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Muhammet Özbilen: Iron Deficiency Beyond Hemoglobin Exploring Mitochondrial and Metabolic Dysfunction

Muhammet Özbilen/LinkedIn

Oct 15, 2026, 07:08

Muhammet Özbilen: Iron Deficiency Beyond Hemoglobin Exploring Mitochondrial and Metabolic Dysfunction

Muhammet Özbilen, Associate Professor Doctor at Ordu University, shared a post on LinkedIn about a recent article by Metin Demirel et al, published in Wiley Online Library, adding:

“Iron deficiency is not a hemoglobin problem. It’s a mitochondrial one.

We still talk about iron deficiency anemia (IDA) in terms of hemoglobin, ferritin, and transferrin saturation. But what actually happens in the tissues when iron runs low?

A new study in Anemia (Demirel et al., 2026) approaches this question through metabolomics: untargeted LC HRMS serum profiling in 47 patients with IDA and 50 healthy controls.

Key findings:

Marked amino acid remodeling: isoleucine, ketoleucine, phenylalanine, and methylhistidine were all higher in the IDA group.
The arginine nitric oxide axis: both ADMA and L arginine were increased. The authors rightly emphasize that the L arginine ADMA balancemay be more informative than either molecule alone.

A three metabolite model (isoleucine plus isonicotinic acid plus phenylalanine) separated IDA from controls with a cross validated mean AUC of 0.964.
These differences persisted after adjustment for age, sex, albumin, and total protein.

What caught my attention most, however, was a negative finding the authors report with real intellectual honesty: when the analysis was restricted to the IDA group alone, no metabolite clinical correlation remained significant after FDR correction.

In other words, this signature is not a gradient tracking disease severity it reflects the biochemical gulf between patients and healthy controls.

Two questions follow:

How much of this signature is the absence of iron itself, and how much is the tissue hypoxia created by anemia? A two arm design cannot separate the two.
And what about non anemic iron deficiency (NAID)? Patients with normal hemoglobin who nonetheless report fatigue, exercise intolerance, and muscular complaints are the cleanest laboratory for this question because the anemia confounder is absent.

In the heart failure literature, 31P MRS studies show that phosphocreatine recovery time shortens after intravenous iron with no change in hemoglobin at all.

Primate data likewise show metabolomic disturbance emerging before hematological indices in the pre anemic stage.

So iron deficiency may be a metabolic event that begins before the blood count changes and may persist after that count has normalized.

The next step, in my view, is three armed studies (healthy, NAID, IDA), matched with symptom scores and built on targeted quantitative panels: BCAAs and their keto acids, arginine ADMA, 3 methylhistidine, acylcarnitines.

What we are looking for is not a new diagnostic marker ferritin already does that job.

What we are looking for is a marker that explains the symptom.

The need to think about iron deficiency beyond hemoglobin is only growing.”

Title: Serum Metabolomic Signatures of Iron Deficiency Anemia: An Untargeted LC-HRMS-Based Case–Control Study

Authors: Metin Demirel, Fatmanur Köktaşoğlu, Halime Dulun Ağaç, Ayşe Zehra Gül, Ufuk Sarıkaya, Ahmet Ceyhan Goren, Cumali Karatoprak, Şahabettin Selek Muhammet Özbilen: Iron Deficiency Beyond Hemoglobin Exploring Mitochondrial and Metabolic Dysfunction