成人血清骨钙素水平与非酒精性脂肪性肝病发生风险的Meta分析

doi:10.12114/j.issn.1007-9572.2023.0442

摘要/Abstract

摘要： 背景非酒精性脂肪性肝病（NAFLD）的发病率逐年上升，已成为重大公共卫生问题之一。血清骨钙素（OCN）是骨形成的标志，可能增加NAFLD的风险。目的本研究进行Meta分析，以定量评估影像学或活检证实的NAFLD与OCN水平之间的关系。方法计算机检索Medline、Embase、Web of Science、Cochrane Library、PROSPERO以及中国知网（CNKI）、万方数据知识服务平台和中维普网（VIP）中有关血清OCN与NAFLD的病例对照研究、横断面研究和队列研究。由2名研究人员筛选文献、提取数据并进行质量评价。采用Stata 16.0软件进行Meta分析。结果共纳入13篇文献，包含11 772例参与者。Meta分析结果显示，NAFLD患者血清OCN水平低于非NAFLD者（SMD=-0.73，95%CI=-1.20~-0.27，P<0.05）；血清OCN最低四分位数NFALD发生率高于OCN最高四分位数（OR=2.19，95%CI=1.15~4.17，P<0.05）。亚组分析结果显示，是否合并基础疾病、研究质量、研究设计不是异质性的来源。敏感性分析结果表明，删除1项研究后Meta荟萃分析的结果没有显著变化，表明结果稳定可靠。Egger's检验未发现统计学发表偏倚（P=0.519）。结论研究结果表明，血清OCN水平与NAFLD发生风险增加呈负相关。

关键词: 非酒精性脂肪性肝病, 骨钙素, 观察性研究, Meta分析

Abstract:

Background

The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing by years and has become a major public health problem. Serum osteocalcin (OCN), as a marker of bone formation, may increase the risk of NAFLD.

Objective

To conduct a Meta-analysis to quantitatively evaluate the association between imaging or biopsy-confirmed NAFLD and serum OCN levels.

Methods

English databases including Medline, Embase, Web of Science, Cochrane, and PROSPERO, as well as Chinese databases including CNKI, Wanfang Data, and VIP were searched for case-control studies, cross-sectional studies, and cohort studies on serum OCN and NAFLD. Two investigators screened the literature, extracted data and performed quality evaluation. Meta-analysis was performed using Stata 16.0 software.

Results

A total of 13 papers involving 11 772 participants were included. Meta-analysis showed that serum OCN levels were lower in patients with NAFLD than in those without NAFLD (SMD=-0.73, 95%CI=-1.20 to -0.27, P<0.05) ; The incidence of NFALD in the lowest quartile of serum OCN was higher than that in the highest quartile of OCN (OR=2.19, 95%CI=1.15 to 4.17, P<0.05). The results of subgroup analysis showed that the presence of comorbid underlying diseases, study quality, and study design were not sources of heterogeneity. The results of the sensitivity analysis showed that the results of Meta-analysis were not significantly affected by the deletion of 1 study, indicating stable and reliable results. Statistical publication bias was not revealed by Egger's test (P=0.519) .

Conclusion

Our results suggest that serum OCN levels are negatively associated with an increased risk of NAFLD.

Key words: Non-alcoholic fatty liver disease, Osteocalcin, Observational study, Meta-analysis

张娜文,黄少敏,田利民. 成人血清骨钙素水平与非酒精性脂肪性肝病发生风险的Meta分析[J]. 中国全科医学, 2024, 27(12): 1519-1524. DOI: 10.12114/j.issn.1007-9572.2023.0442.
ZHANG Nawen,HUANG Shaomin,TIAN Limin. Association between Serum Osteocalcin Level and Non-alcoholic Fatty Liver Disease in Adults: a Meta-analysis[J]. Chinese General Practice, 2024, 27(12): 1519-1524. DOI: 10.12114/j.issn.1007-9572.2023.0442.

图/表 9

参考文献 38

[1]	CHALASANI N, YOUNOSSI Z, LAVINE J E，et al. The diagnosis and management of non-alcoholic fatty liver disease：practice Guideline by the American Association for the Study of Liver Diseases，American College of Gastroenterology，and the American Gastroenterological Association[J]. Hepatology，2012,55(6):2005-2023. DOI：10.1002/hep.25762.
[2]	MACUT D, BOŽIĆ-ANTIĆ I, BJEKIĆ-MACUT J，et al. Management of endocrine disease：polycystic ovary syndrome and nonalcoholic fatty liver disease[J]. Eur J Endocrinol，2017,177(3):R145-158. DOI：10.1530/EJE-16-1063.
[3]	YOUNOSSI Z M, KOENIG A B, ABDELATIF D，et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence，incidence，and outcomes[J]. Hepatology，2016,64(1):73-84. DOI：10.1002/hep.28431.
[4]	YOUNOSSI Z M, GOLABI P, PAIK J M，et al. The global epidemiology of nonalcoholic fatty liver disease （NAFLD） and nonalcoholic steatohepatitis （NASH）：a systematic review[J]. Hepatology，2023,77(4):1335-1347. DOI：10.1097/HEP.0000000000000004.
[5]	GUPTE A A, SABEK O M, FRAGA D，et al. Osteocalcin protects against nonalcoholic steatohepatitis in a mouse model of metabolic syndrome[J]. Endocrinology，2014,155(12):4697-4705. DOI：10.1210/en.2014-1430.
[6]	GERDHEM P, ISAKSSON A, AKESSON K，et al. Increased bone density and decreased bone turnover，but no evident alteration of fracture susceptibility in elderly women with diabetes mellitus[J]. Osteoporos Int，2005,16(12):1506-1512. DOI：10.1007/s00198-005-1877-5.
[7]	CHEN L, LI Q, YANG Z，et al. Osteocalcin，glucose metabolism，lipid profile and chronic low-grade inflammation in middle-aged and elderly Chinese[J]. Diabet Med，2013,30(3):309-317. DOI：10.1111/j.1464-5491.2012.03769.x.
[8]	FERNÁNDEZ-REAL J M, ORTEGA F, GÓMEZ-AMBROSI J，et al. Circulating osteocalcin concentrations are associated with parameters of liver fat infiltration and increase in parallel to decreased liver enzymes after weight loss[J]. Osteoporos Int，2010,21(12):2101-2107. DOI：10.1007/s00198-010-1174-9.
[9]	TAN A H, GAO Y, YANG X B，et al. Low serum osteocalcin level is a potential marker for metabolic syndrome：results from a Chinese male population survey[J]. Metabolism，2011,60(8):1186-1192. DOI：10.1016/j.metabol.2011.01.002.
[10]	ALLER R, CASTRILLON J L, DE LUIS D A，et al. Relation of osteocalcin with insulin resistance and histopathological changes of non alcoholic fatty liver disease[J]. Ann Hepatol，2011,10(1):50-55.
[11]	YILMAZ Y, KURT R, EREN F，et al. Serum osteocalcin levels in patients with nonalcoholic fatty liver disease：association with ballooning degeneration[J]. Scand J Clin Lab Invest，2011,71(8):631-636. DOI：10.3109/00365513.2011.604427.
[12]	DOU J X, MA X J, FANG Q C，et al. Relationship between serum osteocalcin levels and non-alcoholic fatty liver disease in Chinese men[J]. Clin Exp Pharmacol Physiol，2013,40(4):282-288. DOI：10.1111/1440-1681.12063.
[13]	SINN D H, GWAK G Y, RHEE S Y，et al. Association between serum osteocalcin levels and non-alcoholic fatty liver disease in women[J]. Digestion，2015,91(2):150-157. DOI：10.1159/000369789.
[14]	SHAMSEER L, MOHER D, CLARKE M，et al. Preferred reporting items for systematic review and meta-analysis protocols（PRISMA-P） 2015：elaboration and explanation[J]. BMJ，2015,350:g7647. DOI：10.1136/bmj.g7647.
[15]	WANG X J, MALHI H. Nonalcoholic fatty liver disease[J]. Ann Intern Med，2018,169(9):ITC65. DOI：10.7326/aitc201811060.
[16]	STANG A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses[J]. Eur J Epidemiol，2010,25(9):603-605. DOI：10.1007/s10654-010-9491-z.
[17]	VAN DIJK G M, MANEVA M, COLPANI V，et al. The association between vasomotor symptoms and metabolic health in peri- and postmenopausal women：a systematic review[J]. Maturitas，2015,80(2):140-147. DOI：10.1016/j.maturitas.2014.11.016.
[18]	罗德惠，万翔，刘际明，等. 如何实现从样本量、中位数、极值或四分位数到均数与标准差的转换[J]. 中国循证医学杂志，2017,17(11):1350-1356. DOI：10.7507/1672-2531.201706060.
[19]	HIGGINS J P T, THOMPSON S G. Quantifying heterogeneity in a meta-analysis[J]. Stat Med，2002,21(11):1539-1558. DOI：10.1002/sim.1186.
[20]	MIN Y W, SINN D H, PARK Z W，et al. 1320 serum osteocalcin level is closely associated with the presence，new development and regression of ultrasonographically detected fatty liver in aged women[J]. J Hepatol，2012,56:S520. DOI：10.1016/s0168-8278(12)61332-4.
[21]	DENG H, DAI Y, LU H，et al. Analysis of the correlation between non-alcoholic fatty liver disease and bone metabolism indicators in healthy middle-aged men[J]. Eur Rev Med Pharmacol Sci，2018,22(5):1457-1462. DOI：10.26355/eurrev_201803_14493.
[22]	YANG H J, SHIM S G, MA B O，et al. Association of nonalcoholic fatty liver disease with bone mineral density and serum osteocalcin levels in Korean men[J]. Eur J Gastroenterol Hepatol，2016,28(3):338-344. DOI：10.1097/MEG.0000000000000535.
[23]	LIU J J, CHEN Y Y, MO Z N，et al. Relationship between serum osteocalcin levels and non-alcoholic fatty liver disease in adult males，South China[J]. Int J Mol Sci，2013,14(10):19782-19791. DOI：10.3390/ijms141019782.
[24]	LUO Y Q, MA X J, HAO Y P，et al. Inverse relationship between serum osteocalcin levels and nonalcoholic fatty liver disease in postmenopausal Chinese women with normal blood glucose levels[J]. Acta Pharmacol Sin，2015,36(12):1497-1502. DOI：10.1038/aps.2015.81.
[25]	HU X L, HUA Y, SHI Z M，et al. Association of serum 25-hydroxy vitamin D and osteocalcin levels with non-alcoholic fatty liver disease[J]. Int J Clin Exp Med，2016,9(11):22750-22757.
[26]	杜婧. 骨钙素与冠心病人群NAFLD的关系及其通过Nrf2及JNK通路改善小鼠NAFLD的机制研究[D]. 上海：上海交通大学，2016.
[27]	母金娣. 老年2型糖尿病合并非酒精性脂肪性肝病与血清骨钙素水平的相关性研究[D]. 郑州：郑州大学，2016.
[28]	王碧玉. 血清骨钙素及多项生化指标在非酒精性脂肪肝诊断中的临床意义[J]. 国际检验医学杂志，2014,35(10):1356-1357. DOI：10.3969/j.issn.1673-4130.2014.10.058.
[29]	魏亚庆. 2型糖尿病合并非酒精性脂肪性肝病患者血清骨钙素水平的变化及相关影响因素[D]. 兰州：兰州大学，2017.
[30]	吴冰洁. 上海长风社区中老年人群非酒精性脂肪性肝病与血清骨钙素、肝酶及性激素水平的关系研究[D]. 上海：复旦大学，2014.
[31]	XIA M F, RONG S X, ZHU X P，et al. Osteocalcin and non-alcoholic fatty liver disease：lessons from two population-based cohorts and animal models[J]. J Bone Miner Res，2021,36(4):712-728. DOI：10.1002/jbmr.4227.
[32]	BECHMANN L P, HANNIVOORT R A, GERKEN G，et al. The interaction of hepatic lipid and glucose metabolism in liver diseases[J]. J Hepatol，2012,56(4):952-964. DOI：10.1016/j.jhep.2011.08.025.
[33]	DAY C P. From fat to inflammation[J]. Gastroenterology，2006,130(1):207-210. DOI：10.1053/j.gastro.2005.11.017.
[34]	ZHOU B, LI H X, XU L，et al. Osteocalcin reverses endoplasmic reticulum stress and improves impaired insulin sensitivity secondary to diet-induced obesity through nuclear factor-κB signaling pathway[J]. Endocrinology，2013,154(3):1055-1068. DOI：10.1210/en.2012-2144.
[35]	GOWER B A, POLLOCK N K, CASAZZA K，et al. Associations of total and undercarboxylated osteocalcin with peripheral and hepatic insulin sensitivity and β-cell function in overweight adults[J]. J Clin Endocrinol Metab，2013,98(7):E1173-1180. DOI：10.1210/jc.2013-1203.
[36]	KANAZAWA I, YAMAGUCHI T, YAMAMOTO M，et al. Serum osteocalcin level is associated with glucose metabolism and atherosclerosis parameters in type 2 diabetes mellitus[J]. J Clin Endocrinol Metab，2009,94(1):45-49. DOI：10.1210/jc.2008-1455.
[37]	FERRON M, MCKEE M D, LEVINE R L，et al. Intermittent injections of osteocalcin improve glucose metabolism and prevent type 2 diabetes in mice[J]. Bone，2012,50(2):568-575. DOI：10.1016/j.bone.2011.04.017.
[38]	CHALASANI N, YOUNOSSI Z, LAVINE J E，et al. The diagnosis and management of non-alcoholic fatty liver disease：practice guideline by the American Gastroenterological Association，American Association for the Study of Liver Diseases，and American College of Gastroenterology[J]. Gastroenterology，2012,142(7):1592-1609. DOI：10.1053/j.gastro.2012.04.001.

作者	发表时间（年）	研究设计	国家	样本量		男/女		年龄（岁）		NAFLD诊断方法	骨钙素检测方法	BMI（kg/m²）		血清骨钙素水平（ng/mL）		T2DM
作者	发表时间（年）	研究设计	国家	NAFLD组	非NAFLD组	NAFLD组	非NAFLD组	NAFLD组	非NAFLD组	NAFLD诊断方法	骨钙素检测方法	NAFLD组	非NAFLD组	NAFLD组	非NAFLD组	NAFLD组	非NAFLD组
YANG^[22]	2016	横断面研究	韩国	249	610	249/0	610/0	45±6	45±7	超声	化学发光法	25.5±8.5	22.9±2.4	16.07± 4.42	17.36± 4.68	无	无
LIU^[23]	2013	横断面研究	中国	364	1 319	364/0	1 319/0	40.52± 10.18	36.69± 11.37	超声	电化学发光免疫测定	26.25± 2.74	22.25± 2.67	20.81± 1.33	24.51± 1.38	无	无
LUO^[24]	2015	横断面研究	中国	130	603	0/130	0/603	56.0± 5.0	56.2± 4.4	超声	电化学发光免疫测定	25.5± 2.8	22.1± 2.5	19.41± 5.71	22.66± 6.32	无	无
DENG^[21]	2018	横断面研究	中国	232	308	232/0	308/0	50.52± 4.87	50.35± 5.18	超声	电化学发光免疫测定	26.33± 2.68	24.74± 2.71	20.23± 7.26	22.71± 7.67	无	无
DOU^[12]	2013	横断面研究	中国	449	1 109	449/0	1 109/0	53.32± 8.3	54.3± 8.8	超声	电化学发光免疫测定	26.48± 3.05	23.43± 2.76	16.19± 4.94	17.13± 5.43	无	无
HU^[25]	2016	横断面研究	中国	178	190	168/10	105/85	42.69± 9.52	37.69± 10.20	超声	放射免疫测定法	25.12± 2.28	23.68± 2.93	15.24± 2.50	17.28± 3.18	无	无
吴冰洁^[30]	2014	横断面研究	中国	1 087	2 212	365/722	778 /1 434	61.30± 9.87	62.29± 11.50	超声	放射免疫测定法	25.81± 3.19	23.24± 2.89	18.92± 6.5	20.48± 7.12	无	无
杜婧^[26]	2016	横断面研究	中国	44	130	34/10	89/41	64.5± 11.0	67.7± 9.8	超声	电化学发光免疫测定	26.5± 2.9	23.4± 2.7	18.18± 7.36	20.84± 7.95	无	无
王碧玉^[28]	2014	病例对照研究	中国	64	64	38/26	35/29	56	52	超声	电化学发光免疫测定			1.89± 0.97	3.65± 1.55	无	无
母金娣^[27]	2016	病例对照研究	中国	50	47	28/22	20/27	66.5± 5.8	65.9± 4.2	超声	电化学发光免疫测定	25.3± 2.6	23.6± 3.2	12.2± 4.7	18± 6.2	有	有
魏亚庆^[29]	2017	病例对照研究	中国	54	50	54/0	50/0	53.81± 9.24	57.04± 10.82	超声	酶联免疫吸附测定	25.12± 2.784	23.28± 3.049	8.18± 4.649	13.04± 6.367	有	有
YILMAZ^[11]	2011	病例对照研究	土耳其	99	75	50/49	37/38	48±8	48±7	活检	固相酶扩增免疫敏感性分析	30.6± 4.9	27.4± 4.3	2.26± 0.19	2.31± 0.15	有	无
XIA^[31]	2021	队列研究	中国	679	1 376	279/400	578/798			超声	电化学发光免疫测定					无	无

作者	发表时间（年）	研究设计	国家	样本量		男/女		年龄（岁）		NAFLD诊断方法	骨钙素检测方法	BMI（kg/m²）		血清骨钙素水平（ng/mL）		T2DM
作者	发表时间（年）	研究设计	国家	NAFLD组	非NAFLD组	NAFLD组	非NAFLD组	NAFLD组	非NAFLD组	NAFLD诊断方法	骨钙素检测方法	NAFLD组	非NAFLD组	NAFLD组	非NAFLD组	NAFLD组	非NAFLD组
YANG^[22]	2016	横断面研究	韩国	249	610	249/0	610/0	45±6	45±7	超声	化学发光法	25.5±8.5	22.9±2.4	16.07± 4.42	17.36± 4.68	无	无
LIU^[23]	2013	横断面研究	中国	364	1 319	364/0	1 319/0	40.52± 10.18	36.69± 11.37	超声	电化学发光免疫测定	26.25± 2.74	22.25± 2.67	20.81± 1.33	24.51± 1.38	无	无
LUO^[24]	2015	横断面研究	中国	130	603	0/130	0/603	56.0± 5.0	56.2± 4.4	超声	电化学发光免疫测定	25.5± 2.8	22.1± 2.5	19.41± 5.71	22.66± 6.32	无	无
DENG^[21]	2018	横断面研究	中国	232	308	232/0	308/0	50.52± 4.87	50.35± 5.18	超声	电化学发光免疫测定	26.33± 2.68	24.74± 2.71	20.23± 7.26	22.71± 7.67	无	无
DOU^[12]	2013	横断面研究	中国	449	1 109	449/0	1 109/0	53.32± 8.3	54.3± 8.8	超声	电化学发光免疫测定	26.48± 3.05	23.43± 2.76	16.19± 4.94	17.13± 5.43	无	无
HU^[25]	2016	横断面研究	中国	178	190	168/10	105/85	42.69± 9.52	37.69± 10.20	超声	放射免疫测定法	25.12± 2.28	23.68± 2.93	15.24± 2.50	17.28± 3.18	无	无
吴冰洁^[30]	2014	横断面研究	中国	1 087	2 212	365/722	778 /1 434	61.30± 9.87	62.29± 11.50	超声	放射免疫测定法	25.81± 3.19	23.24± 2.89	18.92± 6.5	20.48± 7.12	无	无
杜婧^[26]	2016	横断面研究	中国	44	130	34/10	89/41	64.5± 11.0	67.7± 9.8	超声	电化学发光免疫测定	26.5± 2.9	23.4± 2.7	18.18± 7.36	20.84± 7.95	无	无
王碧玉^[28]	2014	病例对照研究	中国	64	64	38/26	35/29	56	52	超声	电化学发光免疫测定			1.89± 0.97	3.65± 1.55	无	无
母金娣^[27]	2016	病例对照研究	中国	50	47	28/22	20/27	66.5± 5.8	65.9± 4.2	超声	电化学发光免疫测定	25.3± 2.6	23.6± 3.2	12.2± 4.7	18± 6.2	有	有
魏亚庆^[29]	2017	病例对照研究	中国	54	50	54/0	50/0	53.81± 9.24	57.04± 10.82	超声	酶联免疫吸附测定	25.12± 2.784	23.28± 3.049	8.18± 4.649	13.04± 6.367	有	有
YILMAZ^[11]	2011	病例对照研究	土耳其	99	75	50/49	37/38	48±8	48±7	活检	固相酶扩增免疫敏感性分析	30.6± 4.9	27.4± 4.3	2.26± 0.19	2.31± 0.15	有	无
XIA^[31]	2021	队列研究	中国	679	1 376	279/400	578/798			超声	电化学发光免疫测定					无	无

第一作者	研究人群的选择	可比性	暴露或结果评价	总分
YILMAZ^[11]	3	1	2	6
YANG^[22]	4	1	3	8
LIU^[23]	4	1	3	8
LUO^[24]	4	1	3	8
DENG^[21]	3	1	2	6
DOU^[12]	4	1	3	8
HU^[25]	2	2	3	7
吴冰洁^[30]	2	2	3	7
杜婧^[26]	2	1	2	5
王碧玉^[28]	3	1	2	6
母金娣^[27]	2	1	2	5
魏亚庆^[29]	3	1	2	6
XIA^[31]	3	2	3	8

第一作者	研究人群的选择	可比性	暴露或结果评价	总分
YILMAZ^[11]	3	1	2	6
YANG^[22]	4	1	3	8
LIU^[23]	4	1	3	8
LUO^[24]	4	1	3	8
DENG^[21]	3	1	2	6
DOU^[12]	4	1	3	8
HU^[25]	2	2	3	7
吴冰洁^[30]	2	2	3	7
杜婧^[26]	2	1	2	5
王碧玉^[28]	3	1	2	6
母金娣^[27]	2	1	2	5
魏亚庆^[29]	3	1	2	6
XIA^[31]	3	2	3	8