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Histologic Severity of Nonalcoholic Fatty Liver Disease Associates with Reduced Bone Mineral Density in Children

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Abstract

Background

Lower whole body bone mineral density (BMD) has been reported in children with nonalcoholic fatty liver disease (NAFLD), but potential mediators remain uncertain.

Aims

To assess BMD at multiple skeletal sites in children with confirmed NAFLD and controls with obesity, adjusting for known determinants of BMD, and examine potential mediators.

Methods

We assessed age-, sex-, and race-specific, and height-adjusted BMD z-scores of whole body, lumbar spine, hip, femoral neck and forearm by dual-energy-x-ray absorptiometry in 79 children, 8–19 years old: 46 with biopsy-confirmed NAFLD [29 steatohepatitis (NASH)/17 fatty liver (NAFL)] and 33 controls without liver disease. We compared BMD z-scores by multivariable regression, adjusting for known BMD determinants and potential mediators (inflammatory and insulin resistance measures).

Results

Unadjusted mean BMD z-scores in NAFLD were similar to controls, but significantly lower in NASH vs. NAFL at all sites. After covariate adjustment, mean forearm BMD z-score was higher in NAFL (β 0.60 ± SE 0.30, p < 0.05) and lower in NASH (β – 0.49 ± SE 0.26, p = 0.06) vs. controls (p = 0.002 for group), with similar trends at whole body and total hip; hs-CRP negatively associated with whole body and forearm BMD z-scores (p < 0.05), while visceral fat area negatively associated with femoral neck (p < 0.05). Only three children had clinically low whole body BMD z-scores (< – 2), one per group (control, NAFL and NASH).

Conclusions

NASH, but not NAFL, may be associated with increased risk of reduced BMD in children. Systemic inflammation, independent of body composition and load bearing, may mediate reduction in BMD in NASH.

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Abbreviations

ALMI:

Appendicular lean mass index

ALT:

Alanine aminotransferase

AST:

Aspartate aminotransferase

BMI:

Body mass index

BMD:

Bone mineral density

BMDZ:

Bone mineral density Z-scores

DXA:

Dual energy x-ray absorptiometry

FMI:

Fat mass index

GGT:

Gamma glutamyl transferase

HAZ-BMDZ:

Height-adjusted BMD Z-scores

HDL:

High density lipoprotein cholesterol

HbA1c:

Hemoglobin A1C

HOMA-IR:

Homeostasis model assessment of insulin resistance

hs-CRP:

High sensitivity c-reactive protein

LDL:

Low density lipoprotein cholesterol

NAFL:

Nonalcoholic fatty liver

NAFLD:

Nonalcoholic fatty liver disease

NAS:

NAFLD activity score

NASH:

Nonalcoholic steatohepatitis

UNL:

Upper limit of normal

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Acknowledgments

We gratefully acknowledge the assistance of Drs. Marialena Mouzaki and Kristin Bramlage in the recruitment of participants for this study.

Funding

Dr. Khan was funded by the National Institutes of Health (NIH) T32 Training Grant DK007727. This work was supported by the Clinical Center for Translational Science and Training, Clinical and Translational Science Award (CTSA) program grant 5UL1TR001425-04 from the National Center for Advancing Translational Sciences (NCATS) of the NIH. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Author information

Authors and Affiliations

  1. Division of Gastroenterology, Phoenix Children’s, Phoenix, AZ, USA

    Soofia Khan

  2. Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children’s Hospital Medical Center Cincinnati, 3333 Burnet Avenue, Cincinnati, OH, 45229, USA

    Heidi J. Kalkwarf, Ana Catalina Arce-Clachar & Stavra A. Xanthakos

  3. Division of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, USA

    Lindsey Hornung

  4. The Heart Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, USA

    Robert Siegel & Holly M. Ippisch

  5. Department of Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, USA

    Rachel Sheridan

  6. Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA

    Heidi J. Kalkwarf, Robert Siegel, Ana Catalina Arce-Clachar, Rachel Sheridan, Holly M. Ippisch & Stavra A. Xanthakos

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  1. Soofia Khan
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  3. Lindsey Hornung
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  8. Stavra A. Xanthakos
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Contributions

Study concept and design: SK, HK, SX. Drafting of manuscript: LH, HK, SK, SX. All authors contributed to acquisition, analysis, interpretation of data, critical revisions for important intellectual content and gave final approval.

Corresponding author

Correspondence to Stavra A. Xanthakos.

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Conflict of interest

Dr. Xanthakos has received unrelated research grants from Axcella Health and Target RWE (Real World Evidence). The other authors have no disclosures.

Consent to participate

Informed consent and informed assent was obtained from all participants and legal guardians, as appropriate. The CCHMC Institutional Review Board approved the study.

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Khan, S., Kalkwarf, H.J., Hornung, L. et al. Histologic Severity of Nonalcoholic Fatty Liver Disease Associates with Reduced Bone Mineral Density in Children. Dig Dis Sci 68, 644–655 (2023). https://doi.org/10.1007/s10620-022-07563-z

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  • DOI: https://doi.org/10.1007/s10620-022-07563-z

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