Endocrine DOI 10.1007/s12020-015-0587-9
ORIGINAL ARTICLE
Hemoglobin concentration and incident metabolic syndrome: a population-based large-scale cohort study Yoshitaka Hashimoto1 • Muhei Tanaka1 • Toshihiro Kimura1 • Noriyuki Kitagawa1 Masahide Hamaguchi1 • Mai Asano1 • Masahiro Yamazaki1 • Yohei Oda1 • Hitoshi Toda2 • Naoto Nakamura1 • Michiaki Fukui1
•
Received: 14 January 2015 / Accepted: 27 March 2015 Ó Springer Science+Business Media New York 2015
Abstract Previous cross-sectional studies revealed an association between hemoglobin concentration and a prevalence of metabolic syndrome (MetS). However, the association between hemoglobin concentration and incident MetS remains to be elucidated. Thus, the aim of this study was to investigate the association between hemoglobin concentration and incident MetS. We enrolled 2695 subjects (1454 men and 1241 women) and performed 8-year follow-up cohort study. MetS was diagnosed, according to the joint interim statement, when a subject had three or more of the following components: hypertension; hyperglycemia; hypertriglyceridemia; low high-density lipoprotein cholesterol; and abdominal obesity. Logistic regression analyses were performed to assess the impact of hemoglobin concentration on incident MetS by adjusting for age, body mass index, lifestyle factors, including smoking status, habit of alcohol and habit of exercise, systolic blood pressure, fasting plasma glucose, triglycerides, high-density lipoprotein cholesterol, creatinine, and uric acid. The highest (C157 g/L) and third (151–156 g/L) hemoglobin concentration quartiles were associated with the increased risk of incident MetS compared to the lowest (\145 g/L) hemoglobin concentration quartile after adjusting for covariates in men (multivariate odds ratio (OR) 2.24, 95 % CI 1.34–3.85, P = 0.0021 and multivariate OR 2.03, 95 % CI 1.21–3.45, P = 0.0070). On the other hand,
& Michiaki Fukui [email protected] 1
Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
2
Department of Internal Medicine, Oike Clinic, Kyoto, Japan
there was no association between hemoglobin concentration and incident MetS in women. Hemoglobin concentration was a novel risk marker for incident MetS in men. Keywords Epidemiology Metabolic syndrome Hematological parameters Hemoglobin Abbreviations MetS Metabolic syndrome BMI Body mass index HDL High-density lipoprotein eGFR Estimated glomerular filtration rate
Introduction Metabolic syndrome (MetS) is defined by the clustering of several cardiovascular risk factors, including hypertension, hyperglycemia, dyslipidemia, and visceral obesity [1]. MetS is associated with cardiovascular disease which is the leading cause of mortality and morbidity [2]. In view of its emerging epidemic and impact, an early identification of people at high risk for MetS would help prevent the associated cardiovascular complications. In Japan, the prevalence of MetS, using a joint interim statement, was 18.5–37.3 % in men and 4.4–12.8 % in women [3, 4] and may have recently become even more common with the continuous increase in obesity prevalence. Previous cross-sectional studies revealed that there was an association between hematological parameter, including hemoglobin, hematocrit, red blood cell counts, white blood cell counts, or platelet counts, and a prevalence MetS or its components [5–8]. Moreover, recent cross-sectional studies revealed that there was the association between
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hemoglobin concentration and insulin resistance [9, 10] or non-alcohol fatty liver disease [11], which is closely associated with MetS. In addition, recent studies reveled that high hemoglobin concentration was associated with risk of incident type 2 diabetes [12–15], non-alcohol fatty liver disease [16], or cardiovascular diseases [17–19]. Therefore, we hypothesized that high hemoglobin concentration is associated with incident MetS. To our knowledge, however, the association between hemoglobin concentration and incident MetS remains to be elucidated. Therefore, we investigated the association between hemoglobin concentration and incident MetS in this cohort study.
who had hypertensive or prehypertensive blood pressure values. The lowest reading was used as a definition of hypertension. After an overnight fast, venous blood was collected for the measurement of the levels of various factors, including fasting plasma glucose, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, creatinine, uric acid, hemoglobin, white blood cell counts, and platelet counts. Glomerular filtration rate (GFR) was estimated using the Japanese Society of Nephrology equation: estimated GFR (eGFR) = 194 9 Cre-1.094 9 age-0.287 (mL/min/1.73 m2) [20]. For women, the eGFR was multiplied by a correction factor of 0.739. Definition of MetS
Materials and methods
The Oike Health Survey is an ongoing cohort investigation of risk factors for chronic diseases, including hypertension, diabetes, and chronic kidney disease. The Oike Clinic (Kyoto, Japan) provides regular health check-up for employees of various companies. In Japan, yearly routine examinations for employees are legally mandated, and all or most of the costs for the health check-up are usually paid by their employers. The purpose of the medical health check-up program is to promote public health through early detection of chronic diseases and their risk factors. Medical service of this kind, known as ‘‘a human dock,’’ is very popular in Japan. We enrolled subjects who received health check-up in 2001 and performed 8-year follow-up in this cohort study. Exclusion criteria were as follows: medication for hypertension, diabetes and/or dyslipidemia, and/or a presence of MetS at baseline examination, and missing data of covariates. Approval for the study was obtained from the Ethical Committee of Oike Clinic, and the study was conducted in accordance with Declaration of Helsinki. Informed consent was obtained from each subject.
The diagnosis of MetS was determined by a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; the National Heart, Lung, and Blood Institute; the American Heart Association; the World Heart Federation; the International Atherosclerosis Society; and the International Association for the Study of Obesity, using the criteria for Asians [21]. The subjects were diagnosed with the presence of MetS when three or more of the following criteria were present: hypertension (systolic blood pressure C130 mmHg and diastolic blood pressure C85 mmHg and/or medication for hypertension, in both the sexes); hyperglycemia (fasting plasma glucose C5.6 mmol/L and/or medication for diabetes, in both the sexes); hypertriglyceridemia (serum triglycerides C1.70 mmol/L and/or medication for dyslipidemia, in both the sexes); low HDL cholesterol levels (serum HDL cholesterol \1.03 mmol/L in men and \1.29 mmol/L in women); and abdominal obesity (waist circumference C90 cm in men and C80 cm in women). Because waist measurements were not available for entire study sample, we submitted a BMI of C25 kg/m2, which has been proposed as a cutoff for the diagnosis of obesity in Asian people [22], for all subjects as an index of obesity. The validity of this definition was confirmed previously [23].
Data collection and measurements
Statistical analysis
All subjects provided details of their demographics. Smoking was defined as current tobacco usage. Habit of alcohol was defined as daily alcohol consumption. Habit of exercise was defined as performing any kind of sports at least once a week. Body weight was measured with the subjects in light clothing without shoes. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. After a brief period of rest, sitting blood pressure was measured in either arm. Blood pressure was measured once in most subjects, but up to 3 measurements at 1- to 2-min intervals were made in subjects
The statistical analyses were performed using the JMP version 10.0 software (SAS Institute Inc., Cary, North Carolina), and P value \0.05 was considered statistically significant. Mean or frequencies of potential confounding variables were calculated. Skewed variables such as fasting plasma glucose and triglycerides were presented as median (interquartile range), and continuous variables were presented as the mean ± standard deviation (SD). One-way ANOVA for continuous variables or the v2 square test for categorical variables was performed for comparisons across the hemoglobin concentration quartiles in men and
Subjects and study design
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women, separately. Because fasting plasma glucose and triglycerides showed skewed distributions, logarithmic transformation was carried out before performance of logistic regression analyses. Logistic regression analyses were performed to assess the impact of hemoglobin concentration on incident MetS. To examine the effects of various factors on incident MetS, the following factors, which were reported to be risk factors for incident MetS [24–26], were considered simultaneously as independent variables for multiple regression analyses: age, BMI, lifestyle factors, including smoking status, habit of alcohol and habit of exercise, systolic blood pressure, log fasting plasma glucose, log triglycerides, HDL cholesterol, creatinine, and uric acid. Odds ratio (OR) and 95 % confidence interval (CI) were calculated.
Results In 2001, the results of 4127 subjects (2395 men and 1732 women) were served as database (Fig. 1). Among them, 1432 subjects (941 men and 491 women) were excluded. Thus, 2695 subjects (1454 men and 1241 women) were enrolled into this cohort study. Baseline characteristics of subjects The baseline characteristics according to hemoglobin concentration quartiles are shown in Table 1. BMI, blood pressure, and triglycerides showed linear trend related to hemoglobin concentration; however, HDL cholesterol was not different among hemoglobin concentration quartiles in men. On the other hand, blood pressure and triglycerides showed linear trend related to hemoglobin concentration; however, BMI, fasting plasma glucose, and HDL cholesterol were not different among hemoglobin concentration quartiles in women.
Hemoglobin concentration and incident MetS The highest (C157 g/L) and third (151–156 g/L) hemoglobin concentration quartiles were associated with the increased risk of incident MetS compared to the lowest (\145 g/L) hemoglobin concentration quartile after adjusting for covariates in men (multivariate OR 2.24, 95 % CI 1.34–3.85, P = 0.0021 and multivariate OR 2.03, 95 % CI 1.21–3.45, P = 0.0070) (Table 2). On the other hand, there was no association between hemoglobin concentration and incident MetS in women.
Discussion The major finding of our study is that increased hemoglobin concentration is associated with the risk of incident MetS in men, but not in women. Previous crosssectional studies indicated that hemoglobin concentration is associated with the prevalence MetS [5–8]. This is the first study to investigate the association between hemoglobin concentration and incident MetS. Possible explanations for the association between hemoglobin concentration and MetS are as follows. Hematocrit, which is significantly correlated with hemoglobin, is the foremost determinant of whole-blood viscosity, which leads to decreased blood flow [27, 28]. Decreased blood flow decreases the delivery of substrate, including insulin, glucose, and oxygen to the tissue, such as skeletal muscle [27, 29] and adipocyte, which might lead to insulin resistance. Actually, it has been reported that hematocrit was associated with incident diabetes [12–15] or cardiovascular diseases [17–19]. In addition, it has been reported that hemoglobin concentration was associated with serum CD40L concentration, which is one of the proinflammatory cytokines [30]. Moreover, it has been reported that hemoglobin concentration is associated with
Fig. 1 Inclusion and exclusion flow chart
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Endocrine Table 1 Baseline characteristics of study subjects across hemoglobin concentration quartiles Men Age (years) 2
Q1 (\145 g/L) N = 362
Q2 (145–150 g/L) N = 365
Q3 (151–156 g/L) N = 360
Q4 (C157 g/L) N = 366
P
48.8 ± 10.1
46.0 ± 9.6
44.7 ± 9.2
43.5 ± 9.4
\0.0001
Body mass index (kg/m )
21.9 ± 2.3
22.5 ± 2.6
22.8 ± 2.8
22.9 ± 2.5
\0.0001
Systolic blood pressure (mmHg)
112.5 ± 14.0
114.1 ± 13.0
115.3 ± 12.8
118.2 ± 12.8
\0.0001 \0.0001
Diastolic blood pressure (mmHg)
67.9 ± 9.5
69.0 ± 8.8
70.0 ± 8.7
71.5 ± 8.7
Fasting plasma glucose
5.1 (4.8–5.3)
5.1 (4.8–5.3)
5.0 (4.7–5.3)
5.0 (4.7–5.2)
0.0478
Total cholesterol (mmol/L)
5.2 ± 0.8
5.3 ± 0.8
5.4 ± 0.8
5.4 ± 0.8
0.0046
Triglycerides
0.9 (0.7–1.4)
1.0 (0.7–1.5)
1.2 (0.8–1.6)
1.2 (0.9–1.6)
HDL cholesterol (mmol/L)
1.5 ± 0.4
1.5 ± 0.4
1.5 ± 0.4
1.5 ± 0.3
eGFR (mL/min/1.73 m2)
73.8 ± 12.0
73.7 ± 11.5
73.9 ± 11.5
73.4 ± 11.6
0.9462
Uric acid (lmol/L)
340.2 ± 71.3
350.1 ± 67.8
352.4. ± 68.0
353.5 ± 70.9
0.0403
Hemoglobin (g/L) White blood cell counts (9102/mm3)
138.6 ± 5.3 54.2 ± 13.8
147.7 ± 1.6 56.0 ± 14.9
153.5 ± 1.7 59.3 ± 15.8
162.2 ± 4.8 60.4 ± 17.8
\0.0001 0.2198
\0.0001 \0.0001
Platelet counts (9104/mm3)
23.0 ± 5.0
23.6 ± 4.8
23.5 ± 5.0
23.4 ± 4.7
Smoking (±)
291/71
299/67
282/78
257/109
0.0015
Habit of alcohol (±)
208/154
219/147
179/181
180/186
0.0050
Habit of exercise (±)
145/217
147/219
152/208
141/225
0.7349
Women
Q1 (\125 g/L) N = 310
Q2 (125–130 g/L) N = 323
Q3 (131–136 g/L) N = 305
Q4 (C137 g/L) N = 304
0.2937
P
Age (years)
44.0 ± 8.4
45.6 ± 9.1
45.4 ± 9.5
45.6 ± 9.4
Body mass index (kg/m2)
20.8 ± 2.5
20.9 ± 2.4
20.9 ± 2.4
21.2 ± 3.0
0.0724
Systolic blood pressure (mmHg)
107.2 ± 12.3
107.7 ± 13.2
108.5 ± 13.9
113.0 ± 14.8
\0.0001 \0.0001
0.2791
Diastolic blood pressure (mmHg)
63.4 ± 8.3
64.1 ± 8.7
64.4 ± 8.8
68.2 ± 9.9
Fasting plasma glucose
4.8 (4.6–5.1)
4.8 (4.6–5.1)
4.8 (4.6–5.1)
4.8 (4.6–5.1)
Total cholesterol (mmol/L)
5.1 ± 0.8
5.2 ± 0.9
5.4 ± 0.9
5.4 ± 0.9
Triglycerides
0.7 (0.5–0.9)
0.7 (0.5–1.0)
0.7 (0.5–1.0)
0.8 (0.6–1.1)
0.0003
HDL cholesterol (mmol/L)
1.8 ± 0.4
1.8 ± 0.4
1.8 ± 0.4
1.9 ± 0.4
0.3586
0.5153 \0.0001
eGFR (mL/min/1.73 m2)
77.2 ± 13.4
74.1 ± 12.8
74.2 ± 15.6
73.3 ± 13.6
Uric acid (lmol/L)
234.5 ± 46.3
246.2 ± 48.1
251.1 ± 46.9
260.4 ± 54.4
\0.0001
112.8 ± 10.5
127.3 ± 2.0
133.5 ± 1.7
141.5 ± 4.3
\0.0001 \0.0001
Hemoglobin (g/L) 2
3
White blood cell counts (910 /mm )
49.0 ± 11.7
50.7 ± 13.1
52.4 ± 14.1
54.7 ± 13.4
Platelet counts (9104/mm3) Smoking (±)
25.4 ± 6.5 296/14
24.2 ± 5.0 302/21
23.7 ± 4.7 276/29
24.1 ± 5.3 272/32
0.0023
0.0013 0.0204
Habit of alcohol (±)
249/61
268/55
241/64
240/64
0.5460
Habit of exercise (±)
162/148
168/155
145/160
153/151
0.6403
Smoking was defined as current tobacco usage. Habit of alcohol was defined as daily alcohol consumption. Habit of exercise was defined as regular exercise. Data are number, mean ± standard deviation, or median (interquartile range). One-way ANOVA for continuous variables or the v2 test for categorical variables was performed for comparisons across the hemoglobin concentration quartiles in men and women, separately HDL high-density lipoprotein, eGFR estimated glomerular filtration rate
endothelial dysfunction [31], which is associated with insulin resistance [32] in patients with diabetes. Taking these finding together, hemoglobin concentration would be associated with MetS. Previous studies reported that there were associations between MetS and other important parameters, such as uric acid, adiponectin, gamma-glutamyl transferase and C-reactive protein [26, 33–36]. In fact, uric acid was associated
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with hemoglobin concentration (b = 0.07, P = 0.009 in men and b = 0.20, P \ 0.001 in women) in this study. Thus, there is possibility that the association between hemoglobin concentration and MetS was affected by other parameters. Interestingly, our study showed that the linear association between hemoglobin concentration and incident MetS was observed just in men, but not in women. One of
Endocrine Table 2 Odds ratios for incident MetS at 8 years after the baseline examination according to hemoglobin concentration quartiles
Men
Q1 (\145 g/L)
Q2 (145–150 g/L)
Q3 (151–156 g/L)
Q4 (C157 g/L)
Case/N Model 1
30/362
50/365
70/360
83/366
1.00 (Ref)
1.76 (1.10–2.86)
2.67 (1.71–4.27)*
Model 2
3.25 (2.10–5.14)*
1.00 (Ref)
1.47 (0.90–2.44)
2.08 (1.29–3.41)*
2.68 (1.68–4.35)*
Model 3
1.00 (Ref)
1.47 (0.90–2.45)
2.02 (1.25–3.32)*
2.61 (1.63–4.26)*
Model 4
1.00 (Ref)
1.56 (0.92–2.70)
2.03 (1.21–3.45)*
2.24 (1.34–3.85)*
Women
Q1 (\125 g/L)
Q2 (125–130 g/L)
Q3 (131–136 g/L)
Q4 (C137 g/L)
Case/N
13/310
26/323
14/305
23/304
Model 1
1.00 (Ref)
2.00 (1.03–4.09)à
1.10 (0.51–2.41)
1.87 (0.94–3.87)
Model 2
1.00 (Ref)
2.08 (1.02–4.49)à
1.07 (0.47–2.47)
1.42 (0.67–3.13)
Model 3
1.00 (Ref)
2.11 (1.03–4.54)à
1.13 (0.49–2.61)
1.45 (0.68–3.20)
Model 4
1.00 (Ref)
1.67 (0.79–3.63)
0.78 (0.30–1.96)
0.80 (0.35–1.83)
Model 1 was unadjusted. Model 2 adjusted for age and body mass index. Model 3 adjusted for Model 2 and lifestyle factors, including smoking statues, habit of alcohol, and habit of exercise. Model 4 adjusted for Model 3 and systolic blood pressure, log fasting plasma glucose, log triglycerides, high-density lipoprotein cholesterol, creatinine and uric acid MetS Metabolic syndrome * P \ 0.001 versus Q1 (\145 g/L) in men, P \ 0.05 versus Q1 (\145 g/L) in men, à P \ 0.05 versus Q1 (\125 g/L) in women
the possible underlying factors is menstruation. It has been reported that not only iron overload [37] but also iron deficiency [38] was associated with insulin resistance. It has been reported that insulin resistance was improved after treatment of iron deficiency [38]. Unfortunately, we did not measure serum ferritin and iron concentrations, which are marker of iron state, and did not know the exact proportion of premenopausal women in this study. Thus, further studies would be needed to clarify the association between hemoglobin concentration and incident MetS in women. Strengths of our study include the relatively large number of subjects both at baseline and at follow-up. However, this study has some limitations that require consideration. First, the lack of waist circumference weakens the definition of MetS. However, BMI of C25 kg/ m2, by which we defined obesity in this study, was proposed as a cutoff for the diagnosis of obesity in Asian people [22]. Several studies in Japan often used BMI C25 kg/m2 in substitution for central obesity [23, 39]. In addition, this value corresponds to a cutoff point for visceral fat area of 100 cm2, regarded as the gold standard for defining central obesity. Correlation coefficients of visceral fat area with BMI were reported to be 0.61 in men and 0.63 in women [40]. Second, the study population consisted of Japanese men and women; therefore, it is uncertain whether these findings are generalized in other ethnic groups. Third, because we used a standard cuff size for measure blood pressure, there is a possibility that the blood pressure readings can get seemingly high in obese subjects. Fourth,
although we used the data of individuals who received health check-up programs, however, we could not fully exclude the participants who had chronic disease such as malnutrition, hepatic disease, and cancer, which might affect on various parameters. Fifth, we did not measure serum ferritin and iron concentrations. In addition, although the detail data of women, such as menopausal or premenopausal, using hormonal contraceptives or not, or using hormone-replacement therapy or not [41], are important, we did not have exact data of those in this study. Lastly, our study subjects underwent a health examination; thus, there is a possibility that some subjects might have made lifestyle changes based on results of the health examination to prevent incident MetS. Our study showed that increased hemoglobin concentration was associated with the risk of incident MetS even after controlling for traditional MetS risk factors in men. We acknowledge that the finding of an association between increased hemoglobin concentration and incident MetS dose not establish a direct causal relationship. It is possible that increased hemoglobin concentration is merely surrogate biomarker representing underlying pathophysiological processes; however, hemoglobin concentration is easily measured in a clinical setting. In conclusion, increased hemoglobin concentration could be a novel risk marker for incident MetS in men. Thus, men with increased hemoglobin concentration might require aggressive lifestyle modifications for the prevention of incident MetS.
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There are no conflicts of interest. 16.
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ORIGINAL ARTICLE
Hemoglobin concentration and incident metabolic syndrome: a population-based large-scale cohort study Yoshitaka Hashimoto1 • Muhei Tanaka1 • Toshihiro Kimura1 • Noriyuki Kitagawa1 Masahide Hamaguchi1 • Mai Asano1 • Masahiro Yamazaki1 • Yohei Oda1 • Hitoshi Toda2 • Naoto Nakamura1 • Michiaki Fukui1
•
Received: 14 January 2015 / Accepted: 27 March 2015 Ó Springer Science+Business Media New York 2015
Abstract Previous cross-sectional studies revealed an association between hemoglobin concentration and a prevalence of metabolic syndrome (MetS). However, the association between hemoglobin concentration and incident MetS remains to be elucidated. Thus, the aim of this study was to investigate the association between hemoglobin concentration and incident MetS. We enrolled 2695 subjects (1454 men and 1241 women) and performed 8-year follow-up cohort study. MetS was diagnosed, according to the joint interim statement, when a subject had three or more of the following components: hypertension; hyperglycemia; hypertriglyceridemia; low high-density lipoprotein cholesterol; and abdominal obesity. Logistic regression analyses were performed to assess the impact of hemoglobin concentration on incident MetS by adjusting for age, body mass index, lifestyle factors, including smoking status, habit of alcohol and habit of exercise, systolic blood pressure, fasting plasma glucose, triglycerides, high-density lipoprotein cholesterol, creatinine, and uric acid. The highest (C157 g/L) and third (151–156 g/L) hemoglobin concentration quartiles were associated with the increased risk of incident MetS compared to the lowest (\145 g/L) hemoglobin concentration quartile after adjusting for covariates in men (multivariate odds ratio (OR) 2.24, 95 % CI 1.34–3.85, P = 0.0021 and multivariate OR 2.03, 95 % CI 1.21–3.45, P = 0.0070). On the other hand,
& Michiaki Fukui [email protected] 1
Department of Endocrinology and Metabolism, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kawaramachi-Hirokoji, Kamigyo-ku, Kyoto 602-8566, Japan
2
Department of Internal Medicine, Oike Clinic, Kyoto, Japan
there was no association between hemoglobin concentration and incident MetS in women. Hemoglobin concentration was a novel risk marker for incident MetS in men. Keywords Epidemiology Metabolic syndrome Hematological parameters Hemoglobin Abbreviations MetS Metabolic syndrome BMI Body mass index HDL High-density lipoprotein eGFR Estimated glomerular filtration rate
Introduction Metabolic syndrome (MetS) is defined by the clustering of several cardiovascular risk factors, including hypertension, hyperglycemia, dyslipidemia, and visceral obesity [1]. MetS is associated with cardiovascular disease which is the leading cause of mortality and morbidity [2]. In view of its emerging epidemic and impact, an early identification of people at high risk for MetS would help prevent the associated cardiovascular complications. In Japan, the prevalence of MetS, using a joint interim statement, was 18.5–37.3 % in men and 4.4–12.8 % in women [3, 4] and may have recently become even more common with the continuous increase in obesity prevalence. Previous cross-sectional studies revealed that there was an association between hematological parameter, including hemoglobin, hematocrit, red blood cell counts, white blood cell counts, or platelet counts, and a prevalence MetS or its components [5–8]. Moreover, recent cross-sectional studies revealed that there was the association between
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hemoglobin concentration and insulin resistance [9, 10] or non-alcohol fatty liver disease [11], which is closely associated with MetS. In addition, recent studies reveled that high hemoglobin concentration was associated with risk of incident type 2 diabetes [12–15], non-alcohol fatty liver disease [16], or cardiovascular diseases [17–19]. Therefore, we hypothesized that high hemoglobin concentration is associated with incident MetS. To our knowledge, however, the association between hemoglobin concentration and incident MetS remains to be elucidated. Therefore, we investigated the association between hemoglobin concentration and incident MetS in this cohort study.
who had hypertensive or prehypertensive blood pressure values. The lowest reading was used as a definition of hypertension. After an overnight fast, venous blood was collected for the measurement of the levels of various factors, including fasting plasma glucose, total cholesterol, triglycerides, high-density lipoprotein (HDL) cholesterol, creatinine, uric acid, hemoglobin, white blood cell counts, and platelet counts. Glomerular filtration rate (GFR) was estimated using the Japanese Society of Nephrology equation: estimated GFR (eGFR) = 194 9 Cre-1.094 9 age-0.287 (mL/min/1.73 m2) [20]. For women, the eGFR was multiplied by a correction factor of 0.739. Definition of MetS
Materials and methods
The Oike Health Survey is an ongoing cohort investigation of risk factors for chronic diseases, including hypertension, diabetes, and chronic kidney disease. The Oike Clinic (Kyoto, Japan) provides regular health check-up for employees of various companies. In Japan, yearly routine examinations for employees are legally mandated, and all or most of the costs for the health check-up are usually paid by their employers. The purpose of the medical health check-up program is to promote public health through early detection of chronic diseases and their risk factors. Medical service of this kind, known as ‘‘a human dock,’’ is very popular in Japan. We enrolled subjects who received health check-up in 2001 and performed 8-year follow-up in this cohort study. Exclusion criteria were as follows: medication for hypertension, diabetes and/or dyslipidemia, and/or a presence of MetS at baseline examination, and missing data of covariates. Approval for the study was obtained from the Ethical Committee of Oike Clinic, and the study was conducted in accordance with Declaration of Helsinki. Informed consent was obtained from each subject.
The diagnosis of MetS was determined by a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; the National Heart, Lung, and Blood Institute; the American Heart Association; the World Heart Federation; the International Atherosclerosis Society; and the International Association for the Study of Obesity, using the criteria for Asians [21]. The subjects were diagnosed with the presence of MetS when three or more of the following criteria were present: hypertension (systolic blood pressure C130 mmHg and diastolic blood pressure C85 mmHg and/or medication for hypertension, in both the sexes); hyperglycemia (fasting plasma glucose C5.6 mmol/L and/or medication for diabetes, in both the sexes); hypertriglyceridemia (serum triglycerides C1.70 mmol/L and/or medication for dyslipidemia, in both the sexes); low HDL cholesterol levels (serum HDL cholesterol \1.03 mmol/L in men and \1.29 mmol/L in women); and abdominal obesity (waist circumference C90 cm in men and C80 cm in women). Because waist measurements were not available for entire study sample, we submitted a BMI of C25 kg/m2, which has been proposed as a cutoff for the diagnosis of obesity in Asian people [22], for all subjects as an index of obesity. The validity of this definition was confirmed previously [23].
Data collection and measurements
Statistical analysis
All subjects provided details of their demographics. Smoking was defined as current tobacco usage. Habit of alcohol was defined as daily alcohol consumption. Habit of exercise was defined as performing any kind of sports at least once a week. Body weight was measured with the subjects in light clothing without shoes. Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared. After a brief period of rest, sitting blood pressure was measured in either arm. Blood pressure was measured once in most subjects, but up to 3 measurements at 1- to 2-min intervals were made in subjects
The statistical analyses were performed using the JMP version 10.0 software (SAS Institute Inc., Cary, North Carolina), and P value \0.05 was considered statistically significant. Mean or frequencies of potential confounding variables were calculated. Skewed variables such as fasting plasma glucose and triglycerides were presented as median (interquartile range), and continuous variables were presented as the mean ± standard deviation (SD). One-way ANOVA for continuous variables or the v2 square test for categorical variables was performed for comparisons across the hemoglobin concentration quartiles in men and
Subjects and study design
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women, separately. Because fasting plasma glucose and triglycerides showed skewed distributions, logarithmic transformation was carried out before performance of logistic regression analyses. Logistic regression analyses were performed to assess the impact of hemoglobin concentration on incident MetS. To examine the effects of various factors on incident MetS, the following factors, which were reported to be risk factors for incident MetS [24–26], were considered simultaneously as independent variables for multiple regression analyses: age, BMI, lifestyle factors, including smoking status, habit of alcohol and habit of exercise, systolic blood pressure, log fasting plasma glucose, log triglycerides, HDL cholesterol, creatinine, and uric acid. Odds ratio (OR) and 95 % confidence interval (CI) were calculated.
Results In 2001, the results of 4127 subjects (2395 men and 1732 women) were served as database (Fig. 1). Among them, 1432 subjects (941 men and 491 women) were excluded. Thus, 2695 subjects (1454 men and 1241 women) were enrolled into this cohort study. Baseline characteristics of subjects The baseline characteristics according to hemoglobin concentration quartiles are shown in Table 1. BMI, blood pressure, and triglycerides showed linear trend related to hemoglobin concentration; however, HDL cholesterol was not different among hemoglobin concentration quartiles in men. On the other hand, blood pressure and triglycerides showed linear trend related to hemoglobin concentration; however, BMI, fasting plasma glucose, and HDL cholesterol were not different among hemoglobin concentration quartiles in women.
Hemoglobin concentration and incident MetS The highest (C157 g/L) and third (151–156 g/L) hemoglobin concentration quartiles were associated with the increased risk of incident MetS compared to the lowest (\145 g/L) hemoglobin concentration quartile after adjusting for covariates in men (multivariate OR 2.24, 95 % CI 1.34–3.85, P = 0.0021 and multivariate OR 2.03, 95 % CI 1.21–3.45, P = 0.0070) (Table 2). On the other hand, there was no association between hemoglobin concentration and incident MetS in women.
Discussion The major finding of our study is that increased hemoglobin concentration is associated with the risk of incident MetS in men, but not in women. Previous crosssectional studies indicated that hemoglobin concentration is associated with the prevalence MetS [5–8]. This is the first study to investigate the association between hemoglobin concentration and incident MetS. Possible explanations for the association between hemoglobin concentration and MetS are as follows. Hematocrit, which is significantly correlated with hemoglobin, is the foremost determinant of whole-blood viscosity, which leads to decreased blood flow [27, 28]. Decreased blood flow decreases the delivery of substrate, including insulin, glucose, and oxygen to the tissue, such as skeletal muscle [27, 29] and adipocyte, which might lead to insulin resistance. Actually, it has been reported that hematocrit was associated with incident diabetes [12–15] or cardiovascular diseases [17–19]. In addition, it has been reported that hemoglobin concentration was associated with serum CD40L concentration, which is one of the proinflammatory cytokines [30]. Moreover, it has been reported that hemoglobin concentration is associated with
Fig. 1 Inclusion and exclusion flow chart
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Endocrine Table 1 Baseline characteristics of study subjects across hemoglobin concentration quartiles Men Age (years) 2
Q1 (\145 g/L) N = 362
Q2 (145–150 g/L) N = 365
Q3 (151–156 g/L) N = 360
Q4 (C157 g/L) N = 366
P
48.8 ± 10.1
46.0 ± 9.6
44.7 ± 9.2
43.5 ± 9.4
\0.0001
Body mass index (kg/m )
21.9 ± 2.3
22.5 ± 2.6
22.8 ± 2.8
22.9 ± 2.5
\0.0001
Systolic blood pressure (mmHg)
112.5 ± 14.0
114.1 ± 13.0
115.3 ± 12.8
118.2 ± 12.8
\0.0001 \0.0001
Diastolic blood pressure (mmHg)
67.9 ± 9.5
69.0 ± 8.8
70.0 ± 8.7
71.5 ± 8.7
Fasting plasma glucose
5.1 (4.8–5.3)
5.1 (4.8–5.3)
5.0 (4.7–5.3)
5.0 (4.7–5.2)
0.0478
Total cholesterol (mmol/L)
5.2 ± 0.8
5.3 ± 0.8
5.4 ± 0.8
5.4 ± 0.8
0.0046
Triglycerides
0.9 (0.7–1.4)
1.0 (0.7–1.5)
1.2 (0.8–1.6)
1.2 (0.9–1.6)
HDL cholesterol (mmol/L)
1.5 ± 0.4
1.5 ± 0.4
1.5 ± 0.4
1.5 ± 0.3
eGFR (mL/min/1.73 m2)
73.8 ± 12.0
73.7 ± 11.5
73.9 ± 11.5
73.4 ± 11.6
0.9462
Uric acid (lmol/L)
340.2 ± 71.3
350.1 ± 67.8
352.4. ± 68.0
353.5 ± 70.9
0.0403
Hemoglobin (g/L) White blood cell counts (9102/mm3)
138.6 ± 5.3 54.2 ± 13.8
147.7 ± 1.6 56.0 ± 14.9
153.5 ± 1.7 59.3 ± 15.8
162.2 ± 4.8 60.4 ± 17.8
\0.0001 0.2198
\0.0001 \0.0001
Platelet counts (9104/mm3)
23.0 ± 5.0
23.6 ± 4.8
23.5 ± 5.0
23.4 ± 4.7
Smoking (±)
291/71
299/67
282/78
257/109
0.0015
Habit of alcohol (±)
208/154
219/147
179/181
180/186
0.0050
Habit of exercise (±)
145/217
147/219
152/208
141/225
0.7349
Women
Q1 (\125 g/L) N = 310
Q2 (125–130 g/L) N = 323
Q3 (131–136 g/L) N = 305
Q4 (C137 g/L) N = 304
0.2937
P
Age (years)
44.0 ± 8.4
45.6 ± 9.1
45.4 ± 9.5
45.6 ± 9.4
Body mass index (kg/m2)
20.8 ± 2.5
20.9 ± 2.4
20.9 ± 2.4
21.2 ± 3.0
0.0724
Systolic blood pressure (mmHg)
107.2 ± 12.3
107.7 ± 13.2
108.5 ± 13.9
113.0 ± 14.8
\0.0001 \0.0001
0.2791
Diastolic blood pressure (mmHg)
63.4 ± 8.3
64.1 ± 8.7
64.4 ± 8.8
68.2 ± 9.9
Fasting plasma glucose
4.8 (4.6–5.1)
4.8 (4.6–5.1)
4.8 (4.6–5.1)
4.8 (4.6–5.1)
Total cholesterol (mmol/L)
5.1 ± 0.8
5.2 ± 0.9
5.4 ± 0.9
5.4 ± 0.9
Triglycerides
0.7 (0.5–0.9)
0.7 (0.5–1.0)
0.7 (0.5–1.0)
0.8 (0.6–1.1)
0.0003
HDL cholesterol (mmol/L)
1.8 ± 0.4
1.8 ± 0.4
1.8 ± 0.4
1.9 ± 0.4
0.3586
0.5153 \0.0001
eGFR (mL/min/1.73 m2)
77.2 ± 13.4
74.1 ± 12.8
74.2 ± 15.6
73.3 ± 13.6
Uric acid (lmol/L)
234.5 ± 46.3
246.2 ± 48.1
251.1 ± 46.9
260.4 ± 54.4
\0.0001
112.8 ± 10.5
127.3 ± 2.0
133.5 ± 1.7
141.5 ± 4.3
\0.0001 \0.0001
Hemoglobin (g/L) 2
3
White blood cell counts (910 /mm )
49.0 ± 11.7
50.7 ± 13.1
52.4 ± 14.1
54.7 ± 13.4
Platelet counts (9104/mm3) Smoking (±)
25.4 ± 6.5 296/14
24.2 ± 5.0 302/21
23.7 ± 4.7 276/29
24.1 ± 5.3 272/32
0.0023
0.0013 0.0204
Habit of alcohol (±)
249/61
268/55
241/64
240/64
0.5460
Habit of exercise (±)
162/148
168/155
145/160
153/151
0.6403
Smoking was defined as current tobacco usage. Habit of alcohol was defined as daily alcohol consumption. Habit of exercise was defined as regular exercise. Data are number, mean ± standard deviation, or median (interquartile range). One-way ANOVA for continuous variables or the v2 test for categorical variables was performed for comparisons across the hemoglobin concentration quartiles in men and women, separately HDL high-density lipoprotein, eGFR estimated glomerular filtration rate
endothelial dysfunction [31], which is associated with insulin resistance [32] in patients with diabetes. Taking these finding together, hemoglobin concentration would be associated with MetS. Previous studies reported that there were associations between MetS and other important parameters, such as uric acid, adiponectin, gamma-glutamyl transferase and C-reactive protein [26, 33–36]. In fact, uric acid was associated
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with hemoglobin concentration (b = 0.07, P = 0.009 in men and b = 0.20, P \ 0.001 in women) in this study. Thus, there is possibility that the association between hemoglobin concentration and MetS was affected by other parameters. Interestingly, our study showed that the linear association between hemoglobin concentration and incident MetS was observed just in men, but not in women. One of
Endocrine Table 2 Odds ratios for incident MetS at 8 years after the baseline examination according to hemoglobin concentration quartiles
Men
Q1 (\145 g/L)
Q2 (145–150 g/L)
Q3 (151–156 g/L)
Q4 (C157 g/L)
Case/N Model 1
30/362
50/365
70/360
83/366
1.00 (Ref)
1.76 (1.10–2.86)
2.67 (1.71–4.27)*
Model 2
3.25 (2.10–5.14)*
1.00 (Ref)
1.47 (0.90–2.44)
2.08 (1.29–3.41)*
2.68 (1.68–4.35)*
Model 3
1.00 (Ref)
1.47 (0.90–2.45)
2.02 (1.25–3.32)*
2.61 (1.63–4.26)*
Model 4
1.00 (Ref)
1.56 (0.92–2.70)
2.03 (1.21–3.45)*
2.24 (1.34–3.85)*
Women
Q1 (\125 g/L)
Q2 (125–130 g/L)
Q3 (131–136 g/L)
Q4 (C137 g/L)
Case/N
13/310
26/323
14/305
23/304
Model 1
1.00 (Ref)
2.00 (1.03–4.09)à
1.10 (0.51–2.41)
1.87 (0.94–3.87)
Model 2
1.00 (Ref)
2.08 (1.02–4.49)à
1.07 (0.47–2.47)
1.42 (0.67–3.13)
Model 3
1.00 (Ref)
2.11 (1.03–4.54)à
1.13 (0.49–2.61)
1.45 (0.68–3.20)
Model 4
1.00 (Ref)
1.67 (0.79–3.63)
0.78 (0.30–1.96)
0.80 (0.35–1.83)
Model 1 was unadjusted. Model 2 adjusted for age and body mass index. Model 3 adjusted for Model 2 and lifestyle factors, including smoking statues, habit of alcohol, and habit of exercise. Model 4 adjusted for Model 3 and systolic blood pressure, log fasting plasma glucose, log triglycerides, high-density lipoprotein cholesterol, creatinine and uric acid MetS Metabolic syndrome * P \ 0.001 versus Q1 (\145 g/L) in men, P \ 0.05 versus Q1 (\145 g/L) in men, à P \ 0.05 versus Q1 (\125 g/L) in women
the possible underlying factors is menstruation. It has been reported that not only iron overload [37] but also iron deficiency [38] was associated with insulin resistance. It has been reported that insulin resistance was improved after treatment of iron deficiency [38]. Unfortunately, we did not measure serum ferritin and iron concentrations, which are marker of iron state, and did not know the exact proportion of premenopausal women in this study. Thus, further studies would be needed to clarify the association between hemoglobin concentration and incident MetS in women. Strengths of our study include the relatively large number of subjects both at baseline and at follow-up. However, this study has some limitations that require consideration. First, the lack of waist circumference weakens the definition of MetS. However, BMI of C25 kg/ m2, by which we defined obesity in this study, was proposed as a cutoff for the diagnosis of obesity in Asian people [22]. Several studies in Japan often used BMI C25 kg/m2 in substitution for central obesity [23, 39]. In addition, this value corresponds to a cutoff point for visceral fat area of 100 cm2, regarded as the gold standard for defining central obesity. Correlation coefficients of visceral fat area with BMI were reported to be 0.61 in men and 0.63 in women [40]. Second, the study population consisted of Japanese men and women; therefore, it is uncertain whether these findings are generalized in other ethnic groups. Third, because we used a standard cuff size for measure blood pressure, there is a possibility that the blood pressure readings can get seemingly high in obese subjects. Fourth,
although we used the data of individuals who received health check-up programs, however, we could not fully exclude the participants who had chronic disease such as malnutrition, hepatic disease, and cancer, which might affect on various parameters. Fifth, we did not measure serum ferritin and iron concentrations. In addition, although the detail data of women, such as menopausal or premenopausal, using hormonal contraceptives or not, or using hormone-replacement therapy or not [41], are important, we did not have exact data of those in this study. Lastly, our study subjects underwent a health examination; thus, there is a possibility that some subjects might have made lifestyle changes based on results of the health examination to prevent incident MetS. Our study showed that increased hemoglobin concentration was associated with the risk of incident MetS even after controlling for traditional MetS risk factors in men. We acknowledge that the finding of an association between increased hemoglobin concentration and incident MetS dose not establish a direct causal relationship. It is possible that increased hemoglobin concentration is merely surrogate biomarker representing underlying pathophysiological processes; however, hemoglobin concentration is easily measured in a clinical setting. In conclusion, increased hemoglobin concentration could be a novel risk marker for incident MetS in men. Thus, men with increased hemoglobin concentration might require aggressive lifestyle modifications for the prevention of incident MetS.
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Endocrine Conflict of interest
There are no conflicts of interest. 16.
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