Iron Deficiency—Challenging to Diagnose: A Retrospective Chart Review of Referrals to Classical Hematology Clinic

Abstract

Background

Iron deficiency (ID) is the leading nutritional deficiency and a major public health concern globally. Although anemia is the most widely known consequence of ID, ID is also an underrecognized cause of white blood cell and platelet count abnormalities. The primary objective of the current study is to assess physicians’ abilities to diagnose ID.

Methods

This study is a retrospective chart review of 862 adults (mean age ± SD of 52.5 ± 18.4, 447 female) seen by a classical hematologist at an academic center. Data analysis included specialty type of the referring provider, referral reason, and the diagnosis made by the consulting hematologist. ID was defined as a serum ferritin level <30 ng/mL or <100 ng/mL in the presence of inflammatory comorbidities.

Results

Out of 862 initial patient charts, 103 were lost to follow up before completing the workup. Out of the remaining 759 patient charts, 304 (40.0 %) patients received a new diagnosis with ID or iron deficiency anemia (IDA) by the consulting classical hematologist. Of these patients, 21 % were referred from internal medicine (IM), 18 % from family medicine (FM), 14 % from hematology-oncology for a second opinion, and 25 % from other IM subspecialties. In a sub-analysis of 364 patients who had complete blood cell count (CBC) abnormalities, ID was found to play a role in 54.7 % of CBC abnormalities analyzed.

Conclusion

This analysis demonstrates that diagnosing ID is a challenge for first-contact physicians and may easily be missed. This leads to delays in ID treatment and resulting clinical consequences.

1. Introduction

Iron deficiency (ID) is the leading nutritional deficiency and a major public health concern, currently affecting 825 million women and 444 million men globally.1 Timely recognition of ID is crucial, as it not only leads to debilitating symptoms, including fatigue and poor cognitive function, but may also be an early indicator of gastrointestinal malignancy and exacerbate signs and symptoms of chronic comorbidities.2,3 In fact, ID was found to be one of the leading contributors to death and disability.4

ID and iron deficiency anemia (IDA) are two ends of the same spectrum. If ID is not corrected, it will ultimately progress to anemia in stages. First iron stores start to deplete to maintain mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and hemoglobin within normal limits. As the body continues to use iron reserves for its physiological needs, MCV and MCH decline while hemoglobin remains in the normal range. However, eventually hemoglobin levels drop when iron stores are exhausted, resulting in anemia.5

Although anemia is the most widely known consequence of ID, ID is also an underrecognized cause of white blood cell and platelet count abnormalities found in the CBC, which similarly require medical intervention with iron therapy. Misconceptions regarding the clinical and laboratory features of ID can contribute to delayed or overlooked diagnoses, ultimately leading to adverse health outcomes and negative economic impacts.3 The primary objective of this study was to assess physicians’ ability to diagnose ID with a focus on the lesser-known laboratory manifestations of ID.

2. Methods

2.1. Study population

The study population included 862 consecutive outpatient referrals between February 2020 and July 2023 in a single-provider clinic dedicated to adults with non-cancer blood disorders within the division of hematology-oncology at an academic center.

2.2. Study design

This study is a retrospective chart review approved by the local institutional review board and was expedited with a consenting waiver, given many patients were no longer available for consenting. Data extracted from the electronic medical record included sex, age, ethnicity, referring provider specialty type, referral reason or diagnosis, and the diagnosis made by the consulting adult classical hematologist in this clinic. Both the initial and final chart notes for each patient were reviewed to determine the diagnoses made during the classical hematology clinic visit.

The primary objective of this study was to assess physicians’ ability to diagnose ID by quantifying the number of referred patients who were newly diagnosed with ID by the consulting classical hematologist. An additional sub-analysis was conducted for patients with CBC abnormalities. ID was defined as a serum ferritin level less 30 ng/mL or less than 100 ng/mL in the presence of inflammatory comorbidities (including aging).6–9 These cut offs were chosen as the were they lowest ferritin cutoffs found in existing guidelines and original research publications.10–12 Red cell indices also aided in the diagnosis when appropriate.

3. Results

Of the 862 initial patient charts, 103 patients who lost follow up before completion of the work up, were excluded from the analysis. Therefore, 759 charts were utilized in this study. The mean age was 52.5 years (±18.4 years standard deviation), with a median of 53 years, a minimum age of 17, and a maximum age of 100. Four hundred and forty-seven patients were female (59 %). Patient demographics are summarized in Table 1.

Table 1.

Patient demographics.

Characteristic
Age (years), mean (SD)	52.2 (18.4)
Female, n (%)	447 (59)
Race, n (%)
White	318 (41.9)
Asian	130 (17.1)
Hispanic	73 (9.6)
Black	65 (8.6)
Other or mixed race	151 (19.9)
Unreported	19 (2.2)
Native Hawaiian or Pacific Islander	2 (0.3)
American Indian or Alaskan Native	1 (0.1)

A total of 304 (40.0 %) patients were newly diagnosed with ID or IDA by the consulting classical hematologist. Of these newly diagnosed patients, 21 % were referred from internal medicine (IM), 18 % from family medicine (FM), 14 % from hematology-oncology for a second opinion, and 25 % were from other IM subspecialties (Fig. 1).

Fig. 1.

Referrals by specialty for patients found to have undiagnosed ID or IDA. OBGYN= Obstetrics and Gynecology.

A sub-analysis was conducted on 364 referrals for patients with abnormalities seen on CBC, including anemia and neutrophil and platelet count abnormalities (Fig. 2). ID was found to play a role in 54.7 % (n = 199) of the hematologic abnormalities analyzed, as iron therapy contributed to resolving the CBC abnormality in these patients; specifically, in 58.2 % of anemia referrals, 60.9 % of neutropenia referrals, 90.9 % of neutrophilia referrals, 38.2 % of thrombocytopenia referrals, 55.6 % of the thrombocytosis referrals, and 33.3 % of pancytopenia referrals.

Fig. 2.

Breakdown of CBC abnormalities in 364 referrals for CBC abnormalities.

The specialty type of the referring provider for this sub-analysis is demonstrated in Fig. 3.

Fig. 3.

Distribution of referral sources for CBC abnormalities with undiagnosed underlying ID.

4. Discussion

Despite the high prevalence of ID, its laboratory manifestations remain underrecognized and commonly misdiagnosed by many first-contact physicians. Our study found that 40 % of the referring physicians missed the diagnosis of ID or IDA, with primary care (IM and FM) comprising 39 % of these referral sources. Previous research into the approach of primary care physicians (PCPs) to the evaluation and diagnosis of IDA found that PCPs commonly misinterpret iron studies and overutilize laboratory testing.13 Interestingly, our study demonstrated missed diagnoses of ID extended beyond PCPs; strikingly, 14 % of hematology-oncologists and 25 % of other IM subspecialists did not initially recognize the diagnosis of ID or IDA. An inability to diagnose ID or IDA led to delays in ID treatment and resulting clinical consequences. Findings from multiple national and international studies further corroborate that diagnosing ID remains a significant global challenge.14–17 For example, a study of 1010 Swiss women diagnosed with ID found that 35 % of patients were initially misdiagnosed with depression or chronic fatigue, among other incorrect diagnoses. 3 These incorrect initial diagnoses have significant medical costs, which the authors estimated to be 78 million Swiss francs (95 million USD).3 One contributing factor to the missed ID diagnoses may be that the laboratory reference ranges mentioned in the results section are not always updated to reflect the most current cut-off for serum ferritin that was utilized in this data analysis.6

Additionally, more than half of the referrals for CBC abnormalities were associated with ID in the present study, highlighting a knowledge gap among first-contact physicians in recognizing the full spectrum of ID’s laboratory manifestations. Of these referrals, strikingly more than 10 % were second opinions from hematology-oncology (Fig. 3). Possibly underlying this educational shortfall is the fact that the pathophysiology linking ID to abnormalities in platelet and white cell counts is still being investigated. The association between ID and neutrophilia has yet to be fully elucidated, but studies have shown that iron therapy reduces the chemotactic activation and inflammatory properties of neutrophils.18,19 Animal studies have shown that ID can lead to thrombocytosis and thrombosis, and ID has been shown to enhance coagulation, elucidating the mechanism of ID-induced thrombosis.20–23 Additionally, ID has been shown to cause cytopenias, as several case reports have described thrombocytopenia, neutropenia, leukopenia, and pancytopenia in the context of ID with complete reversal of the cytopenia following iron therapy.24–35 To our knowledge, the present study is the first to corroborate the existing case reports in the literature.

Though often seen as benign, ID is a silent public health threat, and its effects may be felt in the economic cost of misdiagnoses and accumulation of sick leave due to ID symptoms.3 Apart from the economic consequences, ID may result in decreased quality of life, as patients with ID may experience vague symptoms, including depression, burnout, sleep disturbances, and diminished cognitive and physical functioning.3 In patients with other medical comorbidities, such as congestive heart failure, ID has been shown to be an independent risk factor in mortality and hospitalization.36 Given these significant impacts, it is crucial that first-contact physicians are well-equipped to diagnose and manage ID effectively.

In terms of limitations, this was a retrospective chart review and only the first and final clinic notes were analyzed; therefore, the true prevalence of ID may have been underestimated. Additionally, in some instances, the CBC abnormalities had multifactorial etiologies, including ID; however, the stepwise management approach demonstrated that correcting ID contributed to the improvement, but the abnormalities did not fully resolve until other contributing factors were also addressed. Given the nature of this retrospective study, CBC and ferritin were completed as part of patients’ clinical care at the laboratories approved by patients’ insurance as opposed to one central laboratory.

In conclusion, diagnosing ID and recognizing the consequences of ID beyond anemia remains a challenge for first-contact physicians, including hematology-oncologists. Educational interventions are needed to improve providers’ knowledge for early diagnosis and management of ID and IDA. Updating laboratory reference ranges in lab reports to reflect current literature could also be beneficial.

Data availability

Data will be made available upon request.