Can ferritin be misleading and when should transferrin saturation be used?
Executive summary
Ferritin measures stored iron but is also an acute-phase reactant, so elevated ferritin can reflect inflammation, liver disease, or other non‑iron causes and therefore mislead clinicians about true iron status [1] [2]. Transferrin saturation (TSAT), which reflects iron readily available for erythropoiesis, is often the more informative test when ferritin is high or clinical context suggests inflammation, but TSAT has its own limitations and is best interpreted alongside ferritin and clinical data [3] [4].
1. Ferritin’s double life: storage marker and inflammation signal
Serum ferritin classically mirrors body iron stores—very low ferritin reliably indicates iron deficiency—yet ferritin is also an acute‑phase protein that rises in inflammation, infection, liver injury and some metabolic states, creating “unexplained hyperferritinemia” that does not necessarily mean iron overload [1] [2]. Kidney disease and multiple comorbidities further cloud ferritin’s meaning; K/DOQI guidelines still anchored many CKD management decisions to ferritin cutoffs (e.g., <100 ng/mL suggesting deficiency), but authors warn that inflammation and chronic illness can make ferritin unreliable in these populations [5] [1]. Multiple sources emphasize that high ferritin with normal/low TSAT often reflects iron sequestration from inflammation rather than excess bioavailable iron [2] [6].
2. What transferrin saturation measures — and when it outperforms ferritin
TSAT is the percentage of transferrin binding sites occupied by iron and more directly signals circulating iron available for red blood cell production; values <20% are commonly used to indicate iron deficiency and >50% to suggest overload in many clinical contexts [4] [3]. Recent heart‑failure cohorts found low TSAT—but not ferritin—was independently associated with worse outcomes and exercise hemodynamics, arguing that TSAT can be a better predictor of functional iron deficiency in some diseases [7] [8] [9]. In conditions where ferritin is elevated by inflammation, a low TSAT points toward iron-restricted erythropoiesis despite high stored iron, a pattern important for treatment decisions [2] [10].
3. Limitations of TSAT and why both tests are usually needed
TSAT is imperfect: serum iron fluctuates diurnally and with recent intake, and TSAT sensitivity for early iron depletion is lower than ferritin in some settings, which is why historical practice combines assays rather than relying on one number [3] [4]. Extremely high ferritin states (laboratory cutoffs vary) can make iron panels unreliable and TSAT interpretation problematic—some labs caution that TSAT is unreliable when ferritin exceeds very high levels (e.g., >1,200 μg/L) [11]. Practical guidance from nephrology and hematology reviews therefore recommends interpreting ferritin and TSAT together and, when discordant or clinical context is complex, adding other markers like soluble transferrin receptor, reticulocyte hemoglobin content or percentage of hypochromic red cells [5] [1].
4. Clinical synthesis: when to distrust ferritin and pivot to TSAT (and beyond)
Ferritin should be distrusted as a sole indicator of iron status when there is clinical or laboratory evidence of inflammation, chronic disease, liver dysfunction, or recent transfusion or IV iron exposure—circumstances in which high ferritin can mask functional iron deficiency; in those cases TSAT, and often additional tests, better indicate whether iron is bioavailable for erythropoiesis [1] [2] [6]. In heart failure and CKD literature the pattern that matters is high ferritin with low TSAT (iron sequestration) versus high ferritin with high TSAT (true overload), and those distinctions have prognostic and therapeutic implications [9] [2] [10]. When ferritin is low, it still reliably signals absolute iron deficiency and TSAT adds confirmation; when ferritin is high and TSAT low, clinicians should consider inflammation‑driven sequestration and consider soluble transferrin receptor or reticulocyte indices to guide therapy [5] [1].
5. Bottom line and research gaps
Ferritin can be misleading whenever inflammation or comorbidity is present; TSAT is the preferred adjunct when the goal is to know how much iron is available for red blood cell production, and TSAT has shown stronger clinical associations than ferritin in some disease cohorts such as heart failure [1] [9] [8]. Neither test is perfect—TSAT has diurnal variability and is unreliable in extreme ferritin states—so best practice is combined interpretation plus additional biomarkers when discordance exists, an approach endorsed by nephrology and hematology reviews that also calls for more research into newer indices [5] [3] [1].