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  • 1. Aims and Scope

    Gut and Liver is an international journal of gastroenterology, focusing on the gastrointestinal tract, liver, biliary tree, pancreas, motility, and neurogastroenterology. Gut atnd Liver delivers up-to-date, authoritative papers on both clinical and research-based topics in gastroenterology. The Journal publishes original articles, case reports, brief communications, letters to the editor and invited review articles in the field of gastroenterology. The Journal is operated by internationally renowned editorial boards and designed to provide a global opportunity to promote academic developments in the field of gastroenterology and hepatology. +MORE

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    Yong Chan Lee Professor of Medicine
    Director, Gastrointestinal Research Laboratory
    Veterans Affairs Medical Center, Univ. California San Francisco
    San Francisco, USA

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    Deputy Editor
    Jong Pil Im Seoul National University College of Medicine, Seoul, Korea
    Robert S. Bresalier University of Texas M. D. Anderson Cancer Center, Houston, USA
    Steven H. Itzkowitz Mount Sinai Medical Center, NY, USA
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High Fatty Liver Index and Fracture Risk: Clinical Implications

Namki Hong

Department of Internal Medicine, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea

Correspondence to: Namki Hong
ORCID https://orcid.org/0000-0002-8246-1956
E-mail nkhong84@yuhs.ac

See See “Relationship between the High Fatty Liver Index and Risk of Fracture” by Min-Ji Kim, et al. on page 119, Vol. 17, No. 1, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Gut Liver 2023;17(1):6-7. https://doi.org/10.5009/gnl220533

Published online January 15, 2023, Published date January 15, 2023

Copyright © Gut and Liver.

Osteoporotic fracture is one of the major health burdens in an aging society, leading to excess mortality and morbidity in older adults. From 2007 to 2011, the societal cost of osteoporotic fracture was estimated to increase annually from US \$88.8 million in 2007 to US \$149.3 million in 2011, and a steeper increase in health costs is expected according to rapid aging in South Korea.1 Among Korean adults aged 50 or older, the cumulative incidence of subsequent fractures gradually increased over 4 years of follow-up once an osteoporotic fracture occurred, along with high crude fatality rates in the first 12 months after hip fracture (14.0% for women and 21.0% for men).2 Despite recent advances in pharmacologic interventions including potent antiresorptive or anabolic agents such as denosumab or romosozumab, more tailored approach to reduce lifetime fracture risk at individual level remains unmet need to improve fracture prevention strategy, including the management of metabolic risk profiles.

Metabolic crosstalk between nonalcoholic fatty liver disease (NAFLD) and osteoporosis, as the most representative and prevalent metabolic diseases reflecting disrupted homeostasis in fat metabolism and the skeletal system, has been intensively investigated in prior literatures. However, the results remain controversial that some studies reported independent association of NAFLD with new onset osteoporosis, whereas some argued null association between NAFLD and bone mineral density.3,4 Although common pathophysiologic links such as chronic inflammation and insulin resistance provide potential biological plausibility, the mechanical aspect of bone mass regulation makes interpretation of association between NAFLD and bone mineral density more complex that tendency toward obesity in individuals with NAFLD lead to constantly higher mechanical loading to axial bones, thereby preserving bone mass. Therefore, it would be important to study the fracture risk as clinical outcome in individuals with NAFLD for providing robust rationale to investigate crosstalk between NALFD and the skeletal system.

In this issue of Gut and Liver, Kim et al.5 comprehensively assessed the association of biochemical indices of NAFLD (fatty liver index, FLI) with incident fracture risk during median 4.6 years of follow-up in a large Korean national claim database. Highest FLI quartile, calculated using triglyceride, body mass index, gamma-glutamyl transferase (GGT), and waist circumference, was associated with 23% increased risk of fracture compared to lowest quartile after adjustment for potential confounders. In subgroup analysis, the association between NALFD and elevated fracture risk remained robust in individuals with body mass index >25 kg/m2, or those with normal blood pressure or fasting glucose level <126 mg/dL. As authors stated, these findings suggest that more clinical attention regarding fracture risk management may be warranted to individuals with high FLI score, with calls for future studies to elaborate mechanisms linking liver-bone axis.

Some clinical implications can be postulated from this finding. Although routine osteoporosis screening or fracture risk assessment in overall patients with NAFLD may not be supported by current evidences,6 presence of risk factors such as prior fracture history, menopause, or concomitant glucocorticoid use can be utilized as clinical indications for bone density testing with fracture risk assessment in patients with NAFLD. Severity of NAFLD assessed by biochemical indices, either by collective score or by separate components, may provide relevant information to set the threshold for indication of fracture risk assessment. Notably, in a recent study using the Korean national claim database, elevated serum GGT level, a component for FLI score, was associated with increased hip fracture risk in continuous fashion (17% increase per one log unit increment) in Korean postmenopausal women, which align well with the finding observed in Kim’s study in this issue.7 Considering the proposed association between elevated GGT and sarcopenia, as another musculoskeletal complication that linked to NAFLD, whether serum GGT testing can improve fracture risk prediction when added to established clinical risk factors is an interesting research topic that intersects liver-bone field.8,9 Given the known negative impact of thiazolidinedione on bone mass and fracture risk in postmenopausal women, careful weighing of benefit and skeletal risk at individual level is warranted when commencing thiazolidinedione to improve NAFLD with biopsy-proven fibrosis. Receptor activator of nuclear factor-κB ligand (RANKL) is a key regulator of osteoclastogenesis. Humanized monoclonal RANKL antibody, denosumab, is now becoming a first-line bone active drug to reduce fracture risk with rapid gain of bone mass. Of note, RANKL is also reported to affect energy metabolism that RANKL blockade recovered hepatic insulin resistance and improved grip strength in rodent model.10 Further evidences are awaited to test whether drug repurposing strategy using bone active drugs to treat NAFLD can be effective.

Taken together, accumulating evidences portend that deterioration of musculoskeletal function, represented by increased fracture risk in Kim’s study, can be one of important clinical aspects in NAFLD that requires individualized management along with trend toward aging. Development of tailored strategy to effectively reduce fracture risk in patients with NAFLD, including targeting sarcopenia as one of potential therapeutic culprit, remains as clinical unmet need that calls further research.

No potential conflict of interest relevant to this article was reported.

  1. Kim J, Lee E, Kim S, Lee TJ. Economic burden of osteoporotic fracture of the elderly in South Korea: a national survey. Value Health Reg Issues 2016;9:36-41.
    Pubmed CrossRef
  2. Ahn SH, Park SM, Park SY, et al. Osteoporosis and osteoporotic fracture fact sheet in Korea. J Bone Metab 2020;27:281-290.
    Pubmed KoreaMed CrossRef
  3. Shen Z, Cen L, Chen X, et al. Increased risk of low bone mineral density in patients with non-alcoholic fatty liver disease: a cohort study. Eur J Endocrinol 2020;182:157-164.
    Pubmed CrossRef
  4. Upala S, Jaruvongvanich V, Wijarnpreecha K, Sanguankeo A. Nonalcoholic fatty liver disease and osteoporosis: a systematic review and meta-analysis. J Bone Miner Metab 2017;35:685-693.
    Pubmed CrossRef
  5. Kim MJ, Kim MS, Lee HB, Roh JH, Jeon JH. Relationship between the high fatty liver index and risk of fracture. Gut Liver 2023;17:119-129.
    Pubmed CrossRef
  6. Wester A, Hagström H. Risk of fractures and subsequent mortality in non-alcoholic fatty liver disease: a nationwide population-based cohort study. J Intern Med 2022;292:492-500.
    Pubmed KoreaMed CrossRef
  7. Kim KJ, Hong N, Yu MH, et al. Elevated gamma-glutamyl transpeptidase level is associated with an increased risk of hip fracture in postmenopausal women. Sci Rep 2022;12:13947.
    Pubmed KoreaMed CrossRef
  8. Hong N, Lee EY, Kim CO. Gamma-glutamyl transferase is associated with sarcopenia and sarcopenic obesity in community-dwelling older adults: results from the Fifth Korea National Health and Nutrition Examination Survey, 2010-2011. Endocr J 2015;62:585-592.
    Pubmed CrossRef
  9. Lee S, Song D, Shin S, Hong N, Rhee Y. Elevated serum γ-glutamyl transferase is associated with low muscle function in adults independent of muscle mass. Nutrition 2022;103-104:111813.
    Pubmed CrossRef
  10. Kiechl S, Wittmann J, Giaccari A, et al. Blockade of receptor activator of nuclear factor-κB (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus. Nat Med 2013;19:358-363.
    Pubmed CrossRef

Article

Editorial

Gut and Liver 2023; 17(1): 6-7

Published online January 15, 2023 https://doi.org/10.5009/gnl220533

Copyright © Gut and Liver.

High Fatty Liver Index and Fracture Risk: Clinical Implications

Namki Hong

Department of Internal Medicine, Endocrine Research Institute, Yonsei University College of Medicine, Seoul, Korea

Correspondence to:Namki Hong
ORCID https://orcid.org/0000-0002-8246-1956
E-mail nkhong84@yuhs.ac

See See “Relationship between the High Fatty Liver Index and Risk of Fracture” by Min-Ji Kim, et al. on page 119, Vol. 17, No. 1, 2023

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Body

Osteoporotic fracture is one of the major health burdens in an aging society, leading to excess mortality and morbidity in older adults. From 2007 to 2011, the societal cost of osteoporotic fracture was estimated to increase annually from US \$88.8 million in 2007 to US \$149.3 million in 2011, and a steeper increase in health costs is expected according to rapid aging in South Korea.1 Among Korean adults aged 50 or older, the cumulative incidence of subsequent fractures gradually increased over 4 years of follow-up once an osteoporotic fracture occurred, along with high crude fatality rates in the first 12 months after hip fracture (14.0% for women and 21.0% for men).2 Despite recent advances in pharmacologic interventions including potent antiresorptive or anabolic agents such as denosumab or romosozumab, more tailored approach to reduce lifetime fracture risk at individual level remains unmet need to improve fracture prevention strategy, including the management of metabolic risk profiles.

Metabolic crosstalk between nonalcoholic fatty liver disease (NAFLD) and osteoporosis, as the most representative and prevalent metabolic diseases reflecting disrupted homeostasis in fat metabolism and the skeletal system, has been intensively investigated in prior literatures. However, the results remain controversial that some studies reported independent association of NAFLD with new onset osteoporosis, whereas some argued null association between NAFLD and bone mineral density.3,4 Although common pathophysiologic links such as chronic inflammation and insulin resistance provide potential biological plausibility, the mechanical aspect of bone mass regulation makes interpretation of association between NAFLD and bone mineral density more complex that tendency toward obesity in individuals with NAFLD lead to constantly higher mechanical loading to axial bones, thereby preserving bone mass. Therefore, it would be important to study the fracture risk as clinical outcome in individuals with NAFLD for providing robust rationale to investigate crosstalk between NALFD and the skeletal system.

In this issue of Gut and Liver, Kim et al.5 comprehensively assessed the association of biochemical indices of NAFLD (fatty liver index, FLI) with incident fracture risk during median 4.6 years of follow-up in a large Korean national claim database. Highest FLI quartile, calculated using triglyceride, body mass index, gamma-glutamyl transferase (GGT), and waist circumference, was associated with 23% increased risk of fracture compared to lowest quartile after adjustment for potential confounders. In subgroup analysis, the association between NALFD and elevated fracture risk remained robust in individuals with body mass index >25 kg/m2, or those with normal blood pressure or fasting glucose level <126 mg/dL. As authors stated, these findings suggest that more clinical attention regarding fracture risk management may be warranted to individuals with high FLI score, with calls for future studies to elaborate mechanisms linking liver-bone axis.

Some clinical implications can be postulated from this finding. Although routine osteoporosis screening or fracture risk assessment in overall patients with NAFLD may not be supported by current evidences,6 presence of risk factors such as prior fracture history, menopause, or concomitant glucocorticoid use can be utilized as clinical indications for bone density testing with fracture risk assessment in patients with NAFLD. Severity of NAFLD assessed by biochemical indices, either by collective score or by separate components, may provide relevant information to set the threshold for indication of fracture risk assessment. Notably, in a recent study using the Korean national claim database, elevated serum GGT level, a component for FLI score, was associated with increased hip fracture risk in continuous fashion (17% increase per one log unit increment) in Korean postmenopausal women, which align well with the finding observed in Kim’s study in this issue.7 Considering the proposed association between elevated GGT and sarcopenia, as another musculoskeletal complication that linked to NAFLD, whether serum GGT testing can improve fracture risk prediction when added to established clinical risk factors is an interesting research topic that intersects liver-bone field.8,9 Given the known negative impact of thiazolidinedione on bone mass and fracture risk in postmenopausal women, careful weighing of benefit and skeletal risk at individual level is warranted when commencing thiazolidinedione to improve NAFLD with biopsy-proven fibrosis. Receptor activator of nuclear factor-κB ligand (RANKL) is a key regulator of osteoclastogenesis. Humanized monoclonal RANKL antibody, denosumab, is now becoming a first-line bone active drug to reduce fracture risk with rapid gain of bone mass. Of note, RANKL is also reported to affect energy metabolism that RANKL blockade recovered hepatic insulin resistance and improved grip strength in rodent model.10 Further evidences are awaited to test whether drug repurposing strategy using bone active drugs to treat NAFLD can be effective.

Taken together, accumulating evidences portend that deterioration of musculoskeletal function, represented by increased fracture risk in Kim’s study, can be one of important clinical aspects in NAFLD that requires individualized management along with trend toward aging. Development of tailored strategy to effectively reduce fracture risk in patients with NAFLD, including targeting sarcopenia as one of potential therapeutic culprit, remains as clinical unmet need that calls further research.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

References

  1. Kim J, Lee E, Kim S, Lee TJ. Economic burden of osteoporotic fracture of the elderly in South Korea: a national survey. Value Health Reg Issues 2016;9:36-41.
    Pubmed CrossRef
  2. Ahn SH, Park SM, Park SY, et al. Osteoporosis and osteoporotic fracture fact sheet in Korea. J Bone Metab 2020;27:281-290.
    Pubmed KoreaMed CrossRef
  3. Shen Z, Cen L, Chen X, et al. Increased risk of low bone mineral density in patients with non-alcoholic fatty liver disease: a cohort study. Eur J Endocrinol 2020;182:157-164.
    Pubmed CrossRef
  4. Upala S, Jaruvongvanich V, Wijarnpreecha K, Sanguankeo A. Nonalcoholic fatty liver disease and osteoporosis: a systematic review and meta-analysis. J Bone Miner Metab 2017;35:685-693.
    Pubmed CrossRef
  5. Kim MJ, Kim MS, Lee HB, Roh JH, Jeon JH. Relationship between the high fatty liver index and risk of fracture. Gut Liver 2023;17:119-129.
    Pubmed CrossRef
  6. Wester A, Hagström H. Risk of fractures and subsequent mortality in non-alcoholic fatty liver disease: a nationwide population-based cohort study. J Intern Med 2022;292:492-500.
    Pubmed KoreaMed CrossRef
  7. Kim KJ, Hong N, Yu MH, et al. Elevated gamma-glutamyl transpeptidase level is associated with an increased risk of hip fracture in postmenopausal women. Sci Rep 2022;12:13947.
    Pubmed KoreaMed CrossRef
  8. Hong N, Lee EY, Kim CO. Gamma-glutamyl transferase is associated with sarcopenia and sarcopenic obesity in community-dwelling older adults: results from the Fifth Korea National Health and Nutrition Examination Survey, 2010-2011. Endocr J 2015;62:585-592.
    Pubmed CrossRef
  9. Lee S, Song D, Shin S, Hong N, Rhee Y. Elevated serum γ-glutamyl transferase is associated with low muscle function in adults independent of muscle mass. Nutrition 2022;103-104:111813.
    Pubmed CrossRef
  10. Kiechl S, Wittmann J, Giaccari A, et al. Blockade of receptor activator of nuclear factor-κB (RANKL) signaling improves hepatic insulin resistance and prevents development of diabetes mellitus. Nat Med 2013;19:358-363.
    Pubmed CrossRef
Gut and Liver

Vol.17 No.1
January, 2023

pISSN 1976-2283
eISSN 2005-1212

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