investigators excluded alcohol use >60 g/day, which is not consistent with the “original definition.”[4] The authors also suggest “overadjustment” as a bias. This is not accurate because to avoid multicollinearity, we purposefully evaluated each risk factor by adjusting for only a few demographic and behavioral confounders. In fact, our findings remained robust when adjusted only for age, sex, race, smoking, and ALD (data not reported). Therefore, overadjustment cannot explain the association of ALD with adverse outcomes of MAFLD. Finally, the authors suggested MAFLD better captures health‐related quality of life (HRQL) impairment than NAFLD.[3] They referred to a study conducted in Egypt by both authors and published as a letter to the editor. The authors stated they used the chronic liver disease questionnaire (CLDQ) and concluded MAFLD/NAFLD, but not NAFLD alone, had HRQL impairment. First, the analysis of CLDQ was not consistent with CLDQ scoring.[9] Second, only including 14 patients with NAFLD is not adequate. Third, the validated CLDQ‐NAFLD/NASH is a more appropriate tool.[9] Fourth, performing only univariable comparison of HRQL data does not address the complexity of HRQL assessment in patients with NAFLD because obesity, T2DM, depression, and fatigue are major drivers of HRQL impairment.[9] Finally, their grouping appears artificial and does not address the comparison of HRQL between NAFLD and MAFLD. It is plausible that FLD in the presence of metabolic abnormality and ALD could result in profound impairment of HRQL, but the referenced study does not provide this evidence. We appreciate the concerns raised by Fouad et al. and Attia et al. As we assess the pros and cons for the appropriate terminology for FLD, it is imperative we understand the correct definitions and generate additional evidence. It is also absolutely critical that we allow international consensus groups from the American Association for the Study of Liver Diseases, the European Association for the Study of the Liver, the Asian Pacific Association for the Study of the Liver, patient advocacy groups, regulatory bodies, and the biopharmaceutical industry to come together and assess the nomenclature. Nevertheless, given the high burden of NAFLD reported from the Middle East/North Africa region,[10] we congratulate the authors for their interest and support this healthy exchange of ideas. CONFLICT OF INTEREST Dr. Younossi consults for Gilead, Viking, Siemens, Merck, and Madrigal.