The index of suspicion for iron deficiency in non-anaemic subjects

Editor – A subnormal level of either the mean corpuscular haemoglobin (MCH) or the mean corpuscular haemoglobin concentration (MCHC) could be the first sign of iron deficiency without anaemia (IDWA). The underlying reason for this phenomenon was identified in a study of 219 female athletes aged 15–20 years. What emerged was that, during the progression from the status of normal iron stores (defined as serum ferritin ≥30 μg/L) to iron deficient status (defined as serum ferritin <30 μg/L) the fall in MCH and MCHC antedated the fall in mean corpuscular volume (MCV), with the consequence that a stage was reached where iron deficient subjects had mean values of MCH and MCHC that were significantly lower (p<0.001) than the levels of those parameters in their iron replete counterparts, despite the fact that mean values for MCV remained the same for both the iron deficient subgroup and the iron replete subgroup. Also among subjects who had progressed to iron deficiency, the mean value for haemoglobin (Hb) was 132.7 g/L vs 139.2 g/L in the iron replete subgroup.¹ In a study where iron deficiency was defined as serum ferritin of ≤30 μg/L in men and ≤20 μg/L in females, or transferrin saturation as ≥20%or reticulocyte haemoglobin as ≤28 pg, there were 770 subjects with IDWA. Among them were 463 who had MCH amounting to ≤28 pg vs 209 with MCV of ≤80 fL.² Accordingly, given the fact that MCH of ≥28 pg is more prevalent than MCV of ≤80 fL in IDWA subjects, a MCH of <28 pg should be a red flag for IDWA, prompting further investigation along the lines proposed by Al-Naseem et al.³

The recognition of IDWA has implications for correction of incident iron deficiency and for identification of its underlying cause. Correction of incident iron deficiency (regardless of Hb level) is a matter of urgency in patients with congestive heart failure (CHF). In Wienbergen et al, where iron deficiency was defined as serum ferritin <100 μg/L or 100–299 μg/L in association with transferrin saturation <20%, predicted mortality in CHF subjects with IDWA was significantly greater (p=0.002) than in CHF subjects without iron deficiency.⁴ Furthermore, among CHF patients in whom iron deficiency has been defined according to the criteria cited by Al-Naseem et al, treatment with intravenous iron improves symptoms, functional capacity and quality of life irrespective of presence or absence of anaemia.^3,5 The rationale for these outcomes might be the one that comes from animal studies.^4–7 In one study, IDWA was shown to be responsible for decreased left ventricular function and reduced mitochondrial complex 1 activity in mice.⁶ In another murine experimental model, deficiency of transferrin in heart muscle was shown to lead to lethal cardiomyopathy.⁷

Also, of some importance is the identification of the underlying cause of IDWA. In the meta-analysis undertaken by Chan et al (five studies), 13 gastrointestinal malignancies were identified in 3,329 participants. Prevalence of gastrointestinal malignancy in those with IDWA was predominantly in the age group of >50 years with little risk in younger age groups. Overall, the number needed to endoscope (to discover one case of malignancy) amounted to 263. When stratified according to age, number needed to endoscope amounted to 39 in those aged ≥50 years.⁸ In a separate study (a retrospective analysis not included in the previous meta-analysis), among 287 CHF patients of mean age 70 years with IDWA, 30 were diagnosed with gastrointestinal malignancies.⁹ In the latter study, anaemia was defined as Hb <12 g/dL in both men and women, and iron deficiency was defined according to the criteria cited by Al-Naseem et al.³ In that study, serum ferritin <30 μg/L had a specificity of 90% for generating a positive endoscopy result but this was at the cost of poor sensitivity (13%), in other words, at the cost of rejecting many potential candidates for endoscopy simply because they had higher serum ferritin values. Conversely, a serum ferritin cut-off level of <100 μg/L had higher sensitivity (93%) in identifying potential candidates for endoscopy but at the cost of a higher ratio of ‘numbers needed to endoscope’ (ie lower specificity, amounting to 31%) for obtaining a positive endoscopy result.⁹

In conclusion, the emerging picture is that of a compelling urgency to identify IDWA in patients with CHF because of its adverse effects on prognosis, and because those adverse effects can be mitigated by treatment. There is a compelling need to identify the underlying cause of IDWA in subjects aged ≥50 years but not such a compelling need in younger subjects.