Young Women with Iron Deficiency Anemia Demonstrate Cerebral Metabolic Stress to Maintain Cerebral Oxygen Metabolism

Introduction: Iron deficiency anemia (IDA) affects approximately 1.2 billion people worldwide with an estimated 1 in 16 adolescent females suffering from IDA in industrialized nations. Anemic patients are known to be at risk of developing cerebral infarctions, with up to 6.7% of patients developing acute silent cerebral ischemic events (PMID 22948048). The brain requires steady cerebral oxygen delivery (cerebral blood flow (CBF) x arterial oxygen content (CaO2)) and oxygen uptake (oxygen extraction fraction (OEF), the percentage of oxygen removed from blood into brain tissue) to maintain the cerebral metabolic rate of oxygen utilization (CMRO2). If CMRO2 demands are not met by compensatory increases in CBF and/or OEF, tissue infarction occurs. In older adults with severe carotid stenosis, where cerebral oxygen delivery is compromised by lowered CBF, high OEF has been shown to be an independent risk factor for subsequent cerebral infarction. To test whether young women with IDA may also show cerebral metabolic stress, brain MRIs were obtained to measure CBF and OEF, permitting calculations of CMRO2. We hypothesized that OEF would be elevated in young women with IDA, correlating with the severity of the anemia, while maintaining similar CMRO2 to age- and sex-matched controls.

Methods: Healthy female control (HC) and females with IDA 12 years or older were recruited from a single institution. IDA was defined as hemoglobin less than the lower limit of normal for age and ferritin < 15 ng/ml. Participants with another etiology of anemia or contraindication to MRI were excluded. Participants underwent brain MRI where OEF was quantified by asymmetric spin echo sequence. CBF, measured by pseudo-continuous arterial spin labeling (pCASL) sequences, was available in a subset of participants. CBF data acquired with 1 second post-label delay or multi-label delay were imputed to a 1.5-second post-label delay through regression equations developed from larger datasets. CMRO2 was calculated as CaO2 x CBF x OEF. Hemoglobin was obtained at the time of MRI. Ferritin was confirmed for IDA participants in the medical record but not obtained in HC. Data are presented as median [interquartile range] and compared with a Mann-Whitney U test. Bivariate correlations were performed with a Spearman's ρ test.

Results: Thirty-one female participants (19 HC and 12 IDA) completed brain MRIs. The cohorts were matched for age (p = 0.165): HC (16.4 [14.7, 19.0] years) and IDA (15.5 [14.3, 16.0] years). As expected, hemoglobin was significantly lower in the IDA cohort (9.0 [7.9, 9.9] g/dL) compared to HC (12.8 [11.9, 13.5] g/dL, p < 0.001). The median ferritin for the IDA cohort was 4.0 [2.6, 6.8] ng/mL. Women with IDA had increased metabolic stress, reflected by higher OEF in GM (IDA 33.2 [31.0, 35.5] % vs HC 27.3 [25.9, 28.6], p < 0.001) and WM (IDA 29.7 [27.1, 32.9] % vs HC 23.9 [21.2, 25.3] %, p < 0.001). Across the entire cohort, a lower hemoglobin correlated with a higher OEF in both GM (rho -0.701, p < 0.001) and WM (rho = -0.709, p < 0.001). CBF, permitting calculation of CMRO2, was available in 12 HC and 6 IDA participants matched for age (p = 0.146). CBF measurements were similar in GM between IDA (83.6 [68.1, 92.4] mL/100g/min) and HC (71.2 [66.4, 74.5] mL/100g/min, p = 0.223), however WM CBF was higher in IDA (33.9 [31.4, 39.4] mL/100g/min) versus HC (27.1 [23.9, 31.5] mL/100g/min, p = 0.015). However, CMRO2 did not differ across GM (p = 0.399) or WM (p = 0.64) between cohorts.

Conclusion: We found that OEF is increased in adolescent females with IDA, reflecting cerebral metabolic stress, compared to healthy controls in both GM and WM. Participants with the lowest hemoglobin values had the highest OEF measurements. Importantly, in a smaller subset of participants, there was no difference in CMRO2 between cohorts in the GM or WM, consistent with OEF reflecting metabolic stress without metabolic compromise. In a subset, WM CBF was significantly elevated in the IDA group compared to the HC, which may reflect additional stress. Further investigations are required to confirm these findings in a larger cohort, determine the anemic threshold at which metabolic stress results in metabolic failure and infarction, and determine whether metabolic stress without infarction still results in subtle neurocognitive symptoms.

Fields:Global Blood Therapeutics: Consultancy; Proclara Biosciences: Current equity holder in publicly-traded company; Pfizer: Consultancy, Research Funding.