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Iron & Ferritin

Iron deficiency can occur without anemia. Ferritin estimates iron stores, but inflammation, infection and liver injury can raise it. Interpret ferritin with the CBC, transferrin saturation (TSAT), symptoms and clinical setting; a low serum iron alone does not establish deficiency. Iron-deficiency anemia (IDA) requires both anemia and evidence of iron deficiency.[1][3]

For major reconstruction, the practical questions are whether anemia is present, what caused it, and whether treatment can improve the patient's readiness for surgery.

Biochemistry​

Ferritin is a hollow shell of 24 H (heavy) and L (light) subunits that stores iron as ferric oxyhydroxide. Iron regulates its synthesis through iron-responsive proteins that bind iron-responsive elements on ferritin mRNA. Inflammatory cytokines also raise ferritin synthesis independent of iron status, which is why ferritin behaves as a positive acute-phase reactant. Serum ferritin is a small, mostly iron-poor fraction that tracks tissue stores.[1]

Diagnostic thresholds​

Ferritin 1 ng/mL = 1 μg/L. Diagnostic thresholds, treatment-entry criteria and treatment targets answer different questions.

SettingInterpretation
General clinical assessmentASH 2026 conditionally suggests ferritin ≤30 ng/mL to diagnose iron deficiency in nonpregnant adults who do not menstruate and in menstruating individuals. Its remarks consider ≤50 ng/mL appropriate for nonpregnant adults who do not menstruate with iron-deficiency symptoms or ongoing risk factors, and for menstruating individuals with heavy menstrual bleeding, other excessive abnormal uterine bleeding, iron-deficiency symptoms, added risk factors, upcoming surgery or planned pregnancy.[15] In nine studies of nonhealthy adults (512 participants) using ferritin <30 ng/mL, the Cochrane review found pooled sensitivity 79% (95% CI 58–91%) and specificity 98% (95% CI 91–100%), with low-certainty evidence.[1]
GI evaluation in a patient with anemiaAGA recommends <45 ng/mL rather than <15 for diagnosing iron deficiency.[4]
Surgical anemia with inflammationICCAMS uses ferritin <30 ng/mL and/or TSAT <20% to identify iron deficiency, and ferritin <100 ng/mL may be appropriate in inflammation. Low TSAT with raised ferritin may reflect iron restriction or mixed disease.[3]
CKDUse the 2026 KDIGO treatment criteria below, with dialysis status specified.[5]
Heart failureCommon trial criteria are ferritin <100 ng/mL, or 100–299 with TSAT <20%. These criteria identify iron deficiency, which need not include anemia.[11]

Laboratory reference intervals can have lower limits below clinically useful decision thresholds. A 2024 systematic review found substantial methodological weaknesses in how many ferritin reference intervals were established; an automatically reported normal result should not end the evaluation when deficiency remains likely.[2]

Interpreting ferritin in inflammation​

Ferritin can be normal or elevated despite depleted stores. Review CRP when inflammation is uncertain and consider recent infection, liver disease, transfusion and iron treatment. TSAT helps assess iron availability, but inflammation also lowers transferrin and can complicate its interpretation. Ferritin 30–100 with low TSAT is not automatically pure functional deficiency; absolute and inflammatory mechanisms can coexist.[1][3]

Reticulocyte hemoglobin or soluble transferrin receptor may help when routine results conflict. The sTfR/log-ferritin index is assay dependent and needs a locally validated interpretation.[3]

CKD: KDIGO 2026​

For anemia with CKD, KDIGO suggests starting iron under these conditions; the recommendations are 2D, reflecting very low-certainty evidence.[5]

PopulationTreatment-entry criteriaRoute
HemodialysisFerritin ≤500 ng/mL AND TSAT ≤30%IV preferred
No dialysis or peritoneal dialysisFerritin <100 AND TSAT <40%, OR ferritin ≥100 to <300 AND TSAT <25%Oral or IV, individualized

Routine iron is generally withheld when ferritin is >700 ng/mL or TSAT is ≥40%. These are thresholds for withholding iron, not treatment targets. Monitor Hb, ferritin and TSAT every 3 months without hemodialysis and every 1–3 months with hemodialysis, sooner after bleeding or treatment changes. Consider pausing during systemic infection. Poor oral tolerance or an inadequate response after 1–3 months supports switching to IV treatment. Profound deficiency without anemia (ferritin <30 with TSAT <20%) can justify treatment after shared decision-making; it does not mandate immediate IV iron for everyone.[5]

Preoperative patient blood management​

Screen for anemia before surgery beyond minor procedures with negligible blood loss, ideally early enough to evaluate and treat the cause. ICCAMS supports Hb <13 g/dL in both sexes as a preoperative anemia threshold and assessment about four weeks before surgery when feasible. A short interval should still prompt evaluation. Look for ongoing bleeding, iron deficiency, renal disease, B12 or folate deficiency and other hematologic causes rather than prescribing iron for every low Hb.[3]

Treat confirmed IDA. The 2024 AGA expert review advises oral iron at most once daily, with every-other-day dosing sometimes better tolerated; it advises IV iron when oral iron is not tolerated, ferritin fails to improve after an oral trial, or absorption is unlikely.[16] IV iron may also suit a preoperative interval too short for oral repletion; ICCAMS generally favors IV iron for preoperative IDA. The decision to delay an elective operation depends on anemia severity, expected blood loss, treatment response and the consequences of delay.[3]

The PREVENTT trial was a blinded, multicenter trial that randomized 487 anemic adults before major open abdominal surgery to ferric carboxymaltose 1,000 mg or placebo 10–42 days preoperatively.[9] From randomization through 30 days after surgery, transfusion or death occurred in 69/237 (29%) versus 67/237 (28%), respectively (RR 1.03, 95% CI 0.78–1.37).[9] Preoperative Hb increased, but neither this composite nor the coprimary transfusion count improved. The study did not require iron deficiency for entry, and its lower eight-week readmission rate was a secondary finding. PREVENTT did not show that IV iron prevents transfusion or death in its abdominal-surgery population.[9] A 2026 network meta-analysis of 34 perioperative randomized trials (4,688 participants) found lower transfusion requirements with ferric carboxymaltose versus placebo (OR 0.72, 95% credible interval 0.55–0.91); mixed surgical populations limit direct application to reconstruction.[14]

IV preparations are not interchangeable​

The following are US adult IDA regimens, not the separate heart-failure dosing schedule. Check the current product label and indication.[7][8]

AgentLabeled course
Ferric carboxymaltose (Injectafer)At ≥50 kg: 750 mg twice, at least seven days apart (1,500 mg total); alternatively 15 mg/kg, maximum 1,000 mg, once per course. Below 50 kg: 15 mg/kg twice, at least seven days apart. 1,500 mg is not a single dose.[7]
Ferric derisomaltose (Monoferric)At ≥50 kg: 1,000 mg once. Below 50 kg: 20 mg/kg once. Infused over at least 20 minutes.[8]

Check product-specific contraindications before infusion: Injectafer is contraindicated with hypersensitivity to it or its components, and Monoferric with a history of serious hypersensitivity to it or its components. Administer where serious hypersensitivity can be treated, and monitor blood pressure after each Injectafer dose.[7][8] Both US labels require observation during administration and for at least 30 minutes afterward, until clinically stable.[7][8]

Injectafer and phosphate depletion

The FDA added a boxed warning on September 1, 2026 for symptomatic hypophosphatemia after single or multiple ferric carboxymaltose doses, including cases with normal baseline phosphate and no apparent risk factors; severe, prolonged hypophosphatemia can cause osteomalacia and fractures.[7] Risk factors in the Injectafer label include gastrointestinal disorders associated with malabsorption of fat-soluble vitamins or phosphate, inflammatory bowel disease, current or prior use of drugs affecting proximal renal tubular function, hyperparathyroidism, vitamin D deficiency, malnutrition and hereditary hemorrhagic telangiectasia. Correct preexisting hypophosphatemia; monitor serum phosphate in patients at risk for chronic low phosphate and before a repeat course in patients at risk for low serum phosphate or anyone retreated within three months.[7] Severe symptomatic or persistent hypophosphatemia may require permanent discontinuation. New weakness, fatigue or bone pain after treatment can reflect phosphate depletion rather than persistent anemia.[6]

Finding the cause​

  • GU or gynecologic bleeding. Quantify and investigate hematuria or heavy menstrual bleeding. Fistula or prior reconstruction does not by itself indicate iron deficiency, and iron replacement does not stop the bleeding source.
  • Poor intake or malabsorption. Consider restrictive intake, bariatric surgery and celiac disease. Other deficiencies may coexist.
  • Diversion or bowel reconstruction. Evaluate anemia according to the bowel segment, renal function, blood loss and laboratory pattern. Diversion-related anemia has several causes; iron infusion has no universal schedule and depends on the cause and laboratory pattern.
  • Unexplained IDA. AGA recommends bidirectional endoscopy for asymptomatic men and postmenopausal women. In asymptomatic premenopausal women it is a conditional suggestion, with the balance of investigation and an initial iron trial discussed in context. In adults with IDA and no identifiable cause after bidirectional endoscopy, AGA conditionally suggests noninvasive H. pylori testing and treatment if positive. For asymptomatic adults with IDA and plausible celiac disease, it conditionally suggests serology first and small-bowel biopsy only if positive. In uncomplicated asymptomatic adults with IDA after negative bidirectional endoscopy, it conditionally suggests an initial iron trial before routine video capsule endoscopy.[4]

Hyperferritinemia​

A high ferritin alone does not establish iron overload. Review inflammation or infection, liver injury, metabolic disease, alcohol, malignancy, transfusions and TSAT. EASL recommends genetic evaluation for the appropriate clinical and biochemical pattern (raised ferritin with elevated TSAT or otherwise unexplained persistently high TSAT), with consent and attention to ancestry and family history. In patients with high TSAT and elevated ferritin but other HFE genotypes, EASL requires hepatic iron overload on MRI or liver biopsy to diagnose haemochromatosis. Do not prescribe venesection solely because ferritin is elevated.[10]

Very high ferritin in a systemically ill patient should raise concern for severe infection, acute liver injury or HLH/MAS, among other causes. No single ferritin threshold, such as 9,000 or 25,000 μg/L, diagnoses HLH/MAS. Assessment integrates the syndrome, serial results and specialist evaluation.[13]

Heart failure: keep the evidence in context​

FAIR-HF2 (2025, 1,105 patients) did not meet its prespecified multiplicity-adjusted primary endpoints despite a nominal HR 0.79, P=.04 for cardiovascular death or first HF hospitalization.[11] The updated six-trial meta-analysis (7,175 patients) found fewer recurrent HF hospitalizations or cardiovascular deaths over complete follow-up (RR 0.81, 95% interval 0.63–0.97), but the cardiovascular-mortality estimate alone remained inconclusive (HR 0.87, 0.73–1.04).[12]

See Also​

References​

1. Garcia-Casal MN, et al. Serum or plasma ferritin concentration as an index of iron deficiency and overload. Cochrane Database Syst Rev. 2021;5:CD011817. doi:10.1002/14651858.CD011817.pub2

2. Truong J, et al. The origin of ferritin reference intervals: a systematic review. Lancet Haematol. 2024;11:e530–e539. doi:10.1016/S2352-3026(24)00103-0

3. Shander A, et al. Recommendations From the International Consensus Conference on Anemia Management in Surgical Patients (ICCAMS). Ann Surg. 2023;277:581–590. doi:10.1097/SLA.0000000000005721

4. Ko CW, et al. AGA Clinical Practice Guidelines on the Gastrointestinal Evaluation of Iron Deficiency Anemia. Gastroenterology. 2020;159:1085–1094. doi:10.1053/j.gastro.2020.06.046. Official recommendations.

5. KDIGO Anemia Work Group. KDIGO 2026 Clinical Practice Guideline for the Management of Anemia in Chronic Kidney Disease. Kidney Int. 2026;109(Suppl 1S):S1–S99. Full guideline. doi:10.1016/j.kint.2025.06.006

6. FDA. FDA Adds Boxed Warning to Labeling for Ferric Carboxymaltose Injection (Injectafer) to Describe Risk of Low Phosphate Levels. September 1, 2026. Drug safety communication.

7. Injectafer (ferric carboxymaltose). US prescribing information, dosage and administration; hypersensitivity precautions. DailyMed. Accessed September 12, 2026; see the separate FDA September 2026 safety communication above.

8. Monoferric (ferric derisomaltose). US prescribing information. DailyMed. Accessed September 12, 2026.

9. Richards T, et al. Preoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): a randomised, double-blind, controlled trial. Lancet. 2020;396:1353–1361. doi:10.1016/S0140-6736(20)31539-7

10. European Association for the Study of the Liver. EASL Clinical Practice Guidelines on haemochromatosis. J Hepatol. 2022;77:479–502. Guideline. doi:10.1016/j.jhep.2022.03.033

11. Anker SD, et al. Intravenous Ferric Carboxymaltose in Heart Failure With Iron Deficiency: The FAIR-HF2 DZHK05 Randomized Clinical Trial. JAMA. 2025;333:1965–1976. doi:10.1001/jama.2025.3833

12. Anker SD, et al. Systematic review and meta-analysis of intravenous iron therapy for patients with heart failure and iron deficiency. Nat Med. 2025;31:2640–2646. doi:10.1038/s41591-025-03671-1

13. Shakoory B, et al. The 2022 EULAR/ACR Points to Consider at the Early Stages of Diagnosis and Management of Suspected Haemophagocytic Lymphohistiocytosis/Macrophage Activation Syndrome. Arthritis Rheumatol. 2023;75:1714–1732. doi:10.1002/art.42636

14. Xue Q, Zhang B, Xing Z, Sun F, Zhao Q, Mu S. "Efficacy and safety of intravenous iron supplementation for perioperative iron deficiency anemia: a systematic review and network meta-analysis of randomized controlled trials." J Clin Anesth. 2026;108:112062. doi:10.1016/j.jclinane.2025.112062

15. Powers JM, Lim MY, Achebe MO, et al. "American Society of Hematology 2026 guidelines for diagnosis of iron deficiency." Blood Adv. Published online August 24, 2026. doi:10.1182/bloodadvances.2025015950

16. DeLoughery TG, Jackson CS, Ko CW, Rockey DC. "AGA Clinical Practice Update on Management of Iron Deficiency Anemia: Expert Review." Clin Gastroenterol Hepatol. 2024;22(8):1575–1583. doi:10.1016/j.cgh.2024.03.046