How does inflammation alter ferritin and what tests distinguish inflammation‑driven ferritin elevation from true iron overload?
Executive summary
Inflammation raises serum ferritin as part of the acute‑phase response — cytokines drive iron sequestration in macrophages and increased ferritin synthesis so that ferritin can be high even when body iron stores are low (anemia of inflammation) [1] [2]. Distinguishing inflammation‑driven hyperferritinemia from true systemic iron overload requires combining ferritin with markers of inflammation (CRP/AGP), iron availability (transferrin saturation/TSAT, TIBC), specialized tests (soluble transferrin receptor and the sTfR/log ferritin index), imaging (liver MRI), and targeted genetic or clinical evaluation guided by WHO and regional guidelines [3] [4] [5] [6].
1. How inflammation pushes ferritin up: the biology in brief
Proinflammatory cytokines such as IL‑6 and TNF‑α stimulate ferritin synthesis and secretion and elevate hepcidin, which blocks iron export from enterocytes and macrophages — the net effect is withdrawal of iron from plasma, more iron trapped in the reticuloendothelial system, and higher circulating ferritin despite reduced serum iron and TSAT [2] [1] [7].
2. Why ferritin alone misleads: acute‑phase protein and storage marker at once
Serum ferritin behaves both as an iron store marker and an acute‑phase reactant, so moderate or high ferritin values can reflect inflammation rather than excess tissue iron; studies in chronic disease and dialysis patients show ferritin often reflects inflammation equally as well as iron stores, producing diagnostic dilemmas when TSAT is low [6] [1] [2].
3. First‑line discrimination: pair ferritin with CRP/hsCRP and TSAT
Clinical guidance and research recommend measuring an inflammation marker (CRP or AGP) alongside ferritin because ferritin thresholds for overload (e.g., >150 μg/L in menstruating women, >200 μg/L in men/non‑menstruating women per WHO) lose validity in inflammation; if ferritin is high but TSAT is low (<45% generally excludes overload in some regional guidance), inflammation is more likely, whereas high ferritin with high TSAT points toward true iron excess [4] [3] [5].
4. Second‑line and specialty tests: sTfR, sTfR/log ferritin index, MRI and genetics
Soluble transferrin receptor (sTfR) rises in iron deficiency and is relatively less affected by inflammation, so the sTfR/log ferritin index helps discriminate iron deficiency masked by inflammation from iron overload; conversely, sTfR tends to be low in iron overload [3] [8]. When biochemical tests remain ambiguous, noninvasive liver iron quantification by MRI is the standard for detecting organ iron deposition, and HFE genetic testing or assessment for transfusional causes is indicated when iron overload is suspected [9] [5].
5. Practical algorithms, limitations and clinical caveats
Guidelines advise rechecking ferritin after transient inflammatory events resolve and adjusting ferritin interpretation using CRP/AGP correction factors in population surveys because a single elevated ferritin in the context of active inflammation is unreliable for diagnosing overload; yet thresholds and correction methods carry uncertainty and are condition‑dependent — for example, dialysis patients can show ferritin >500 ng/mL from inflammation alone, prompting careful use of MRI or clinical judgment before withholding iron therapy [5] [3] [6] [4].
6. Conflicts, hidden agendas and the cost of error
There are competing imperatives: failing to recognize true iron overload risks organ toxicity while mislabeling inflammation‑driven ferritin as overload can deny needed iron therapy; guideline groups and clinicians therefore favor multimarker assessment and, when available, imaging — commercial test producers and local practice norms can influence which tests are ordered, and evidence gaps remain about optimal cutoffs and correction formulas in diverse populations [4] [9] [3].