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Observational Study
. 2016 Jun 1;126(6):2139-50.
doi: 10.1172/JCI85715. Epub 2016 May 3.

Clinical iron deficiency disturbs normal human responses to hypoxia

Matthew C Frise, Hung-Yuan Cheng, Annabel H Nickol, M Kate Curtis, Karen A Pollard, David J Roberts, Peter J Ratcliffe, Keith L Dorrington, Peter A Robbins
Observational Study

Clinical iron deficiency disturbs normal human responses to hypoxia

Matthew C Frise et al. J Clin Invest. .

Abstract

Background: Iron bioavailability has been identified as a factor that influences cellular hypoxia sensing, putatively via an action on the hypoxia-inducible factor (HIF) pathway. We therefore hypothesized that clinical iron deficiency would disturb integrated human responses to hypoxia.

Methods: We performed a prospective, controlled, observational study of the effects of iron status on hypoxic pulmonary hypertension. Individuals with absolute iron deficiency (ID) and an iron-replete (IR) control group were exposed to two 6-hour periods of isocapnic hypoxia. The second hypoxic exposure was preceded by i.v. infusion of iron. Pulmonary artery systolic pressure (PASP) was serially assessed with Doppler echocardiography.

Results: Thirteen ID individuals completed the study and were age- and sex-matched with controls. PASP did not differ by group or study day before each hypoxic exposure. During the first 6-hour hypoxic exposure, the rise in PASP was 6.2 mmHg greater in the ID group (absolute rises 16.1 and 10.7 mmHg, respectively; 95% CI for difference, 2.7-9.7 mmHg, P = 0.001). Intravenous iron attenuated the PASP rise in both groups; however, the effect was greater in ID participants than in controls (absolute reductions 11.1 and 6.8 mmHg, respectively; 95% CI for difference in change, -8.3 to -0.3 mmHg, P = 0.035). Serum erythropoietin responses to hypoxia also differed between groups.

Conclusion: Clinical iron deficiency disturbs normal responses to hypoxia, as evidenced by exaggerated hypoxic pulmonary hypertension that is reversed by subsequent iron administration. Disturbed hypoxia sensing and signaling provides a mechanism through which iron deficiency may be detrimental to human health.

Trial registration: ClinicalTrials.gov (NCT01847352).

Funding: M.C. Frise is the recipient of a British Heart Foundation Clinical Research Training Fellowship (FS/14/48/30828). K.L. Dorrington is supported by the Dunhill Medical Trust (R178/1110). D.J. Roberts was supported by R&D funding from National Health Service (NHS) Blood and Transplant and a National Institute for Health Research (NIHR) Programme grant (RP-PG-0310-1004). This research was funded by the NIHR Oxford Biomedical Research Centre Programme.

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Figures

Figure 1
Figure 1. Study recruitment flow diagram.
During the period of recruitment there were 25 expressions of interest from deferred blood donors and 126 responses to advertisements for healthy volunteers. In total, 16 participants were enrolled to the IR group and 15 to the ID group. Two female participants in the ID group were withdrawn during the first hypoxic exposure. The first developed headache and nausea consistent with altitude sickness. The second experienced vasovagal syncope. Both recovered promptly without sequelae on return to air. One participant in the IR group had echocardiographic data during hypoxia that precluded accurate measurement of PASP, despite a successful screening visit. No suitable ID participants presented themselves as matches for 2 young males recruited to the IR group early in the course of the study; data for these individuals were not analyzed. Thus, 13 ID individuals completed the study and were matched with an equal number of IR controls in the per-protocol analysis; there were no missing data.
Figure 2
Figure 2. PASP responses to hypoxia.
(A) First study day (saline infusion). (B) Second study day (iron infusion). (C) Difference in response between study days. Responses for the ID group are shown in red, and those for the IR group are shown in blue (data are means ± SEM; n = 13 in each group). Solid black bars indicate the 6-hour periods of eucapnic hypoxia. Continuous lines represent responses during hypoxia. Broken lines indicate the change in air-breathing PASP induced by the 6-hour period of hypoxia, which reflects the degree of acclimatization of the pulmonary vasculature. On the first study day, the increase in PASP during hypoxia was significantly greater in the ID group. On the second study day, following iron infusion, the increase in PASP was significantly attenuated in both groups. Euoxic PASP was significantly elevated following exposure to 6 hours of hypoxia in both groups on the first study day, but this effect was abolished by prior administration of i.v. iron on the second day. Panel C illustrates that the effect on PASP of prior iron administration was minimal for the first 2 hours of hypoxia. Thereafter, iron administration attenuated hypoxic pulmonary hypertension to a greater extent in the ID group. Asterisks indicate significance of comparisons between or within groups: *P < 0.05; **P < 0.01; ***P < 0.001; NS, not significant (mixed-effects model).
Figure 3
Figure 3. Peripheral oxyhemoglobin saturation and partial pressures of oxygen and carbon dioxide on each study day.
Left, first study day (circles); right, second study day (squares). Top panel, peripheral oxyhemoglobin saturation (SpO2); middle panel, end-tidal partial pressure of oxygen (PETO2) and carbon dioxide (PETCO2); bottom panel, inspired partial pressure of oxygen (PIO2) and carbon dioxide (PICO2). Data for the ID group are shown in red and for the IR group in blue (n = 13 in each group); data are means ± SD based on time-averaged continuous recordings.
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