Ferritin reference ranges and improving diagnosis of iron deficiency without anemia Free

Background: Iron deficiency without anemia (IDWA) is increasingly recognized as a distinct cause of morbidity separate from iron deficient anemia (IDA), notably causing fatigue, poor exercise intolerance, impaired cognition, among other symptoms (Bruner et al., Lancet, 1996; Verdon et al., BMJ, 2003). Conventional diagnostic criteria for IDWA recommends serum ferritin thresholds of <30ng/mL (Pasricha et al., Lancet, 2021) or even <50ng/mL (Martens and DeLoughery, Hematology Am Soc Hematol Educ Program, 2023). However, our internal clinical laboratory provides lower limits of normal (LLN) from presumably healthy volunteers of 7.3 ng/mL in adult women and 10.5 ng/mL in adult men. This study seeks to understand the clinical impact of discordant laboratory reference ranges and current IDWA recommendations on the diagnosis, treatment, and symptoms of IDWA as part of a broader quality improvement initiative.

Methods: This study was reviewed and approved by the UNC IRB (#25-1395). Serum ferritin, hemoglobin, age, sex, medications, and any iron deficiency diagnosis (ICD-10-CM codes D50, E61.1, R79) were retrieved from the Electronic Health Record of patients with ferritin measured in primary care settings, comprising a patient population with known or suspected iron deficiency. Serum ferritin values were classified as abnormally low using the laboratory's provided LLN and the recommended thresholds for iron deficiency of <30ng/mL and <50ng/mL. We also identified individuals with serum ferritin levels <20ng/mL based on practice patterns of some hematologists within our center who routinely use a lower threshold for iron deficiency than the published recommendations. Using these ferritin thresholds and age- and sex- specific ranges for hemoglobin and ferritin, patients were classified as either having iron deficiency anemia (IDA), iron deficiency without anemia (IDWA), or no iron deficiency. Agreement in classification between each ferritin threshold was calculated. We convened a multidisciplinary panel (including representatives from primary care, hematology, pharmacy, and laboratory medicine) to review these data and identify opportunities/barriers for improving care.

Results: As of August 5, 2025, clinical data has been extracted from 228 patients with serum ferritin measured in a primary care setting between May 5, 2025-June 5, 2025. Using current age- and sex-specific reference ranges, 43 (19%) had IDA and 36 (16%) had IDWA using current laboratory LLNs. Of the 228, 149 (65%) had ferritin <50ng/mL (115 without anemia), 115 (51%) had ferritin <30ng/mL (85 without anemia), and 79 (35%) <20ng/mL (54 without anemia). Sixty-eight (30%) had IDWA with ferritin between current LLN and 30ng/mL, 88% of whom were adult women, 7% were adult men, and 4% were children ≤18 years. Nearly two-thirds of these 68 individuals with IDWA and serum ferritin above the LLN had no documented current diagnosis or treatment for iron deficiency. Most patients in each subgroup (≥90%) were female. Concordance of IDWA criteria comparing current ferritin LLN versus <30ng/mL was 79%, and 65% when using <50ng/mL. At the multidisciplinary panel, clinicians expressed broad support for altering laboratory reference ranges or providing automated annotations to contextualize results. Laboratory medicine representatives noted heterogeneity between assay platforms, complicating utilization of “universal” cut-offs.

Conclusions: Nearly one-third of patients evaluated to-date had ferritin levels below 30ng/mL yet above current LLN. Most did not show evidence of diagnosis or treatment of IDWA during the study window, suggesting potential underdiagnosis and treatment. However, more work is needed to generate assay-specific thresholds for diagnosis of IDWA that address the lack of harmonization for ferritin assays, and multidisciplinary panel discussions are ongoing. Limitations of our study include inability to examine indication for ferritin screening and the presence of symptoms, as well as the reliance on diagnostic codes. Future analysis will evaluate clinical manifestations of IDWA such as fatigue, exercise tolerance, and impaired cognition in correlation with ferritin, iron, and hemoglobin measurements.