CurrentHealthfirstPolicy PO-RE-005v5

Diagnostic Testing of Iron Homeostasis and Metabolism

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Defines medical coverage criteria and clinical background for laboratory testing of iron status (serum ferritin, transferrin/transferrin saturation, and related assays) including indications, limitations, and excluded tests for Healthfirst members.

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CurrentHealthfirstPolicy PO-RE-005v5

Diagnostic Testing of Iron Homeostasis and Metabolism

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Policy Summary

PayerHealthfirst

PolicyDiagnostic Testing of Iron Homeostasis and Metabolism

Policy CodePolicy PO-RE-005v5

Change TypeNo material changes

Effective DateMay 1, 2026

Last ReviewMar 16, 2026

Next Review DateN/A

Key ActionDocument the clinical indication that matches listed covered situations when ordering ferritin or transferrin tests.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

1/monthroutine ferritin frequency

ferritin, TSATprimary covered tests

hepcidin, GlycAexplicit exclusions

<30 µg/Ldiagnostic thresholds cited

6procedure code lines

Coverage Criteria: Indications and Exclusions

inv-01: Serum ferritin — covered indications

Measurement of serum ferritin levels meets coverage criteria when ANY of the following are present (frequency limits apply as noted):

Covered ferritin indications: a. Individuals with anemia; b. Individuals with an iron overload disorder (once every three weeks); c. Individuals with symptoms of hemochromatosis; d. Individuals with first-degree relatives with confirmed hereditary hemochromatosis; e. Evaluation of individuals with liver disease; f. Evaluation of hemophagocytic lymphohistiocytosis (HLH) and Still Disease; g. Males with secondary hypogonadism; h. Individuals with chronic kidney disease — one test every three months if not receiving dialysis; one test every month if receiving dialysis; i. Individuals on iron therapy; j. Individuals with restless legs syndrome or periodic limb movement disorder.No more than one serum ferritin test per month unless otherwise specified

Frequency exceptions noted in policy for iron overload disorders and CKD.

inv-02: Transferrin transferrin saturation — covered indications

Measurement of serum transferrin saturation meets coverage criteria when ANY of the following are present:

Covered transferrin/TSAT indications: a. Evaluation of iron overload in individuals with symptoms of hemochromatosis; b. Evaluation of iron overload in individuals with first-degree relatives with confirmed hereditary hemochromatosis; c. Evaluation of iron deficiency anemia; d. Individuals with restless legs syndrome or periodic limb movement disorder.

Transferrin saturation used in diagnostic evaluation of both iron overload and deficiency.

inv-05: Diagnostic evaluation — Covered testing for diagnosis of iron deficiency or iron overload when guideline-based criteria are met

Covered testing for diagnosis of iron deficiency or iron overload when guideline-based criteria are met:

Basic evaluation for suspected iron deficiency or overload: All of: measurement of serum ferritin and TSAT (or serum iron and TIBC), CBC with indices; in inflammatory states consider CRP and reticulocyte hemoglobin content or serum hepcidin if available.Ferritin <30 ng/mL and/or TSAT <20%; ferritin <100 ng/mL may indicate deficiency in inflammatory states

ICCAMS/ICCAMS and ECCO guidance cited for diagnostic thresholds and recommended components of the workup.

inv-06: IV iron therapy criteria — Use of IV iron therapy and related testing

Use of IV iron therapy and related testing:

When IV iron is indicated: Any of: intolerance to oral iron; failure of ferritin to improve after an oral iron trial; conditions with impaired oral absorption (eg, post-bariatric surgery, active IBD); or need for rapid repletion. Document prior oral therapy when practical.Prefer IV formulations that replace iron deficits in 1–2 infusions.

AGA guidance supports IV iron in these scenarios and recommends formulations that minimize number of infusions.

inv-07: Guideline-based testing and monitoring recommendations — Monitoring and testing recommendations from specialty guidelines (IBD, CKD, general management)

Monitoring and testing recommendations from specialty guidelines (IBD, CKD, general management):

IBD monitoring (ECCO): Anemia parameters should be evaluated every 6-12 months in patients in remission or with mild disease; active disease should be monitored at least every 3 months. After iron deficiency treatment, monitor hemoglobin and ferritin every 3-6 months for at least a year and every 6-12 months thereafter. Ferritin <30 µg/L indicates deficiency in remission; ferritin up to ~100 µg/L may still indicate deficiency with active inflammation.ferritin <30 µg/L; ferritin up to ~100 µg/L contextual

ECCO guidance.

CKD monitoring (KDIGO/NKF-KDOQI/ISN): Initial anemia evaluation should include CBC, reticulocyte count, serum ferritin, TSAT, B12 and folate. For patients on ESA or receiving iron, test TSAT and ferritin at least every 3 months (monthly for hemodialysis). Withhold iron if ferritin ≥700 ng/mL or TSAT ≥40%.ferritin ≥700 ng/mL or TSAT ≥40% for withholding iron

KDIGO guidance.

inv-03: Not covered — Explicit not covered tests

Explicit not covered tests:

Not covered tests: Serum hepcidin testing, including immunoassays, and GlycA testing to measure or monitor transferrin or other glycosylated proteins.

Policy states these tests do not meet coverage criteria due to insufficient published evidence.

inv-04: Other situations — not covered (general non-coverage statement)

General non-coverage statement

Other situations: For all other situations not addressed above, measurement of ferritin or transferrin levels, including transferrin saturation, does not meet coverage criteria.

Coverage limited to listed indications.

The following tests are excluded from coverage: serum hepcidin testing (including immunoassays) and GlycA testing. These assays do not meet coverage criteria due to insufficient published evidence supporting their clinical utility for diagnosis or treatment in the indicated settings.

Routine population screening for iron deficiency anemia in asymptomatic individuals is not supported by current USPSTF evidence. The USPSTF concludes the evidence is insufficient to assess benefits and harms of screening for iron deficiency anemia in asymptomatic pregnant people and in children ages 6–24 months; clinicians should follow individualized clinical judgment and guideline-based screening rather than universal screening.

Measurement of serum ferritin or transferrin (including transferrin saturation) for clinical indications that are not specifically listed in this policy does not meet coverage criteria and is considered not medically necessary.

This policy does not support routine population screening of asymptomatic pregnant individuals or asymptomatic children (including ages 6–24 months) for iron deficiency or iron deficiency anemia given the USPSTF finding of insufficient evidence to recommend universal screening in these groups.

The USPSTF has assigned a grade of I (insufficient evidence) for routine screening for iron deficiency anemia in asymptomatic pregnant people and in children ages 6–24 months, indicating that current evidence does not allow assessment of the balance of benefits and harms.

Per the Government of British Columbia guidance, serum iron, iron binding capacity, and transferrin saturation are not routinely useful for investigating iron deficiency anemia; ferritin is recommended as the test of choice for diagnosis and monitoring in routine practice.

Covered Indications: When Tests are Authorized

inv-40: Serum ferritin measurement — covered indications (anemia, iron overload monitoring, hemochromatosis symptoms, family history, liver disease, etc.)

Covered for the following clinical contexts (frequency limits apply as noted):

Serum ferritin measurement — covered indications: a. Individuals with anemia; b. Individuals with an iron overload disorder (monitor q3 weeks); c. Individuals with symptoms of hemochromatosis; d. Individuals with first-degree relatives with confirmed hereditary hemochromatosis; e. Evaluation of liver disease; f. Evaluation of HLH and Still Disease; g. Males with secondary hypogonadism; h. Individuals with chronic kidney disease (q3 months if not on dialysis; monthly if on dialysis); i. Individuals on iron therapy; j. Individuals with restless legs syndrome or periodic limb movement disorder.Generally no more than 1 test per month unless otherwise specified

Frequency exceptions for iron overload disorders and CKD are specified in policy.

inv-41: Serum transferrin/transferrin saturation — covered indications (evaluation of overload, iron deficiency anemia, RLS, etc.)

Covered transferrin/transferrin saturation indications include:

Testing Frequency and Monitoring Intervals

inv-45: serum ferritin — maximum routine frequency (1/month unless specified)

Routine maximum frequencyNo more than one serum ferritin test per month unless otherwise specified

Exception — iron overload disorderSee specific frequency rules for iron overload (q3 weeks) — overrides monthly limit

Ordering noteClinical indication must be documented to justify frequency beyond routine monthly testing

inv-46: serum ferritin for individuals with an iron overload disorder — one test every three weeks

Frequency for iron overloadOne serum ferritin test every three weeks for individuals with an iron overload disorder

ContextUsed for monitoring iron overload and managing chelation or phlebotomy decisions

Provider Actions: Documentation, Authorization, and Treatment Pathways

Documentation Required

Ordering and documentation requirements

Document the clinical indication on the laboratory order or supporting medical record showing alignment with covered situations (e.g., suspected anemia, iron overload symptoms, first‑degree relative with hereditary hemochromatosis, liver disease, HLH/Still disease, restless legs syndrome, chronic kidney disease, monitoring during iron therapy, perioperative anemia workup). Include relevant laboratory context when applicable (recent CBC, hemoglobin, CRP or other markers of inflammation, prior iron studies such as ferritin and TSAT, and prior response to oral iron if relevant).

Required: specific clinical indication that matches a listed covered situation.
Include: recent hemoglobin/CBC, ferritin, TSAT (or iron + TIBC), CRP or other inflammation markers when inflammation suspected.
If continuation of therapy or monitoring, document timeframe (eg, dialysis status, testing frequency per condition).

Step Therapy

Step therapy and oral-before-IV guidance

There are no step‑therapy requirements specified in this section for ordering iron studies or IV iron; providers are not required to complete mandated step edits beyond documenting clinical indication and prior therapies where noted. However, clinical guidance favors a trial of oral iron when appropriate before IV iron unless contraindicated or not tolerated.

Coding and Diagnostic Thresholds

Applicable procedure codesCPT | Proprietary

82728	Ferritin
83540	Iron
83550	Iron binding capacity
84466	Transferrin
84999	Unlisted chemistry procedure
0024U	Glycosylated acute phase proteins (GlycA), nuclear magnetic resonance spectroscopy, quantitative (Proprietary: GlycA, LabCorp)
0251U	Hepcidin-25, enzyme-linked immunosorbent assay (ELISA), serum or plasma (Proprietary: Intrinsic Hepcidin IDx™ Test, IntrinsicDx)

inv-15: Serum ferritin diagnostic thresholds — ferritin <30 µg/L; CHF/CKD/IBD: ferritin <100 µg/L or TSAT <20% diagnostic

General diagnostic cutoffSerum ferritin <30 µg/L indicates iron deficiency (ICCAMS/ICCAMS-derived guidance)

Inflammatory states/CHF/CKD/IBDFerritin <100 µg/L or TSAT <20% can be considered diagnostic for iron deficiency in congestive heart failure, CKD, and IBD

Intermediate ferritinIf ferritin 100–300 µg/L, TSAT <20% is required to confirm iron deficiency

inv-16: Ferritin / TSAT thresholds — examples including HEIRS thresholds and diagnostic cutoffs

HEIRS trigger valuesFerritin >200 ng/mL in women or >300 ng/mL in men warrant additional testing per HEIRS study

Deficiency indicators

Ordering Requirements and Documentation

Documentation Required

ORDERING: document covered clinical indication

Orders should document the clinical indication that matches the policy's covered indications (eg, anemia, family history of hereditary hemochromatosis, symptoms of hemochromatosis) to support testing and frequency.

Documentation Required

ORDERING: include clinical context and requested tests

Provide concise clinical context on the order—suspected anemia, inflammatory status, prior iron therapy, and which tests are requested (eg, ferritin, TSAT, CBC, CRP, RET‑He)—so the laboratory and payer can assess medical necessity.

Documentation Required

ORDERING: LDT validation and CLIA requirements

No ordering provider restrictions are stated; laboratories performing laboratory‑developed tests must validate those assays and operate under CLIA (high‑complexity) standards—ensure tests are sent to appropriately certified laboratories.

Definitions and Test Descriptions

inv-32: Ferritin — definition and role

Definition — FerritinFerritin is a cellular protein that stores intracellular iron; circulating serum ferritin primarily reflects iron stores but is also an acute phase reactant and can be elevated with inflammation or liver disease

Clinical roleSerum ferritin is the most commonly used metric to monitor iron stores and guide diagnosis of iron deficiency or overload

Interpretation caveatBecause ferritin is an acute phase reactant, interpret levels in the context of inflammation, infection, or liver disease

inv-33: Transferrin saturation (TSAT) — definition and use

Definition — TSATTransferrin saturation (TSAT) is the proportion of transferrin bound to iron, calculated from serum iron and total iron binding capacity (TIBC)

Clinical use

Not Covered Tests and Screening

Serum hepcidin testing, including immunoassays, and GlycA testing are explicitly listed as not covered because the policy found insufficient published scientific literature demonstrating they are required or beneficial for diagnosis or treatment.

Routine screening for iron deficiency anemia in asymptomatic pregnant individuals is not supported by sufficient evidence per USPSTF. The USPSTF found current evidence insufficient to assess benefits and harms of such screening and reconfirmed this position in 2024.

Routine population screening for iron deficiency in asymptomatic groups (including pregnant people and children ages 6–24 months) is considered unsupported by the USPSTF due to insufficient evidence to determine net benefit; such screening therefore does not meet routine coverage as a population-level service.

Clinical Background and Rationale

Iron homeostasis is tightly regulated through absorption, transport, storage, and hormonal control. Ferritin reflects intracellular iron stores but is also an acute-phase reactant and may be elevated with inflammation or liver disease. Transferrin transports iron in plasma and transferrin saturation (TSAT) represents the proportion of transferrin bound to iron; TSAT is used together with ferritin to evaluate iron deficiency and iron overload. Hepcidin is a peptide hormone that modulates iron export by binding ferroportin and contributes to hypoferremia in inflammatory states.

Policy Summary

PayerHealthfirst

PolicyDiagnostic Testing of Iron Homeostasis and Metabolism

Policy CodePolicy PO-RE-005v5

Change TypeNo material changes

Effective DateMay 1, 2026

Last ReviewMar 16, 2026

Next Review DateN/A

Key ActionDocument the clinical indication that matches listed covered situations when ordering ferritin or transferrin tests.

SourceLink

On This Page

RLS screening and treatment thresholds (AASM): In clinically significant restless legs syndrome, test ferritin and TSAT; consider iron supplementation if ferritin ≤75 ng/mL or TSAT <20%; IV iron may be considered when ferritin between 75–100 ng/mL.ferritin ≤75 ng/mL or TSAT <20%

AASM guidance referenced in policy.

Oral iron monitoring (Government of British Columbia): Reassess moderate–severe anemia with CBC at 2–4 weeks; hemoglobin should increase 10–20 g/L by 4 weeks. Continue oral iron 4–6 months after correction; re-check ferritin 3–6 months after normalization of hemoglobin. Target ferritin >100 µg/L.target ferritin >100 µg/L

Government of British Columbia guideline.

Serum transferrin/TSAT — covered indications: a. Evaluation of iron overload (symptoms of hemochromatosis); b. Evaluation of iron overload in individuals with first-degree relatives with confirmed hereditary hemochromatosis; c. Evaluation of iron deficiency anemia; d. Individuals with restless legs syndrome or periodic limb movement disorder.

TSAT used for both overload and deficiency assessment.

inv-42: Evaluation of anemia or suspected iron deficiency, preoperative assessment, monitoring iron therapy and overload — recommended component tests

Recommended component tests for evaluation of anemia, suspected iron deficiency, preoperative assessment, and monitoring iron therapy or overload:

Recommended test components: All of: serum ferritin and TSAT (or serum iron and TIBC), complete blood count (CBC) with indices; consider reticulocyte hemoglobin (RET-He) or serum hepcidin in inflammatory or complex states, and CRP when inflammation is suspected.Diagnostic thresholds: ferritin <30 µg/L and/or TSAT <20%; ferritin <100 µg/L may indicate deficiency in inflammatory states.

ICCAMS and ECCO recommend these components for diagnosis and perioperative evaluation.

inv-43: Assessment in specific populations where expanded iron studies may provide additional information (CKD, HF, thalassemia, sepsis) — indication list

Assessment in specific populations where expanded iron studies may provide additional information:

Specific populations where expanded testing may help: CKD, heart failure, thalassemia, and sepsis — in these populations additional biomarkers such as hepcidin, GDF-15, and RET-He may provide diagnostic or prognostic information and can be considered when clinically indicated.

Studies cited in policy support utility of expanded biomarkers in these populations.

inv-44: Evaluation and monitoring in CKD, IBD, iron overload disorders, and symptomatic conditions — guideline-aligned monitoring

Evaluation and monitoring aligned with guideline recommendations for CKD, IBD, iron overload disorders, and symptomatic conditions:

CKD management: Initial anemia evaluation should include CBC, reticulocyte count, serum ferritin, and TSAT. For patients receiving iron or ESA therapy, test ferritin and TSAT at least every 3 months (monthly for hemodialysis). Withhold iron if ferritin ≥700 ng/mL or TSAT ≥40%.ferritin ≥700 ng/mL or TSAT ≥40%

KDIGO guidance.

IBD monitoring: Screening with CBC, serum ferritin, and CRP every 6–12 months in remission and at least every 3 months in active disease. After treatment, monitor hemoglobin and ferritin every 3–6 months for at least one year and then every 6–12 months.ferritin <30 µg/L (remission); ferritin up to ~100 µg/L may indicate deficiency with active inflammation

ECCO guidance.

Oral iron response monitoring: Reassess moderate–severe anemia with CBC at 2–4 weeks; hemoglobin should rise 10–20 g/L by 4 weeks. Continue iron therapy 4–6 months after correction and re-check ferritin 3–6 months after normalization; target ferritin >100 µg/L.target ferritin >100 µg/L

Government of British Columbia guidance.

DocumentationDocument diagnosis of iron overload to support q3-week testing

inv-47: serum ferritin for individuals with chronic kidney disease — frequency by dialysis status

CKD — not on dialysisOne serum ferritin test every three months if the individual is not receiving dialysis

CKD — on dialysisOne serum ferritin test every month if the individual is receiving dialysis

KDIGO guidanceKDIGO recommends testing ferritin and TSAT at least every 3 months (monthly for hemodialysis) and more frequently during therapy initiation or blood loss

inv-48: hemoglobin and ferritin monitoring post-treatment — every 3–6 months

Post-treatment monitoring intervalMonitor hemoglobin and ferritin every 3–6 months after iron deficiency restoration for at least one year

Long-termAfter the first year, continue monitoring every 6–12 months as clinically indicated

IBD contextECCO recommends more frequent checks during active disease (see IBD-specific guidance)

inv-49: CBC, serum ferritin, CRP for IBD patients — monitoring every 6–12 months (remission) or ≥ every 3 months (active)

IBD in remissionCBC, serum ferritin, and CRP every 6–12 months for patients in remission or with mild disease

IBD active diseaseCBC, serum ferritin, and CRP at least every 3 months for patients with active disease

Post-treatment in IBDAfter iron deficiency treatment monitor hemoglobin and ferritin every 3–6 months for at least a year

inv-50: Ferritin and TSAT monitoring interval — every 3 months

Routine intervalFerritin and TSAT should be measured every 3 months for routine monitoring during/after therapy or for CKD patients not on dialysis

When to increase frequencyTest more frequently when initiating/increasing ESA, after IV iron, or when blood loss occurs

DocumentationClinical context should be provided to support the monitoring interval

inv-51: Ferritin/TSAT and hemoglobin monitoring — monthly

Monthly monitoringFerritin/TSAT and hemoglobin tested monthly when initiating or increasing ESA, during initial treatment, or for hemodialysis patients

CKD hemodialysisMonthly testing aligns with KDIGO updated guidance for patients receiving hemodialysis

Clinical triggersAlso monitor monthly when there is active blood loss or recent IV iron administration

inv-52: Serum ferritin monitoring interval example — every 3-6 weeks

ASH recommendation exampleCheck serum ferritin frequently (every 3–6 weeks) when monitoring iron chelation therapy to calculate running averages and correct for transient fluctuations

PurposeFrequent checks enable running averages to mitigate variability from inflammation or liver damage

ApplicabilityPrimarily used for patients on iron chelation or with rapidly changing iron status

inv-53: Ferritin re-check recommendation — re-check ferritin 3-6 months

Re-check interval after normalizationRe-check ferritin 3–6 months after normalization of hemoglobin or after initiation of iron supplementation in non-anemic patients

TargetAim for target ferritin >100 µg/L per guideline guidance when replenishing stores

Clinical follow-upAdjust timing based on severity, adherence, ongoing bleeding, or malabsorption

No payer step‑therapy rule specified for iron testing in this section.
Clinical note: attempt oral iron (eg, every‑other‑day dosing or with vitamin C to enhance absorption) before IV iron unless intolerance, malabsorption (including post‑bariatric surgery), or urgent need for repletion.

Documentation Required

IV iron therapy recommendation

Intravenous iron therapy should be considered in accordance with clinical guidelines: use IV iron when oral iron is not tolerated, when ferritin/hemoglobin do not improve after a documented oral iron trial, or when oral absorption is likely impaired (eg, post‑bariatric surgery, active inflammatory bowel disease with absorption compromise). Prefer formulations that can replete iron deficits in 1–2 infusions when clinically appropriate. Document prior oral iron trial or the contraindication to oral therapy in the medical record.

Indications for IV iron: documented intolerance to oral iron; failure to respond to an adequate oral iron trial; malabsorption or conditions impairing oral absorption; urgent need for iron repletion (per specialty guidance).
Preferred: IV formulations that achieve deficit replacement in 1–2 infusions where appropriate.
Document: dates/duration of oral iron trial, dosing, tolerance, and objective response (hemoglobin and ferritin/TSAT trends).

Denial Risk

Coverage denial for unlisted indications

Tests or therapies for indications that are not listed in the covered indications in this policy section do not meet coverage criteria and may be denied. Ensure the submitted clinical indication matches one of the covered situations; otherwise the request or claim is at risk for denial.

Coverage does NOT apply for unlisted indications outside the enumerated covered situations.
Orders and claims lacking a covered indication may be denied as not medically necessary.

Note

Additional testing and escalation triggers

Ferritin thresholds may trigger additional testing or actions. Specifically, ferritin >200 ng/mL in women or >300 ng/mL in men without evidence of inflammation should prompt additional evaluation for iron overload per clinical guidance (eg, repeat TSAT, genetic testing, specialty referral). Extremely elevated ferritin (eg, >1000 ng/mL) may prompt consideration of therapeutic phlebotomy or evaluation for HLH when clinically indicated.

Trigger: ferritin >200 ng/mL (women) or >300 ng/mL (men) without inflammatory markers → obtain further testing and clinical evaluation.
Trigger: ferritin substantially elevated (eg, >1000 ng/mL) → consider therapeutic phlebotomy and/or HLH workup based on clinical context.

Billing Rule

Codes to reference for authorization and claims

Use the following codes as references when ordering, authorizing, or submitting claims for iron studies and related proprietary tests. Providers should include the appropriate CPT/HCPCS/Proprietary code(s) on claims; charges may be subject to review for medical necessity.

Covered/commonly used chemistry codes: 82728 (Ferritin), 83540 (Iron), 83550 (Iron binding capacity), 84466 (Transferrin).
Other: 84999 (Unlisted chemistry procedure) for unlisted assays.
Proprietary/PLA codes: 0024U (GlycA — LabCorp), 0251U (Hepcidin-25 — IntrinsicDx).

Ferritin <30 µg/L or TSAT <20% suggest iron deficiency; ferritin <100 µg/L may indicate deficiency in inflammatory states

WHO contextWHO provides age/sex/inflammation-specific cutoffs for iron deficiency and overload; apply context-specific thresholds

inv-17: Transferrin saturation safety threshold (~85% above which NTBI appears)

High TSAT safety thresholdTransferrin saturation ≈85% (above which non-transferrin-bound iron species begin to appear) — associated with risk of endocrine and cardiac iron accumulation

Clinical implicationVery high TSAT may indicate risk for NTBI and organ toxicity; interpret with clinical context and chelation status

Monitoring noteTSAT values may be affected by presence of iron chelators or recent therapy — withhold chelators before testing if possible

inv-18: KDIGO withholding threshold for iron therapy — ferritin ≥700 ng/mL or TSAT ≥40%

KDIGO withholding thresholdWithhold iron therapy if ferritin ≥700 ng/mL or TSAT ≥40%

Testing cadenceKDIGO recommends testing TSAT and ferritin at least every 3 months (monthly for hemodialysis) and more frequently during ESA initiation or after IV iron

Clinical applicationUse these thresholds to guide initiation/continuation/withholding of iron therapy in CKD patients

Confirm LDT validation and CLIA certification for proprietary or in‑house assays.

Used with ferritin to evaluate iron overload and iron deficiency and to guide iron therapy decisions

LimitationsTSAT interpretation can be affected by recent iron therapy or presence of iron chelators; withhold chelators before testing if indicated

inv-34: Hepcidin — definition and assay discussion

Definition — HepcidinHepcidin is a peptide hormone that binds ferroportin to reduce iron export and modulate serum iron concentrations

Assay considerationsHepcidin assays (eg, competitive ELISA, mass spectrometry) exist but hepcidin testing is not covered by this policy

Clinical contextHepcidin mediates hypoferremia in inflammation and may aid interpretation in complex cases, but is not routinely available

inv-36: RET-He — reticulocyte hemoglobin equivalent explanation

Definition — RET-HeReticulocyte hemoglobin equivalent (RET-He) is a CBC-derived parameter used to identify iron deficiency and predict responsiveness to IV iron

PerformanceReported sensitivity ~68% for identifying iron deficiency and ~84% sensitivity for predicting responsiveness to IV iron (Auerbach et al.)

Clinical useConsider RET-He in inflammatory or complex states where ferritin/TSAT may be misleading

inv-37: Genetic loci associated with iron biomarkers — GWAS findings

GWAS findingsGenome-wide analyses identified 56 genetic loci associated with ferritin, TIBC, iron saturation, and TSAT; specific genes (eg, TMPRSS6, HFE, TFR2) associate with iron deficiency or overload phenotypes

Clinical implicationGenetic variants can inform predisposition to iron disorders but are not primary diagnostics in routine testing

Research useFindings support biological understanding and may guide future personalized approaches

inv-35: Ferritin thresholds — HEIRS and context-dependent cutoffs

HEIRS thresholdsHEIRS: ferritin >200 ng/mL (women) or >300 ng/mL (men) warrant additional testing

Diagnostic cutoffs summaryFerritin <30 µg/L indicates iron deficiency; ferritin <100 µg/L may indicate deficiency in inflammatory states; if ferritin 100–300 µg/L, TSAT <20% required to confirm deficiency

WHO guidanceWHO provides age/sex/inflammation-specific ferritin cutoffs for deficiency and overload—apply context-specific thresholds

inv-38: Ferritin — serum ferritin as acute phase reactant and monitoring caveats

Acute phase reactant cautionSerum ferritin is an acute phase reactant and can be elevated with inflammation or liver disease; interpret results in clinical context

Monitoring caveatVariability due to inflammation/liver injury supports using running averages or adjunct markers (CRP, RET-He) when monitoring

Guideline noteECCO and ICCAMS provide specific ferritin thresholds adjusted for inflammatory states

inv-39: TSAT — calculation and high-saturation implications

TSAT calculation and roleTSAT is calculated from serum iron and TIBC and assesses circulating iron availability to guide diagnosis and therapy

High-saturation implicationTSAT >~85% is associated with appearance of NTBI species and increased risk for organ iron toxicity

Testing limitationsTSAT values can be invalid if iron chelators are present; withhold chelators before measurement when possible