Iron Deficiency in Obese Postmenopausal Women Albert Lecube,* Alicia Carrera,† Eladio Losada,* Cristina Herna´ndez,‡ Rafael Simo´,‡ and Jordi Mesa*
Abstract LECUBE, ALBERT, ALICIA CARRERA, ELADIO ´ NDEZ, RAFAEL SIMO ´, LOSADA, CRISTINA HERNA AND JORDI MESA. Iron deficiency in obese postmenopausal women. Obesity. 2006;14:1724 –1730. Objective: This study evaluates whether the iron deficiency suggested in children and adolescents with overweight is also present with increasing age. Research Methods and Procedures: We examined 50 consecutive postmenopausal nondiabetic white women with a BMI ⱖ30 kg/m2 and 50 non-obese seemingly healthy women as a control group. In addition to the traditional indices of iron status, we measured the soluble transferrin receptor (sTfR) levels, a sensitive and highly quantitative indicator of early iron deficiency not influenced by the acute phase response. Results: Obese women have higher serum sTfR levels than control subjects [1.38 (range, 0.89 to 2.39) vs. 1.16 mg/dL (range, 0.69 to 2.03 mg/dL); p ⬍ 0.001]. However, no difference in ferritin concentration was observed between the groups [70.50 (range, 18 to 219) vs. 69.50 ng/mL (range, 24 to 270 ng/mL); p ⫽ not significant]. A positive correlation between BMI and sTfR concentration was detected. On multiple regression analyses, BMI (positively) and ferritin (inversely) were independent predictors accounting for sTfR. Discussion: These results suggest that a moderate degree of iron deficiency is also present among adult women with obesity. The determination of sTfR is useful in the evaluation of iron status in this condition. Further studies with a
Received for review November 21, 2005. Accepted in final form July 13, 2006. The costs of publication of this article were defrayed, in part, by the payment of page charges. This article must, therefore, be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. *Obesity Research Unit, Endocrinology Division, Hospital General Vall d’Hebron, Barcelona, Spain; †Hematology Department, Hospital General Vall d’Hebron, Barcelona, Spain; and ‡Diabetes Research Unit, Endocrinology Division, Hospital General Vall d’Hebron, Barcelona, Spain. Address correspondence to Albert Lecube, Division of Endocrinology (8a planta centro), Hospital General Vall d’Hebron, Passeig Vall d’Hebron, 119 –129, 08035 Barcelona, Spain. E-mail:
[email protected] Copyright © 2006 NAASO
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greater number of patients are required to investigate the relationship between tissue iron concentrations and obesity. Key words: iron status, adult, soluble transferrin receptor, women, anemia
Introduction Iron is a transition metal capable of causing oxidative tissue damage by catalyzing the formation of free radicals (1). Given that cross-sectional studies have shown a link between increased ferritin levels and several metabolic and vascular disorders (2– 4), it could be speculated that iron stores participate in the higher prevalence of the metabolic syndrome in obese patients. Unexpectedly, the Third National Health and Nutrition Examination Survey (5) has shown that overweight children and adolescents are more than two times more likely than those with normal weight to be deficient of iron. Additionally, compared with lean mice, congenitally obese mice showed lower tissue iron concentration (6). Little, if any, information is available on iron stores in adult obese subjects. Serum ferritin accurately reflects body iron stores in healthy individuals (7). However, serum ferritin is an acutephase reactant (8), and a chronic, low-grade, inflammatory status has recently been associated with obesity and the etiopathogenesis of type 2 diabetes (9 –11). We have recently communicated that elevated ferritin levels in type 2 diabetes are caused mainly by inflammatory mechanisms rather than by iron overload (12). In the steady state, circulating iron is bound to transferrin and is taken up from the blood by a high-affinity specific transferrin receptor (TfR).1 The synthesis of TfR and the iron storage protein ferritin is regulated reciprocally at the post-transcriptional level according to the cellular iron status (13). Circulating concentrations of TfR [soluble TfR (sTfR)] are proportional to cellular expression of the membrane-associated TfR (14). Therefore, serum sTfR concentration is closely related to
1 Nonstandard abbreviations: TfR, transferrin receptor; sTfR, soluble transferrin receptor; TSI, transferrin saturation index; HOMA-IR, homeostasis model assessment.
Iron Deficiency in Obesity, Lecube et al.
cellular iron demands, and, therefore, the higher the ferritin levels the lower the sTfR concentration. Indeed, as sTfR concentration is not influenced by the acute phase response (15), its measurement permits us to determine more accurately the iron stores in adult obese subjects. The objective of this study was to determine whether overweight nondiabetic postmenopausal women have an increased prevalence of iron deficiency compared with a group of non-overweight controls.
Research Methods and Procedures Patients A total of 50 consecutive white women with BMI ⱖ30 kg/m2 attending the outpatient Obesity Unit of a university hospital were prospectively recruited for the study from January to March 2005. Women were selected because of the higher prevalence of obesity in women worldwide (16). Fifty non-obese (BMI ⬍ 30 kg/m2) women recruited from healthy staff working in our hospital and their relatives were used as a control group. The exclusion criteria for this case-control study were conditions that could influence body iron stores: pre-menopause, clinical evidence of hemorrhage in the preceding 6 months, serum ferritin levels ⬍10 ng/mL, treatment in the previous year with iron, blood donation within the last 6 months, type 2 diabetes, alcohol consumption ⬎50 g/d, hemochromatosis (by testing hemochromatosis gene mutations in patients with transferrin saturation index ⬎45%), and concomitant infections or chronic diseases. Obesity was defined according to the World Health Organization definition as a BMI of at least 30 kg/m2 (17). Type 2 diabetes was defined according to the criteria recommended by the Expert Committee on the Diagnosis and Classification of Diabetes (18). Menopausal status was defined as self-reported 12-months’ cessation of menstruation or hysterectomy. Informed written consent was obtained from all participants, and the study was approved by the Hospital’s human ethics committee. Laboratory Analysis All laboratory measurements were performed on fasting blood samples. sTfR was measured by particle-enhanced nephelometry (Dade Behring Marburg, Marburg, Germany). The normal values range from 0.83 to 1.76 mg/liter in both sexes. The coefficients of variation for intra-assay precision are 1.4% to 2.1%, and the total coefficient of variation is 1.5% to 2.1%. Ferritin was measured by a turbidimetric fixed rate method (Olympus System Reagent; Olympus Diagnostica, Hamburg, Germany). The normal values range from 20 to 300 ng/mL in adult men and from 10 to 200 ng/mL in adult women. Serum iron was measured by a photometric color
test for clinical chemistry analyzers (Olympus System Reagent; Olympus Diagnostica). Transferrin was measured by a turbidimetric endpoint method (Olympus System Reagent; Olympus Diagnostica). Transferrin saturation index (TSI) was calculated as serum iron ⫻ 70.9/transferrin. The ratio of the concentrations of sTfR to log ferritin (sTfR/log ferritin ratio) was used as an additional marker for biochemical identification of iron-deficient erythropoiesis (19,20). Reticulocytes were measured by flow cytometry techniques [Analyzer AN-HA-04 (L); Coulter Corp., Miami, FL]. Insulin resistance was determined by the homeostasis model assessment (HOMA-IR) according to the following formula: {[glucose (mg/dL)/18] ⫻ insulin (mU/liter)}/22.5 (21). Hemochromatosis gene mutations C282Y and H63D were screened using enzymatic digestion of polymerase chain reaction products encompassing the mutation sites as previously described (22). Statistical Analysis Normal distribution of the variables was evaluated using the Kolmogorov-Smirnov test. Given their skewed distribution, serum ferritin, sTfR, sTfR/log ferritin ratio, HOMAIR, and reticulocytes are expressed as median (range). For parametric tests, those parameters were logarithmically transformed to achieve a normal distribution. Comparisons between groups were done using Student t tests for continuous variables and the 2 test for categorical variables. The relationship between continuous variables was examined by the Pearson linear correlation test in all subjects and separately in obese and non-obese subjects. A stepwise multiple regression analysis to explore the variables independently related to sTfR levels was performed. The independent variables included in the analysis were BMI, log ferritin, serum iron, age, reticulocytes, and HOMA-IR. All p values are based on a two-sided test of statistical significance. Significance was accepted at the level of p ⬍ 0.05. Statistical analyses were performed with the SSPS statistical package (SAS Institute, Cary, NC).
Results The main clinical features and the iron status of obese women and control groups are presented in Table 1. No differences in age, serum ferritin, iron, transferrin, TSI, hemoglobin, and reticulocytes were observed. Obese women had higher serum sTfR levels [1.38 (range: 0.89 to 2.39) vs. 1.16 mg/dL (range: 0.69 to 2.03 mg/dL); p ⱕ 0.001] and sTfR/log ferritin ratio [0.73 (range: 0.45 to 1.67) vs. 0.64 (range: 0.36 to 1.26); p ⫽ 0.009] than control subjects. As expected, obese women also had higher levels of insulin resistance. The correlations obtained between BMI and the parameters of iron metabolism are shown in Table 2. A significant OBESITY Vol. 14 No. 10 October 2006
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Table 1. Main clinical features and laboratory data of subjects included in the study
BMI (kg/m2) Age (years) Ferritin (ng/mL) Iron (g/dl) Transferrin (mg/dl) TSI (%) Hemoglobin (g/dl) Reticulocytes (/1000 hem) sTfR (mg/dl) sTfR/log ferritin HOMA-IR
Obese women (BMI >30 kg/m2) n ⴝ 50
Non-obese women (BMI 30 kg/m2)
All subjects
Log ferritin Iron Transferrin TSI Log sTfR Log sTfR-log ferritin Log reticulocytes
r
p
r
p
r
p
⫺0.000 ⫺0.196 ⫺0.007 ⫺0.172 0.479 0.352 0.160
0.997 0.048 0.943 0.083 ⬍0.001 ⬍0.001 0.153
⫺0.057 ⫺0.141 0.186 ⫺0.197 0.365 0.271 0.348
0.687 0.320 0.187 0.161 0.008 0.052 0.018
0.087 0.333 0.207 ⫺0.359 0.381 0.241 0.093
0.548 0.018 0.149 0.010 0.006 0.092 0.597
Log, logarithmically transformed; TSI, transferrin saturation index; sTfR, soluble transferrin receptor.
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Non-obese women (BMI
