Impact of obesity on iron metabolism and the effect of intravenous iron supplementation in obese patients with absolute iron deficiency

Abstract

Obesity and iron deficiency (ID) are widespread health issues, with subclinical inflammation in obesity potentially contributing to ID through unclear mechanisms. The aim of the present work was to elucidate how obesity-associated inflammation disturb iron metabolism and to investigate the effect of intravenous (IV) iron supplementation on absolute iron deficient pre-obese (BMI 25.0-29.9 kg/m²) and obese (BMI > 30 kg/m²) individuals compared to healthy weight (HW) group (BMI 18.5-24.9 kg/m²). Iron-related, hematological and inflammatory biomarkers along with erythropoietin (EPO) were studied based on body mass index (BMI) in a Spanish cohort of non-anemic participants (n = 721; 67% women; median age of 48 years [IQR: 39-57]) and in a subgroup of subjects (n = 110) with absolute ID (ferritin < 50 ng/mL) after completing an IV iron therapy. Obese group exhibited higher levels of ferritin, hemoglobin (Hb), soluble transferrin receptor (sTfR) and hepcidin compared to HW group. Elevated BMI was independently associated with increased sTfR levels. While no statistical differences were found in EPO among groups, obese showed increased levels that inversely correlated with Hb only in pre-obese and obese groups. IV iron therapy on obese participants had significant improvements on iron-related parameters and Hb levels. Notable obesity-associated disturbances in iron metabolism are described and indicate a mixed ID among both, women and men. These findings highlight the importance of tailored interventions to correctly address ID in obese population.

Keywords: Hemoglobin; Inflammation; Iron deficiency; Iron metabolism; Obesity.

Fig. 1

Flow chart of the participants selection. BMI, body mass index.

Fig. 2

Inflammatory and iron-related parameters by body mass index category and sex. Bars show the median and interquartile range of serum ferritin (A), Hb (B), hepcidin (C), anisocytosis index (D) and sTfR (E) based on body mass index categories and sex. Women and men are indicated in purple and blue dots, respectively. BMI categories: healthy weight (18.5–24.9 kg/m²), pre-obese (25.0–29.9 kg/m²), obese (≥ 30–34.9 kg/m²). The yellow shading in A indicates the range of ferritin values < 50 ng/ml, threshold for absolute iron deficiency. Hb, hemoglobin; sTfR, soluble transferrin receptor. Differences between categories were determined using Mann–Whitney U-test. Only comparisons with p-value < 0.1 are indicated. Ө 0.1 > p-value ≥ 0.05; *0.01 ≤ p-value < 0.05; **0.001 ≤ p-value < 0.01; ***0.0001 ≤ p-value < 0.001; **** p-value < 0.0001.

Fig. 3

Iron-related and hematological parameters by body mass index category and sex. Bars show the median and interquartile range of sideremia (A), transferrin (B), TfSI (C), MCH (D), MCHC (E) and MCV (F) based on body mass index categories and sex. BMI categories: healthy weight (18.5–24.9 kg/m²), pre-obese (25.0–29.9 kg/m²), obesity (≥ 30–34.9 kg/m²). TfSI, transferrin saturation index; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume. Women and men are indicated in purple and blue dots, respectively. Differences between categories were determined using Mann–Whitney U-test. Only comparisons with p-value < 0.1 are indicated. Ө 0.1 > p-value ≥ 0.05; *0.01 ≤ p-value < 0.05; **0.001 ≤ p-value < 0.01; ***0.0001 ≤ p-value < 0.001; **** p-value < 0.0001.

Fig. 4

Association of factors with increased sTfR levels. Statistics: data were calculated by univariate (left) and multivariate (right) logistic regression model after adjustment and by Stepwise methods. sTfR, soluble transferrin receptor; Hb, hemoglobin; BMI, body mass index; 95% CI, 95% of confidence interval; p-value, level of significance.

Fig. 5

Erythropoietin levels among BMI, sex and correlations with iron-related and hematological biomarkers. Bars show the median and interquartile range of erythropoietin based on body mass index categories and sex (A). Heat map showing the correlations between erythropoietin levels and iron-related and hematological variables in all participants and among body mass index categories (B). Detailed correlations between erythropoietin levels and hemoglobin among body mass index categories (C). EPO, erythropoietin; Hb, hemoglobin; sTfR, soluble transferrin receptor; TfSI, transferrin saturation index; MCH, mean corpuscular hemoglobin; MCHC, mean corpuscular hemoglobin concentration; MCV, mean corpuscular volume. Differences between body mass index categories and women and men were determined using Mann–Whitney U-test. The Spearman rho correlation coefficient test was used. Only comparisons with p-value < 0.1 are indicated. Ө 0.1 > p-value ≥ 0.05; *0.01 ≤ p-value < 0.05; **0.001 ≤ p-value < 0.01; ***0.0001 ≤ p-value < 0.001; **** p-value < 0.0001.

Fig. 6

Changes in iron related levels before and after intravenous iron sucrose infusion by body mass index category. Bars show the median and interquartile range of serum ferritin (A), Hb (B), sTfR (C), transferrin (E), TfSI (F) and sideremia (G) before (baseline time-point, B) and after (final time-point, F) intravenous iron sucrose infusion and the respective fold change per BMI category. Body mass index categories: healthy weight (18.5–24.9 kg/m²), pre-obese (25.0–29.9 kg/m²), obese (≥ 30–34.9 kg/m²). HW, healthy weight; B, baseline time-point; F, final time-point; Hb, hemoglobin; sTfR, soluble transferrin receptor and TfSI, transferrin saturation index. Differences between paired time-points were determined using Wilcoxon signed rant test and differences between BMI categories were determined using Mann–Whitney U-test. Only comparisons with p-value < 0.1 are indicated. Ө 0.1 > p-value ≥ 0.05; *0.01 ≤ p-value < 0.05; **0.001 ≤ p-value < 0.01; ***0.0001 ≤ p-value < 0.001; **** p-value < 0.0001.

Fig. 7

Current understanding of links between obesity and iron deficiency. Obesity is marked by persistent systemic inflammation and increased production of pro-inflammatory cytokines and adipokines in adipose tissue. This directly impacts iron absorption from the duodenum enterocytes by inhibiting the iron transporter ferroportin 1, regulated by hepcidin. Moreover, pro-inflammatory cytokines like IL-6 act as powerful inducers of hepcidin in the liver, which may further impair iron absorption. Both, cytokines and hepcidin contribute to iron sequestration in macrophages, reducing iron recycling, sideremia, and iron availability for erythropoiesis. In obese conditions, compromised chest mobility during breathing causes restrictive ventilatory insufficiency which, along with potential episodes of sleep apnea, contribute to tissue hypoxia, another potential mechanism contributing to ID in obesity. These hypoxic conditions activate the hypoxia-inducible factor 1 pathway that induces the production of the hormone erythropoietin, primarily in the kidney, stimulating erythropoiesis in the bone marrow, leading to elevated circulating hemoglobin levels. This process demands a substantial amount of iron for hemoglobin synthesis, resulting in reduced availability. These combined factors result in an absolute and functional ID (mixed), reflected in low sideremia, TfSI and high sTfR as primary soluble biomarkers in serum. CRP, C-reactive protein; hypoxia-inducible factor 1, HIF-1; EPO, erythropoietin; TfSI, transferrin saturation index; sTfR, soluble transferrin receptor.