To our knowledge, this is the first study to show higher hemoglobin, serum ferritin, haptoglobin and also erythropoietin levels in subjects with MetS and extending these findings to include individual MetS components.
Recently, increasing evidence has suggested that reduced adipose tissue oxygenation and cellular hypoxia may be an underlying cause of adipose tissue dysfunction contributing to metabolic changes associated with obesity and MetS [8
]. It was demonstrated that hypoxia creates an insulin resistant state in human adipocytes by inhibiting phosphorylation of the insulin receptor, leading to a decrease in glucose transport [10
]. Insulin resistance has been the most accepted and unifying hypothesis to describe the pathophysiology of the metabolic syndrome [1
Also, previous studies have shown reduced adipose tissue oxygenation in obese compared to normal-weight subjects and EPO gene transcription stimulating factor (HIF-1) over-expression in the adipose tissue of obese subjects [8
]. Hypoxia is a known stimulator of erythropoietin production as well as EPO is a stimulator of hemoglobin synthesis [7
]. EPO levels were significantly higher in subjects with MetS as well as in subjects with MetS abdominal obesity component in this study which may suggest underlying adipose tissue hypoxia in MetS.
Hemoglobin levels were significantly higher in subjects with MetS or with any of the components of MetS. This is supported by a previous study of working-age thai subjects that showed increased hemoglobin concentrations with increasing numbers of MetS components but only in women [14
Further research is needed to investigate possible association between higher hemoglobin and EPO levels in subjects with MetS.
Previously, it was shown that nocturnal intermittent hypoxia, a marker for obstructive sleep apnea (OSA), is positively associated with MetS and its components [15
]. One previous study reported lower serum EPO concentrations after continuous positive pressure airway treatment in patients with OSA [16
]. Also, higher serum EPO concentrations have been reported in patients with central sleep apnea and nocturnal hypoxia compared to healthy controls [17
Previous studies have shown associations between serum ferritin or sTFR and increased risk of type 2 diabetes [18
]. Recently, it was also shown that single nucleotide polymorphism (SNP) in genes that are related to body iron status are associated with risk of type 2 diabetes (T2D). SNP in gene that was related high sTFR levels and low ferritin levels was associated with lower risk of T2D, as well [20
The finding that subjects with MetS had significantly higher serum ferritin levels supports previous results [3
]. In addition, ferritin levels were significantly higher in subjects with abdominal obesity or high TG or elevated glucose or low high-density cholesterol MetS component but not in subjects with blood pressure component. Previous studies have shown that higher serum ferritin concentrations are associated with increased TG concentration in men and with elevated glucose in women [3
Because ferritin is an acute phase reactant, all results were adjusted for hs-CRP to estimate the impact of inflammation. Ferritin levels remained significantly higher after hs-CRP standardization suggesting that mechanisms other than inflammation may be influencing ferritin concentration in the subjects with MetS. However, we were not able to estimate other markers of inflammation or level of proinflammatory cytokines like tumor necrosis factor alfa and interleukins in this study.
Higher hs-CRP levels have also previously shown to be associated with MetS and its separate components as well as median hs-CRP levels to be increased with increasing number of MetS components [21
]. In addition, the degree of central obesity seemed to be the main determinant of an increased hs-CRP level [24
]. In our study hs-CRP levels were significantly higher in women with MetS and almost significantly higher in men with MetS compared those without (Table
Under hypoxia and also when erythropoiesis is stimulated, human iron-regulatory hormone, hepcidin, production is suppressed [25
]. Theoretically, suppression in hepcidin production could result in higher ferritin levels seen in subjects with MetS. However, althought reduced adipose tissue oxygenation was found in obese subjects, hepcidin expression levels were increased, not suppressed, in the adipose tissue of obese patients [27
]. Consequently, it is unlikely that purely adipose tissue hypoxia could cause hepcidin supression and elevated ferritin levels.
Haptoglobin is an acute phase reactant which plasma levels are increased during inflammation [28
]. Although the liver is the major source of haptoglobin, research has demonstrated that it is also secreted into plasma by adipose tissue [29
]. Serum haptoglogin level was previously shown to be positively associated with body fat [30
]. Our study shows higher serum haptoglobin levels in subjects with MetS and subjects with elevated glucose or blood pressure component even after adjusting for hs-CRP.
Serum transferrin receptor levels did not differ between subject with or without MetS, but sTFR level was higher in subjects with abdominal obesity component of MetS. sTFR levels are increased in iron defiency with inadequate iron supply for erythropoiesis [31
] but also, for example secondary to use of erythropoiesis stimulating agents such as erythropoietin [32
]. Higher sTFR levels in subjects with abdominal obesity component of MetS suggest that despite of higher ferritin levels, these subjects are not iron overloaded. Previous studies have shown higher sTFR leves in obese subjects as well as no iron accumulation in liver biopsies of obese patients [27
The strength of our study is the study population with five age groups and no exclusion criteria. Smoking habits between subjects with and without MetS did not differ significantly. In addition, all results were adjusted for smoking to exclude its influence particularly on hemoglobin and erythropoietin levels. All results were also hs-CRP adjusted to estimate the impact of inflammation. A limitation is that hematological parameters were measured only at the second health check-up and cross-sectional study design does not allow identification of proper causal relationships. Information about women’s menopause status was not available. However, the separate analysis was done in women for age adjusment (Table
, all data not shown). The age adjusment did not affect the results in women. Unfortunately, we were unable to evaluate a possibly impact of obstructive or central sleep apnea on subjects hemoglobin or erythropoietin levels. Also, information about nutritional content of subjects’ diets or consumption of dietary supplements like iron or antioxidants was not available.
In conclusion, Subjects with MetS have elevated hemoglobin, ferritin, erythropoietin and haptoglobin concentrations. Higher hemoglobin levels are related to all components of MetS. Higher ferritin levels associate with TG, abdominal obesity, elevated glucose or low high-density cholesterol. Haptoglobin levels associate with blood pressure or elevated glucose. However, erythropoietin levels are related only with abdominal obesity. Higher serum erythropoietin concentrations may suggest underlying adipose tissue hypoxemia in MetS.