Original Paper Received: August 14, 2014 Accepted: November 10, 2014 Published online: February 11, 2015
Digestion 2015;91:150–157 DOI: 10.1159/000369789
Association between Serum Osteocalcin Levels and Non-Alcoholic Fatty Liver Disease in Women Dong Hyun Sinn a Geum-Youn Gwak a Sang Youl Rhee b Juhee Cho c, d Hee Jung Son a, e Yong-Han Paik a Moon Seok Choi a Joon Hyeok Lee a Kwang Cheol Koh a Byung Chul Yoo a Seung Woon Paik a
a Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, b Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, and c Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Korea; d Department of Health, Behavior and Society and Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md., USA; e Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Abstract Background and Aims: Osteocalcin was found to have a significant role in insulin resistance. Insulin resistance is considered a pathophysiological mechanism of nonalcoholic fatty liver disease (NAFLD). However, the relationship between serum osteocalcin level and NAFLD is not well known. Methods: A total of 7,067 women undergoing abdominal ultrasonography, bone mineral density, and serum osteocalcin level measurement were analyzed. Results: Serum osteocalcin level was independently associated with menopausal status, bone mineral density, calcium, phosphate, alkaline phosphatase, fasting blood glucose, triglyceride, low-density lipoprotein cholesterol, alanine aminotransferase, γ-glutamyltransferase, and NAFLD. When women were grouped according to their menopausal status and
© 2015 S. Karger AG, Basel 0012–2823/15/0912–0150$39.50/0 E-Mail [email protected] www.karger.com/dig
bone mineral density, the serum osteocalcin level showed an independent inverse association with NAFLD in premenopausal women without osteopenia or osteoporosis (n = 2,941) [odd ratio (OR): 0.94, 95% confidence interval (CI): 0.91–0.96, p < 0.001] and postmenopausal women without osteopenia or osteoporosis (n = 2,155) (OR: 0.96, 95% CI: 0.95–0.98, p < 0.001), however, not in premenopausal (n = 308) or postmenopausal women (n = 1,663) with osteopenia or osteoporosis. Conclusions: The serum osteocalcin level was an independent factor associated with NAFLD, especially for women with normal bone mineral density. © 2015 S. Karger AG, Basel
Introduction
Nonalcoholic fatty liver disease (NAFLD) is a term used to describe a spectrum of related disorders, characterized by the evidence of hepatic steatosis without Seung Woon Paik, MD, PhD Department of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Irwon-ro 81 Gangnam-Gu 135–710, Seoul (South Korea) E-Mail sw.paik @ samsung.com
Downloaded by: University of Auckland, Philson Library 130.216.30.116 - 5/14/2015 11:49:33 PM
Key Words Osteocalcin · Non-alcoholic fatty liver disease · Women · Menopause · Bone mineral density
Osteocalcin and NAFLD in Women
pausal status and BMD should be appropriately assessed. In this study, we analyzed the association between serum osteocalcin levels and NAFLD in women according to their menopausal status and BMD.
Methods Study Participants We screened consecutive women who underwent routine health examinations at the Center for Health Promotion Center of the Samsung Medical Center in Seoul, South Korea from January 2009 to December 2009. We included women aged between 30– 69, who had abdominal ultrasonography (US), BMD and serum osteocalcin measurement on the same day as part of the health examination. Serum osteocalcin and BMD measurement was part of a health check-up program to assess bone health in women. Women with alcoholic or secondary causes of hepatic fat accumulation were excluded by the following criteria: a daily alcoholic intake of 10 grams or more, positive serologic findings of hepatitis B or C virus, history of malignancy, stroke, cardiovascular disease or hepatectomy, abnormal findings on US (intrahepatic stone, liver mass, bile duct dilatation, etc.), any regular use of medications other than vitamins, anti-hypertensives, and anti-hyperglycemics and incomplete data on alcohol intake, medication history. The final study population included 7,067 women. The study protocol was approved by the Institutional Review Board of the Samsung Medical Center, Seoul, Korea. The requirement for informed consent was exempted by the Institutional Review Board because the study was based on retrospective analyses of existing administrative and clinical data. Health Examination A self-administered health questionnaire and a detailed physical examination were routinely completed as part of the screening program. Personal history including questions on smoking, alcohol consumption, history of diabetes, hypertension, malignancy, stroke, cardiovascular disease, and history of medication use were obtained. Height, weight, and waist circumference were measured to the nearest half-centimeter or half-kilogram. Waist circumference was measured at the mid-point between the lower border of the rib cage and the iliac crest. Blood pressure was measured using a standard mercury sphygmomanometer after the subject had been seated for at least 10 min. Laboratory evaluation included measurements of aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (GGT), fasting blood glucose, fasting insulin, c-peptide, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride, follicle stimulating hormone (FSH), and estradiol levels. Diagnosis of NAFLD Abdominal ultrasound was performed by experienced radiologists at the Health Promotion Center. Fatty liver was diagnosed by US based on known standard criteria, including parenchymal brightness, liver-to-kidney contrast, deep beam attenuation and bright vessel walls [14, 15]. NAFLD was defined when abdominal ultrasonography revealed ≥ mild fatty liver.
Digestion 2015;91:150–157 DOI: 10.1159/000369789
151
Downloaded by: University of Auckland, Philson Library 130.216.30.116 - 5/14/2015 11:49:33 PM
causes for secondary hepatic fat accumulation such as significant alcohol consumption, use of steatogenic medication, or hereditary disorders [1]. NAFLD is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidemia [1], and is suggested as a hepatic manifestation of metabolic syndrome, with insulin resistance as the common pathophysiological mechanism [2, 3]. Classically, the bone has been regarded as a passive tissue that responds only to systemic signals; however, in recent decades, active involvement of skeleton in a variety of metabolic activities has been shown [4]. Notably, the metabolic effects of bones were suggested to be mediated by the release of osteocalcin into circulation [4]. Osteocalcin, an osteoblast-producing protein, was originally identified as a noncollagenous protein that is primarily responsible for bone formation [4, 5]. Osteocalcin level was found to be correlated with high bone turnover rate, and decreased bone mineral density (BMD) [6]. However, an unexpected finding of an abnormal accumulation of visceral fat in the osteocalcin gene knockout model suggested the metabolic activity of osteocalcin [5], and an active role of osteocalcin in energy metabolism was subsequently demonstrated [7]. Osteocalcin can induce beta cells in the pancreas to release insulin, and at the same time direct fat cells to release adiponectin, which increases insulin sensitivity [8]. In humans, the circulating osteocalcin level was associated with glucose tolerance, insulin secretion, and insulin sensitivity [9, 10]. Therefore, it is plausible that osteocalcin may be associated with NAFLD in which insulin resistance is an important feature. Indeed, some previous studies have shown an association between osteocalcin and NAFLD. Yilmaz et al. compared 99 patients with biopsy-proven NAFLD with 75 age- and sex-matched controls, and found lower serum osteocalcin levels in patients with NAFLD [11]. Dou et al. assessed the relationship between serum osteocalcin levels and NAFLD in 1,558 Chinese men, and found that serum osteocalcin levels were inversely correlated with NAFLD [12]. These findings suggest that skeleton, via osteocalcin, may participate in the pathogenesis of NAFLD. More data are clearly needed to understand the dynamic interaction between bone and liver. There is no large data set available on the relationship between osteocalcin and NAFLD, especially in women. Furthermore, loss of ovarian function during menopause leads to high turnover in bone, which increases the serum osteocalcin levels in women [13]. Therefore, to prove that the serum osteocalcin level is correlated with NAFLD in women, both meno-
Serum Osteocalcin Measurement, Assessment of BMD, Menopausal Status and Metabolic Syndrome The osteocalcin level was measured using Elecsys (Roche Diagnostic Corp., Indianapolis, Ind., USA). BMD was measured in the lumbar spine of the study subjects using dual energy X-ray absorptiometry (Lunar Radiation Co., Madison, Wisc., USA) in the posterior – anterior projection. The reported BMD values were calculated as the mean of 4 measured values from L1–L4. Osteoporosis was defined as a T score –2.5 and
Digestion 2015;91:150–157 DOI: 10.1159/000369789
Association between Serum Osteocalcin Levels and Non-Alcoholic Fatty Liver Disease in Women Dong Hyun Sinn a Geum-Youn Gwak a Sang Youl Rhee b Juhee Cho c, d Hee Jung Son a, e Yong-Han Paik a Moon Seok Choi a Joon Hyeok Lee a Kwang Cheol Koh a Byung Chul Yoo a Seung Woon Paik a
a Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, b Department of Endocrinology and Metabolism, Kyung Hee University School of Medicine, and c Department of Health Science and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Korea; d Department of Health, Behavior and Society and Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Md., USA; e Center for Health Promotion, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Abstract Background and Aims: Osteocalcin was found to have a significant role in insulin resistance. Insulin resistance is considered a pathophysiological mechanism of nonalcoholic fatty liver disease (NAFLD). However, the relationship between serum osteocalcin level and NAFLD is not well known. Methods: A total of 7,067 women undergoing abdominal ultrasonography, bone mineral density, and serum osteocalcin level measurement were analyzed. Results: Serum osteocalcin level was independently associated with menopausal status, bone mineral density, calcium, phosphate, alkaline phosphatase, fasting blood glucose, triglyceride, low-density lipoprotein cholesterol, alanine aminotransferase, γ-glutamyltransferase, and NAFLD. When women were grouped according to their menopausal status and
© 2015 S. Karger AG, Basel 0012–2823/15/0912–0150$39.50/0 E-Mail [email protected] www.karger.com/dig
bone mineral density, the serum osteocalcin level showed an independent inverse association with NAFLD in premenopausal women without osteopenia or osteoporosis (n = 2,941) [odd ratio (OR): 0.94, 95% confidence interval (CI): 0.91–0.96, p < 0.001] and postmenopausal women without osteopenia or osteoporosis (n = 2,155) (OR: 0.96, 95% CI: 0.95–0.98, p < 0.001), however, not in premenopausal (n = 308) or postmenopausal women (n = 1,663) with osteopenia or osteoporosis. Conclusions: The serum osteocalcin level was an independent factor associated with NAFLD, especially for women with normal bone mineral density. © 2015 S. Karger AG, Basel
Introduction
Nonalcoholic fatty liver disease (NAFLD) is a term used to describe a spectrum of related disorders, characterized by the evidence of hepatic steatosis without Seung Woon Paik, MD, PhD Department of Medicine, Samsung Medical Center Sungkyunkwan University School of Medicine, Irwon-ro 81 Gangnam-Gu 135–710, Seoul (South Korea) E-Mail sw.paik @ samsung.com
Downloaded by: University of Auckland, Philson Library 130.216.30.116 - 5/14/2015 11:49:33 PM
Key Words Osteocalcin · Non-alcoholic fatty liver disease · Women · Menopause · Bone mineral density
Osteocalcin and NAFLD in Women
pausal status and BMD should be appropriately assessed. In this study, we analyzed the association between serum osteocalcin levels and NAFLD in women according to their menopausal status and BMD.
Methods Study Participants We screened consecutive women who underwent routine health examinations at the Center for Health Promotion Center of the Samsung Medical Center in Seoul, South Korea from January 2009 to December 2009. We included women aged between 30– 69, who had abdominal ultrasonography (US), BMD and serum osteocalcin measurement on the same day as part of the health examination. Serum osteocalcin and BMD measurement was part of a health check-up program to assess bone health in women. Women with alcoholic or secondary causes of hepatic fat accumulation were excluded by the following criteria: a daily alcoholic intake of 10 grams or more, positive serologic findings of hepatitis B or C virus, history of malignancy, stroke, cardiovascular disease or hepatectomy, abnormal findings on US (intrahepatic stone, liver mass, bile duct dilatation, etc.), any regular use of medications other than vitamins, anti-hypertensives, and anti-hyperglycemics and incomplete data on alcohol intake, medication history. The final study population included 7,067 women. The study protocol was approved by the Institutional Review Board of the Samsung Medical Center, Seoul, Korea. The requirement for informed consent was exempted by the Institutional Review Board because the study was based on retrospective analyses of existing administrative and clinical data. Health Examination A self-administered health questionnaire and a detailed physical examination were routinely completed as part of the screening program. Personal history including questions on smoking, alcohol consumption, history of diabetes, hypertension, malignancy, stroke, cardiovascular disease, and history of medication use were obtained. Height, weight, and waist circumference were measured to the nearest half-centimeter or half-kilogram. Waist circumference was measured at the mid-point between the lower border of the rib cage and the iliac crest. Blood pressure was measured using a standard mercury sphygmomanometer after the subject had been seated for at least 10 min. Laboratory evaluation included measurements of aspartate aminotransferase (AST), alanine aminotransferase (ALT), γ-glutamyltransferase (GGT), fasting blood glucose, fasting insulin, c-peptide, total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride, follicle stimulating hormone (FSH), and estradiol levels. Diagnosis of NAFLD Abdominal ultrasound was performed by experienced radiologists at the Health Promotion Center. Fatty liver was diagnosed by US based on known standard criteria, including parenchymal brightness, liver-to-kidney contrast, deep beam attenuation and bright vessel walls [14, 15]. NAFLD was defined when abdominal ultrasonography revealed ≥ mild fatty liver.
Digestion 2015;91:150–157 DOI: 10.1159/000369789
151
Downloaded by: University of Auckland, Philson Library 130.216.30.116 - 5/14/2015 11:49:33 PM
causes for secondary hepatic fat accumulation such as significant alcohol consumption, use of steatogenic medication, or hereditary disorders [1]. NAFLD is associated with metabolic risk factors such as obesity, diabetes mellitus, and dyslipidemia [1], and is suggested as a hepatic manifestation of metabolic syndrome, with insulin resistance as the common pathophysiological mechanism [2, 3]. Classically, the bone has been regarded as a passive tissue that responds only to systemic signals; however, in recent decades, active involvement of skeleton in a variety of metabolic activities has been shown [4]. Notably, the metabolic effects of bones were suggested to be mediated by the release of osteocalcin into circulation [4]. Osteocalcin, an osteoblast-producing protein, was originally identified as a noncollagenous protein that is primarily responsible for bone formation [4, 5]. Osteocalcin level was found to be correlated with high bone turnover rate, and decreased bone mineral density (BMD) [6]. However, an unexpected finding of an abnormal accumulation of visceral fat in the osteocalcin gene knockout model suggested the metabolic activity of osteocalcin [5], and an active role of osteocalcin in energy metabolism was subsequently demonstrated [7]. Osteocalcin can induce beta cells in the pancreas to release insulin, and at the same time direct fat cells to release adiponectin, which increases insulin sensitivity [8]. In humans, the circulating osteocalcin level was associated with glucose tolerance, insulin secretion, and insulin sensitivity [9, 10]. Therefore, it is plausible that osteocalcin may be associated with NAFLD in which insulin resistance is an important feature. Indeed, some previous studies have shown an association between osteocalcin and NAFLD. Yilmaz et al. compared 99 patients with biopsy-proven NAFLD with 75 age- and sex-matched controls, and found lower serum osteocalcin levels in patients with NAFLD [11]. Dou et al. assessed the relationship between serum osteocalcin levels and NAFLD in 1,558 Chinese men, and found that serum osteocalcin levels were inversely correlated with NAFLD [12]. These findings suggest that skeleton, via osteocalcin, may participate in the pathogenesis of NAFLD. More data are clearly needed to understand the dynamic interaction between bone and liver. There is no large data set available on the relationship between osteocalcin and NAFLD, especially in women. Furthermore, loss of ovarian function during menopause leads to high turnover in bone, which increases the serum osteocalcin levels in women [13]. Therefore, to prove that the serum osteocalcin level is correlated with NAFLD in women, both meno-
Serum Osteocalcin Measurement, Assessment of BMD, Menopausal Status and Metabolic Syndrome The osteocalcin level was measured using Elecsys (Roche Diagnostic Corp., Indianapolis, Ind., USA). BMD was measured in the lumbar spine of the study subjects using dual energy X-ray absorptiometry (Lunar Radiation Co., Madison, Wisc., USA) in the posterior – anterior projection. The reported BMD values were calculated as the mean of 4 measured values from L1–L4. Osteoporosis was defined as a T score –2.5 and
