Symptomatic Iron Deficiency without Anemia: An Underrecognized Phenomenon

Background: Iron deficiency is a multifactorial condition affecting millions globally and is the leading cause of anemia worldwide. The identification of iron deficiency usually occurs during the work-up of anemia. However, iron deficiency without anemia may adversely affect patients’ quality of life. Our objective is to highlight the link between iron deficiency and various patient symptoms in the absence of anemia.

Methods: We conducted a retrospective chart review of patients identified using ICD-10 codes D64.9 (Anemia, unspecified), D50.9 (Iron deficiency anemia, unspecified), and E61.1 (Iron deficiency) who were seen in a tertiary care hospital hematology clinic between 01/2019 and 09/2022. Patient symptoms were obtained from two consecutive visit notes. Hemoglobin (Hb), hematocrit, MCV, ferritin, and iron profile values associated with the visits were obtained from the electronic health records. Documentation of intravenous (IV) treatment was obtained from infusion center flowsheets.

Results: Our study identified a total of 65 patients. 24 patients with Hb above 12 g/dL were found, 16.67% (4/24) were male, 83.33% (18/24) were female. The most common age groups were 30-40 at 33.33% (8/24) and 40-50 at 20.83% (5/24). The mean Hb for this group of patients was 13.44 ± 1 g/dL, MCV 83.3 ± 7.1 fL, and the mean ferritin was 16.13 ± 10.37 ng/mL. 87.5% (21/24) of patients reported symptoms, with fatigue being reported by 83.33% (20/24) of patients. Pica was reported by 8.33% (2/24), restless leg syndrome by 12.5% (3/24), cold intolerance by 12.5% (3/24), and hair and/or nail changes by 25% (6/24) of patients. 70.83% (17/24) of patients received IV iron treatment, 16.67% (4/24) received oral iron treatment. Iron dextran was the most frequently used preparation at 76.47% (13/17). Mean post-treatment Hb was 13.92 ± 0.77 g/dL, MCV 88.53 ± 5.18 fL, and mean post-treatment ferritin 135.64 ± 99.66 ng/mL. In our study, 62.5% (15/24) of patients stated their symptoms improved, 4.17% (1/24) of patients stated their symptoms did not improve, 33% (8/24) of patients could not be evaluated at a subsequent visit for symptoms.

Discussion: Iron deficiency without anemia can be a significant contributor to patient morbidity, and patients are not routinely assessed for iron deficiency in the absence of anemia. A recent study (Weyand et al. JAMA 2023) suggests up to 40% of females can have iron deficiency when defined by a ferritin level of 15 ng/mL, and up to 80% of females when a less stringent cut-off of 50 ng/mL is used. Our study suggests both male and female patients can report symptoms of iron deficiency without the presence of anemia and subjective improvement following iron replacement without significant changes in Hb. The high prevalence of iron deficiency indicates a greater need for screening for this underrecognized phenomenon. We recommend considering ferritin and iron panel evaluation while assessing patients for symptoms such as those seen in iron deficiency anemia, even without the presence of low Hb. Importantly, it appears correction of the iron deficiency can improve fatigue, even without affecting the Hb level. Further studies utilizing validated Quality of Life instruments should be done to more accurately assess this issue.