The Surreptitious Burden of Nonalcoholic Fatty Liver Disease in the Elderly in the Asia-Pacific Region: An Insight from the Global Burden of Disease Study 2019

Round 1

Reviewer 1 Report

GENERAL COMMENT

Based on the assumption that the aging population and a rise in metabolic syndrome might affect the epidemiology of MASLD among the elderly, this study finds that the burden of MASLD in the elderly population in Asia-Pacific has increased, with notable sex differences among the two principal geographic areas being investigated.  

SPECIFIC COMMENT

1. Title – I am afraid the adjective “SURREPTITIOUS” (synonims HIDDEN, COVERT) is never explained across the manuscript. What do these Authors exactly mean? I suggest addressing this point both in the abstract and in the discussion/conclusion.
2. Data of the present study are based on ICD-10 code for nonalcoholic fatty liver disease. Therefore, why not to use “NAFLD” instead of MASLD? As far as I know, “NAFLD” has not yet been abolished by law yet and using NAFLD would mirror the essence of the study more faithfully.
3. If available, it would be important to add some data regarding how hospitals diagnosed NAFLD, namely with liver biopsy/imaging/biomarkers.
4. The background information, namely that the aging population and a rise in metabolic syndrome might affect the epidemiology of MASLD among the elderly, should also consider that “metabolic fatty liver syndromes” (MFLS: NAFLD/MAFLD/MASLD) may decrease life expectancy selectively among young adults (principally owing to mortality due to cardiovascular disease); additionally, steatosis is known to regress over time, especially (but not only) in the presence of fibrosing liver disease. Taken together, these two phenomena may generate a heavy selection bias when studying MFLS among the elderly.      
5. Across the manuscript sometimes authors use “Asian” and other times “Asia-Pacific” which may possibly generate misunderstandings as to whether also Australia is being considered or not. Please address this point by making clear at the beginning of the paper, further to the list of those which are being investigated also those geographic areas of Pacific which are excluded.
6. I appreciate that authors emphasize sex differences being identified by their research. However, such sex disparities are not sufficiently discussed nor confronted with current views of sex dimorphism of MFLS.
7. Also, literature on MFLS (and particularly seminal studies on geriatric NAFLD) is incompletely addressed for comparison purposes.
8. “the liver-related burden of metabolic dysfunction-associated steatohepatitis is increasing. It is also vital to view MASLD not just as a standalone liver disease but as a holistic disorder closely tied to significant cardiovascular complications” It seems to me that the adjective “cardiometabolic” might be preferrable in this context and that the cancer burden of disease should not be neglected. Please rephrase accordingly.
9. Please, develop discussion of the implications of findings reported here as regards personalized medicine approaches in the arena of NAFLD and metabolic disorders.
10. Additional readings and suggested citations: J Hepatol. 2012 Dec;57(6):1305-11.  World J Gastroenterol. 2014 Oct 21;20(39):14185-204.  Aging Clin Exp Res. 2020 Dec;32(12):2657-2665. Metab Target Organ Damage. 2021, 1, 3. http://dx.doi.org/10.20517/mtod.2021.03 Liver Int. 2017 Nov;37(11):1706-1714. . Clin Interv Aging. 2021 Sep 13;16:1633-1649. Aging Dis. 2022 Jul 11;13(4):1239-1251. Endocr J. 2022 Aug 29;69(8):1007-1014.  Ann Nutr Metab. 2022;78(1):21-32. Aging Dis. 2022 Jul 11;13(4):1239-1251. 

 

 

Author Response

REVIEWER 1 COMMENTS:

Comment 1: Title – I am afraid the adjective “SURREPTITIOUS” (synonims HIDDEN, COVERT) is never explained across the manuscript. What do these Authors exactly mean? I suggest addressing this point both in the abstract and in the discussion/conclusion.

Response 1: (Page 1, Line 40 and Page 12, Lines 281 to 283) We express our gratitude to the reviewer for their valuable input. In our revised manuscript, we have expanded upon the notion that this disease is often considered "surreptitious" due to its tendency to go unnoticed. This is primarily attributed to its asymptomatic nature and the lack of specific guidelines for managing this condition in the elderly. We have added this information about the terms surreptitious (silent) that we used in the revised version of the manuscript, including

From Page 1, Line 40: However, there is a lack of limited understanding of the burden and recommendation of NAFLD in this group.

From Page 12, Line 281 to 283: Furthermore, it's important to note that there are currently no specific guidelines offering recommendations for diagnostic procedures to be followed in elderly individuals with NAFLD.

We appreciate the reviewer's contribution and have incorporated this aspect into the updated version of our manuscript.

Comment 2: Data of the present study are based on ICD-10 code for nonalcoholic fatty liver disease. Therefore, why not to use “NAFLD” instead of MASLD? As far as I know, “NAFLD” has not yet been abolished by law yet and using NAFLD would mirror the essence of the study more faithfully.

Response 2: (Page 3, Lines 91 to 96) The term NAFLD is the older nomenclature, which was subsequently updated to MASLD by the committee of NAFLD collaborators. Importantly, data related to these two terms can be used interchangeably. Initially, we employed the term MASLD, but as we extracted data from the ICD-10 and databases documenting it as NAFLD, we concurred with the reviewer's suggestion to utilize the more appropriate term. We have made the necessary terminology adjustments from MASLD to NAFLD throughout our data, including the manuscript, abstract, figures, tables, and supplementary material. We highly appreciate the reviewer's insightful recommendation to align the terminology with the study's accuracy.

Comment 3: If available, it would be important to add some data regarding how hospitals diagnosed NAFLD, namely with liver biopsy/imaging/biomarkers.

Response 3: (Page 3, Lines 91 to 96 and Lines 121 to 168) We extend our gratitude to the reviewer for emphasizing this critical aspect. In response, we have incorporated details about the specific statistical method utilized in the Global Burden of Disease Study 2019 into our manuscript. In summary, this method relies on the ICD-10 and extends its reach to estimate the burden of disease in populations and regions where data might have been incomplete. The detailed information about the specific NAFLD diagnostic methods used is not provided in the data sources. However, the comprehensive methodology for calculating NAFLD-related data is now included in the revised manuscript's methodology section. We genuinely value the insightful contribution made by the reviewer.

Comment 4: The background information, namely that the aging population and a rise in metabolic syndrome might affect the epidemiology of MASLD among the elderly, should also consider that “metabolic fatty liver syndromes” (MFLS: NAFLD/MAFLD/MASLD) may decrease life expectancy selectively among young adults (principally owing to mortality due to cardiovascular disease); additionally, steatosis is known to regress over time, especially (but not only) in the presence of fibrosing liver disease. Taken together, these two phenomena may generate a heavy selection bias when studying MFLS among the elderly. 

Response 4: (Page 3, Lines 91 to 96 and Page 12, Lines 279 to 283) We express our sincere appreciation to the reviewer for bringing up this important matter. We want to clarify that the terms we initially introduced, namely MASLD (Metabolic Dysfunction Associated Fatty Liver Disease), an updated term from the older NAFLD (Nonalcoholic Fatty Liver Disease),  are indeed interchangeable and convey the same meaning. However, the original database used in this study specifically referred to the term "NAFLD." Therefore, in line with Comment 2 and for consistency with the database and previous research, we have opted to use the term "NAFLD," which aligns more accurately. Additionally, it's noteworthy that the term "Metabolic Fatty Liver Disease" or MFLS does not have an official nomenclature. Hence, we have made the decision to employ the term "NAFLD," which is more in line with established terminology. The observation regarding the potential regression of steatosis, particularly during the fibrotic stage, is indeed insightful. However, it's essential to recognize that the Global Burden of Disease Study uses the term "NAFLD" to encompass the total burden of the condition, including individuals who have progressed to fibrosis stages. We also acknowledge the reviewer's valid point concerning the heightened burden of cardiovascular disease in NAFLD patients, which could introduce selection bias. The revised version in the section is “However, when interpreting the burden of NAFLD in the elderly in comparison to the younger population, caution is advised. This is due to the fact that individuals with NAFLD tend to be at an elevated risk of developing cardiometabolic complications, which could potentially introduce a selection bias into this elderly group.” In response to this concern, we have integrated this valuable comment into our manuscript. We are genuinely thankful for the reviewer's contributions, which have enhanced the quality of our work.

Comment 5: Across the manuscript sometimes authors use “Asian” and other times “Asia-Pacific” which may possibly generate misunderstandings as to whether also Australia is being considered or not. Please address this point by making clear at the beginning of the paper, further to the list of those which are being investigated also those geographic areas of Pacific which are excluded.

Response 5: We want to express our profound gratitude to the reviewer for their valuable insights concerning the technical terminology we utilized. We have duly considered the reviewer's reference to the GBD World Health Organization region, which encompasses Australia and have integrated this information throughout our manuscript, including revising the title accordingly. In the interest of improved clarity, we have also replaced the term "Asia" with "Asia Pacific" across our manuscript, including the title. Once more, we extend our heartfelt thanks to the reviewer for their insightful comments, as we believe these adjustments will significantly contribute to the quality of our revised manuscript.

Comment 6: I appreciate that authors emphasize sex differences being identified by their research. However, such sex disparities are not sufficiently discussed nor confronted with current views of sex dimorphism of MFLS.

Response 6: (Page 12 Lines 285 to 304) We extend our appreciation to the reviewer for their valuable insights. We have conducted a thorough review of the existing literature and have subsequently revised our manuscript, including a detailed comparison and contrast with previous studies, including those utilizing the same global database. In the updated manuscript, we have also introduced a comprehensive discussion on gender-related differences. We sincerely thank the reviewer for their insightful comments, which have contributed significantly to the refinement of our work.

Comment 7: Also, literature on MFLS (and particularly seminal studies on geriatric NAFLD) is incompletely addressed for comparison purposes.

Response 7: (Page 12, Lines 272 to 283) We acknowledge and appreciate the reviewer's comment. It's worth highlighting that research on geriatric NAFLD, or the more contemporary official term MASLD, is still in its nascent stages. Nonetheless, we have integrated these updates into the revised version of our manuscript. We extend our sincere thanks to the reviewer for their valuable contributions.

Comment 8:  “the liver-related burden of metabolic dysfunction-associated steatohepatitis is increasing. It is also vital to view MASLD not just as a standalone liver disease but as a holistic disorder closely tied to significant cardiovascular complications” It seems to me that the adjective “cardiometabolic” might be preferrable in this context and that the cancer burden of disease should not be neglected. Please rephrase accordingly.

Response 8: (Page 13, Line 316) We agree with the reviewer's recommendation that utilizing the term "cardiometabolic" may be more effectively encompass the burden of the complications we aim to convey. We extend our gratitude to the reviewer for highlighting this crucial terminology.

Comment 9: Please, develop discussion of the implications of findings reported here as regards personalized medicine approaches in the arena of NAFLD and metabolic disorders.

Response 9: (Page 14, Lines 345 to 358) We want to express our sincere appreciation to the reviewer for bringing to our attention numerous valuable and pertinent studies that have substantially enhanced our manuscript's refinement and overall quality. In response, we conducted an extensive literature review and cited the suggested studies within the manuscript. The reviewer's comments have had a profound impact on the trajectory and excellence of our work, and we genuinely value their insightful contributions. These modifications have been integrated into the revised manuscript, and we are truly thankful for the reviewer's valuable input.

Comment 10: Additional readings and suggested citations: J Hepatol. 2012 Dec;57(6):1305-11.  World J Gastroenterol. 2014 Oct 21;20(39):14185-204.  Aging Clin Exp Res. 2020 Dec;32(12):2657-2665. Metab Target Organ Damage. 2021, 1, 3. http://dx.doi.org/10.20517/mtod.2021.03 Liver Int. 2017 Nov;37(11):1706-1714. . Clin Interv Aging. 2021 Sep 13;16:1633-1649. Aging Dis. 2022 Jul 11;13(4):1239-1251. Endocr J. 2022 Aug 29;69(8):1007-1014.  Ann Nutr Metab. 2022;78(1):21-32. Aging Dis. 2022 Jul 11;13(4):1239-1251.

Response 10: We want to convey our appreciation to the reviewer for pointing out several engaging studies that have played a substantial role in refining and elevating our manuscript. We have diligently conducted an extensive literature review and integrated citations from these recommended studies into the manuscript. Your invaluable insights have been pivotal in enhancing the quality of our work.

Reviewer 2 Report

In the manuscript “The surreptitious burden of metabolic dysfunction associated steatotic liver disease in the elderly Asians: an insight from the global burden of disease study 2019", the authors take advantage of the global burden of disease study 2019 to show the increasing prevalence of MASLD in the elderly Asians. The paper is interesting, although it is known that MASLD is increasing. Moreover, I have some suggestions that could improve the scientific outcome of the manuscript.

 

Line 76: "(1)" is it a reference?

Figure 1A and C: Is "frequency of cases" adjusted for the population in each area (Southeast vs Western Pacific)? If yes, this should be stated. If not, then the areas are not comparable.

In figure 2C, there is a significant decrease in females (2017-2019). Do the authors know the reason for this decrease?

Author Response

REVIEWER 2 COMMENTS:

Comment 1: Line 76: "(1)" is it a reference?

Response 1: (Page 3, Line 83) We extend our gratitude to the reviewer for their insightful comment. We have made the necessary corrections to align with the citation format used for the Global Burden of Disease Study 2019 reference. Your feedback is highly valued, and we appreciate your contribution.

Comment 2: Figure 1A and C: Is "frequency of cases" adjusted for the population in each area (Southeast vs Western Pacific)? If yes, this should be stated. If not, then the areas are not comparable.

Response 2: (Page 6, Lines 186 to 187) We want to convey our appreciation to the reviewer for their exceptionally insightful comment. We have taken this feedback into serious consideration and have made the required adjustments to eliminate any comparisons between the two World Health Organization regions. We genuinely value the valuable perspective provided by the reviewer, and this modification has been integrated into the revised manuscript.

Comment 3: In Figure 2C, there is a significant decrease in females (2017-2019). Do the authors know the reason for this decrease?

Response 3: (Page 15, Lines 377 to 382) We would like to thank the reviewer for their insightful comment regarding the mild downtrend observed in Figure 2C. While we have not found an exact answer to explain this temporal progression, we believe this downtrend could be attributed to a decrease in the burden of other causes of liver disease. The Global Burden of Disease (GBD) methodology first calculates overall DALYs from total liver-related deaths, including those due to alcohol, NAFLD, viral hepatitis, and other etiologies. We hypothesize that the success in reducing total liver-related deaths from viral hepatitis during this timeframe may have contributed to the overall lower DALYs in NAFLD. We genuinely appreciate the reviewer's insightful comments and have incorporated this explanation into the revised manuscript.

Round 2

Reviewer 1 Report

Dear Authors,

many thanks for acepting my suggestions. After I submitted my first revision a groups from Sweden has published in J Hepatol evidence that MASLD overlaps 99% with NAFLD and has the same natural course.

Kind Regards and good luck to your important publication.