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      Increased risk of osteoporosis in patients with nonalcoholic fatty liver disease : A population-based retrospective cohort study

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          Abstract

          The study aims to investigate the association between nonalcoholic fatty liver disease (NAFLD) and osteoporosis.

          We employed a retrospective cohort study design using the National Health Insurance Research Database in Taiwan. Our study included 2 cohorts: 4318 patients with NAFLD and 17,272 patients without NAFLD for comparison. They were matched by sex and age on the date of enrollment between January 1, 2000 and December 31, 2003. The study population in both groups was observed from the enrollment date until December 31, 2013. The incidence and the risk ratios of subsequent osteoporosis were calculated separately in both cohorts. A Cox proportional hazards model was used to assess the potential confounding variables of NAFLD on the pathogenesis of osteoporosis.

          The eligible study participants comprised 4318 patients in the NAFLD and 17,272 in control cohorts. The median follow-up duration was 10.7 and 10.83 years in the NAFLD and control groups, respectively. The risk of new-onset osteoporosis was higher in patients with NAFLD than in the comparison cohort. In addition, the difference of the incidence of new-onset osteoporosis remained significant among the 2 cohorts in the follow-up durations of within 1 year and more than 10 years. Patients with NAFLD were 1.35 times more likely to develop subsequent osteoporosis compared with those without NAFLD (95% confidence interval = 1.20–1.53).

          Our finding indicates that NAFLD might increase the risk of developing new-onset osteoporosis. For earlier detection and intervention, screening for osteoporosis in patients with the NAFLD, especially those with lower income and co-morbid with diabetes mellitus and chronic obstructive pulmonary disease, may be recommended.

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          Associations between serum 25-hydroxyvitamin D3 concentrations and liver histology in patients with non-alcoholic fatty liver disease.

          To explore associations between serum 25-hydroxyvitamin D(3) [25(OH)D] concentrations and liver histology in patients with non-alcoholic fatty liver disease (NAFLD). We studied 60 consecutive patients with biopsy-proven NAFLD, and 60 healthy controls of comparable age, sex and body mass index (BMI). NAFLD patients had a marked decrease in winter serum 25(OH)D concentrations (51.0+/-22 vs. 74.5+/-15 nmol/L, P<0.001) compared with controls. Metabolic syndrome (MetS; as defined by the Adult Treatment Panel III criteria) and its individual components occurred more frequently among NAFLD patients. The marked differences in 25(OH)D concentrations observed between the groups were little affected by adjustment for age, sex, BMI, creatinine, calcium, homeostasis model assessment (HOMA)-insulin resistance, and the presence of the MetS. Interestingly, among NAFLD patients, decreased 25(OH)D concentrations were closely associated with the histological severity of hepatic steatosis, necroinflammation and fibrosis (P<0.001 for all) independent of age, sex, BMI, creatinine, calcium, HOMA-insulin resistance, and presence of the MetS. Compared with controls, NAFLD patients have a marked decrease in serum 25(OH)D concentrations, which is closely associated with histopathological features of NAFLD. Further investigation into whether vitamin D(3) may play a role in the development and progression of NAFLD appears to be warranted.
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            Adipokines and proinflammatory cytokines, the key mediators in the pathogenesis of nonalcoholic fatty liver disease.

            Nonalcoholic fatty liver disease (NAFLD) is a condition in which excess fat accumulates in the liver of a patient with no history of alcohol abuse or other causes for secondary hepatic steatosis. The pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) has not been fully elucidated. The "two-hit" hypothesis is probably a too simplified model to elaborate complex pathogenetic events occurring in patients with NASH. It should be better regarded as a multiple step process, with accumulation of liver fat being the first step, followed by the development of necroinflammation and fibrosis. Adipose tissue, which has emerged as an endocrine organ with a key role in energy homeostasis, is responsive to both central and peripheral metabolic signals and is itself capable of secreting a number of proteins. These adipocyte-specific or enriched proteins, termed adipokines, have been shown to have a variety of local, peripheral, and central effects. In the current review, we explore the role of adipocytokines and proinflammatory cytokines in the pathogenesis of NAFLD. We particularly focus on adiponectin, leptin and ghrelin, with a brief mention of resistin, visfatin and retinol-binding protein 4 among adipokines, and tumor necrosis factor-α, interleukin (IL)-6, IL-1, and briefly IL-18 among proinflammatory cytokines. We update their role in NAFLD, as elucidated in experimental models and clinical practice.
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              Vitamin D deficiency in obese rats exacerbates nonalcoholic fatty liver disease and increases hepatic resistin and Toll-like receptor activation.

              Childhood obesity is associated with type 2 diabetes mellitus and nonalcoholic fatty liver disease (NAFLD). Recent studies have found associations between vitamin D deficiency (VDD), insulin resistance (IR), and NAFLD among overweight children. To further explore mechanisms mediating these effects, we fed young (age 25 days) Sprague-Dawley rats with a low-fat diet (LFD) alone or with vitamin D depletion (LFD+VDD). A second group of rats was exposed to a Westernized diet (WD: high-fat/high-fructose corn syrup) that is more typically consumed by overweight children, and was either replete (WD) or deficient in vitamin D (WD+VDD). Liver histology was assessed using the nonalcoholic steatohepatitis (NASH) Clinical Research Network (CRN) scoring system and expression of genes involved in inflammatory pathways were measured in liver and visceral adipose tissue after 10 weeks. In VDD groups, 25-OH-vitamin D levels were reduced to 29% (95% confidence interval [CI]: 23%-36%) compared to controls. WD+VDD animals exhibited significantly greater hepatic steatosis compared to LFD groups. Lobular inflammation as well as NAFLD Activity Score (NAS) were higher in WD+VDD versus the WD group (NAS: WD+VDD 3.2 ± 0.47 versus WD 1.50 ± 0.48, P < 0.05). Hepatic messenger RNA (mRNA) levels of Toll-like receptors (TLR)2, TLR4, and TLR9, as well as resistin, interleukins (IL)-1β, IL-4, and IL-6 and oxidative stress marker heme oxygenase (HO)-1, were higher in WD+VDD versus WD animals (P < 0.05). Logistic regression analyses showed significant associations between NAS score and liver mRNA levels of TLRs 2, 4, and 9, endotoxin receptor CD14, as well as peroxisome proliferator activated receptor (PPAR)γ, and HO-1. VDD exacerbates NAFLD through TLR-activation, possibly by way of endotoxin exposure in a WD rat model. In addition it causes IR, higher hepatic resistin gene expression, and up-regulation of hepatic inflammatory and oxidative stress genes. Copyright © 2011 American Association for the Study of Liver Diseases.
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                Author and article information

                Journal
                Medicine (Baltimore)
                Medicine (Baltimore)
                MEDI
                Medicine
                Wolters Kluwer Health
                0025-7974
                1536-5964
                October 2018
                19 October 2018
                : 97
                : 42
                : e12835
                Affiliations
                [a ]Department of Family Medicine, Kaohsiung Veterans General Hospital, Kaohsiung
                [b ]Department of Psychiatry, Chiayi Branch, Taichung Veterans General Hospital, Chiayi
                [c ]School of Medicine, National Yang-Ming University
                [d ]Division of Gastroenterology and General Medicine, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung
                [e ]Division of Cardiology, Department of Internal Medicine, Shin Kong Wu Ho-Su Memorial Hospital
                [f ]Institute of Emergency and Critical Care Medicine, National Yang-Ming University, Taipei, Taiwan.
                Author notes
                []Correspondence: Tzu-Lin Wang, No 95, Wen Chang Road, Shih Lin District, Taipei City 11101, Taiwan (e-mail: mail2chris59@ 123456gmail.com ); Hao-Yu Yang, No 386, Dazhong 1st Road, Zuoying District, Kaohsiung City 81362, Taiwan (e-mail: hyyang0509@ 123456vghks.gov.tw ).
                Article
                MD-D-18-01645 12835
                10.1097/MD.0000000000012835
                6211874
                30334985
                5fe62521-b4fd-48ac-aa54-795ce6d063d9
                Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.

                This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial License 4.0 (CCBY-NC), where it is permissible to download, share, remix, transform, and buildup the work provided it is properly cited. The work cannot be used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc/4.0

                History
                : 6 March 2018
                : 21 September 2018
                Categories
                7400
                Research Article
                Observational Study
                Custom metadata
                TRUE

                epidemiology,nonalcoholic fatty liver disease,osteoporosis,risk factors

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