Introduction
Pathophysiology of ID in chronic inflammation
Definition of iron deficiency
Diagnosis of iron deficiency
Types of biochemical markers
Serum iron
Serum transferrin
Transferrin saturation (TSAT)
Serum ferritin
Soluble transferrin receptor (sTfR)
sTfR–ferritin index
Guideline recommendations for ID diagnostics
Professional association | Origin | Year | Condition | Threshold values for ID diagnostic | ||
---|---|---|---|---|---|---|
Serum ferritin (μg/L) | TSAT (%) | Additional biomarkers | ||||
General population | ||||||
WHO [38] | International | 2020 | ID in | – | sTfR#, CRP** | |
˗ Infants and children < 5 years | < 12 | |||||
with infection/inflammation | < 30 | |||||
˗ Children > 5 years, adolescents, adults, older person (60 + years) | < 15 | |||||
with infection/inflammation | < 70 | |||||
˗ Pregnant women (only for first trimester) | < 15 | |||||
AAFP [39] | American | 2013 | IDA | < 30 | – | low serum iron#, low TSAT#, high TIBC# |
with infection/ inflammation | < 50 | |||||
BCG [40] | British | 2019 | ID in children | < 12 | additional < 20 | serum iron#, TIBC#, TSAT |
- Possible ID | 12–20 | |||||
ID in adults | < 15 | |||||
- Probable ID | 15–30 | |||||
- Unlikely ID | > 30 | |||||
or with chronic inflammatory disease | > 70–100 | |||||
or in elderly patients | > 50 | |||||
Chronic heart failure (HF) | ||||||
ACCF/AHA [30] | American | 2017 | AID | < 100 | – | – |
FID | or 100–300 | and < 20 | ||||
ESC [23] | European | 2021 | AID | < 100 | and < 20 | sTfR# |
FID | or 100–299 | and < 20 | ||||
Chronic kidney disease (CKD) | ||||||
KIDIGO [31] | International | 2012 | IDA only | – | – | – |
ND/HD-CKD + IDA | ≤ 500 | and ≤ 30 | ||||
Pediatric CKD + IDA | ≤ 100 | and ≤ 20 | ||||
Severe ID | ≤ 30 | – | ||||
KDOQI [32] | American | 2013 | IDA only | – | – | – |
ERBP [33] | European | 2013 | ID/IDA (AID) | < 100 | and < 20 | – |
UK NICE [34] | British | 2021 | IDA only | < 100* | and < 20* | Red blood cell markers: %HRC > 6%, CHr < 29 pg |
JSDT [35] (2015 version) | Japanese | 2017 | HD-CKD + ID | ≤ 100 | ≤ 20 | – |
Inflammatory bowel disease (IBD) | ||||||
ECCO [21] | European | 2015 | ID/IDA (quiescent disease, without inflammation) | < 30 | – | Tests to distinguish between IDA and ACD: sTfR, sTfR–ferritin index |
AID and ACD | 30–100 | and/or < 20 | ||||
FID and ACD | > 100 | and < 20 | ||||
BSG [36] | British | 2021 | ID/IDA (AID) | < 15 | – | sTfR# (in healthy subjects), sTfR–ferritin index#, CHr#, HYPO%# (in chronic disease and/or raised ESR#, CRP) |
FID | ≥ 100 | < 20 | ||||
Cancer | ||||||
NCCN [37] | America | 2021 | ID/IDA (AID) | < 30 | and < 20 | – |
FID (often when receiving ESAs) | 30–500 | and < 50 | ||||
Possible FID | > 500–800 | and < 50 | ||||
ESMO [20] | European | 2018 | ID/IDA (AID) | < 30–100 | and < 20 | AID: sTfR#, ZPP# AID and FID: %HYPO > 5%, CHr < 28 pg, CRP** |
FID | > 100 | and < 20 | ||||
DGHO [11] | Germany | 2022 | ID/IDA (AID) | < 30–100 | < 20 | sTfR > 0.76–1.76 mg/L (Dade Behring Test), sTfR–ferritin index > 0.2–3.7 men, > 0.6–3.8 women (Roche Test), ZPP > 80 µmol/mol Häm, HYPO% > 10%, CHr < 26 pg, CRP** |
FID | 100–800 | and < 20 |
Iron deficiency diagnosis and outcome in chronic diseases
Iron deficiency in heart failure (HF)
Study | Study population | ID definition / iron status | ID / iron status-associated outcome |
---|---|---|---|
Jankowska et al. (2011) [49] | ID and stable systolic CHF | Serum ferritin < 100 μg/L or Serum ferritin 100–300 μg/L + TSAT < 20% | • Exercise capacity: reduced peak oxygen consumption VO2 and increased ventilatory response to exercise VE-VCO2 slope |
Klip et al. (2013) [8] | ID and CHF | Serum ferritin < 100 μg/L or Serum ferritin 100–299 μg/L + TSAT < 20% | • Higher NYHA class • Higher NT-proBNP levels • Lower mean corpuscular volume levels • Higher risk of morality |
Comín-Colet et al. (2013) [50] | ID and/or IDA and CHF | Serum ferritin < 100 µg/L or Serum ferritin < 800 µg/L + TSAT < 20% or sTfR ≥ 1.62 mg/L | • Worse QoL (assessed with MLHFQ) |
Núñez et al. (2016) [56] | ID and AHF | AID: serum ferritin < 100 μg/L or FID: serum ferritin 100–299 μg/L + TSAT < 20% | • Increased risk of early rehospitalization (only for AID) |
Moliner et al. (2017) [52] | ID and CHF | Serum ferritin < 100 µg/L and/or TSAT < 20% | • Higher NT-proBNP levels* • Worse QoL* • Higher risk of all-cause mortality |
Martens et al. (2018) [7] | ID, IDA and HF with HFrEF, HFmrEF and HFpEF | Serum ferritin < 100 μg/L or Serum ferritin 100–300 μg/L + TSAT < 20% | • Lower VO2max • Progression to IDA • Higher risk of HF hospitalization • Higher risk of all-cause mortality |
Grote Beverborg et al. (2018) [24] | ID and HF | TSAT ≤ 19.8% + serum iron ≤ 13 μmol/L | • Higher risk of all-cause mortality |
Grote Beverborg et al. (2019) [51] | ID and HF | Serum ferritin ≤ 128 µg/L + TSAT < 20% | • Impaired 6MWT • Higher proportion of anemia • Poorer QoL • Higher risk of all-cause mortality • Higher risk of HF hospitalization |
Serum ferritin > 128 µg/L + TSAT < 20% | • Impaired 6MWT • Higher levels of inflammatory markers (CRP, IL-6) | ||
Grammer et al. (2019) [54] | ID/IDA and undergoing coronary angiography | Hb, serum iron, TSAT, sTfR, serum ferritin# | • J-shaped associations with cardiovascular and total mortality (marginal for Hb) |
Hepcidin# | • Inverse association with mortality | ||
Alcaide-Aldeano et al. (2020) [53] | ID and CHF with HFpEF | Serum ferritin < 100 µg/L and/or TSAT < 20% or sTfR n/a** | • Worse functional capacity (measured by 6MWT) • Worse QoL (assessed with MLHFQ) |
Ambrosy et al. (2020) [55] | Older adults (aged ≥ 65 years) with HF and IDA | IDA: Hb < 13 g/dL men or < 12 g/dL women + TSAT < 20% | • Higher risk of HF hospitalization • Higher risk of all-cause mortality |
Campodonico et al. (2021) [58] | ID and HF | AID: serum ferritin < 100 μg/L or FID: serum ferritin 100–300 μg/L + TSAT < 20% | • Worse prognosis (survival rate) (only for TSAT < 20% or serum ferritin 100 – 300 μg/L + TSAT < 20%) |
Fitzsimons et al. (2021) [57] | ID and HF (HFpEF, HFrEF) over time (6 months) | IDFerritin: serum ferritin < 100 μg/L or serum ferritin 100–300 μg/L + TSAT < 20% or IDTsat: TSAT < 20% | • Persistent IDTSAT is strongly associated with mortality (only for HFrEF) • IDTsat is the superior definition of ID |
Iron deficiency in chronic kidney disease (CKD)
Study | Study population | ID definition / iron status | ID / iron status-associated outcome |
---|---|---|---|
Kaneko et al. (2003) [75] | ID/IDA and HD-CKD*, treated with rhEPO, iv iron | TSAT level < 20% | • Higher CRP > 5 mg/L level; associated with inflammatory process and EPO resistance → iron marker for iron supplementation therapy |
Kalantar-Zadeh et al. (2004) [70] | ID and MHD-CKD, treated with epoetin-alfa, iv iron | Serum iron < 45.3 μg/dL [< 8.1 μmol/L] | • Higher risk of mortality† • Higher risk of hospitalization† |
Pollak et al. (2009) [69] | IDA and HD-CKD, treated with epoetin-alfa, iv iron | Serum ferritin ≤ 100 μg/L + TSAT ≤ 16% | • Worst long-time survival |
Serum ferritin > 600 μg/L + TSAT > 25% | • Best long-time survival | ||
Koo et al. (2014) [72] | IDA and HD-CKD | TSAT ≤ 20% | • Higher risks of composite cardiovascular and all-cause mortality§ |
Gaweda et al. (2014) [74] | IDA and HD-CKD | TSAT 34% | • Max. Hb response |
Hamano et al. (2015) [76] | ID/IDA and HD-CKD* | Serum ferritin > 100 µg/L + TSAT < 20% | • Higher ERIs (ESA resistance index) → iron marker for ESA response |
Eisenga et al. (2018) [73] | ID and ND-CKD | TSAT < 10% | • Higher risk of all-cause mortality • Higher risk of cardiovascular mortality • Higher risk for developing anemia |
Cho et al. (2019) [66] | ID and ND-CKD with/without diabetic issues | Abnormal iron balance: TSAT 0.4–16% or 28–99.6%, serum ferritin 0.4–55 μg/L or 205–4941 μg/L FID: TSAT 0.8–16%, serum ferritin 109–2783 μg/L | • Higher risk of all-cause mortality** |
Awan et al. (2019) [67] | IDA and ND-CKD | AID: serum ferritin < 100 μg/L + TSAT ≤ 20% | • Higher risk of cardiovascular hospitalization |
FID: serum ferritin > 100–500 µg/L + TSAT ≤ 20% | • Higher risk of mortality • Higher risk of cardiovascular hospitalization | ||
Sato et al. (2019) [68] | MHD-CKD* (evaluated iron profiles) | TSAT < 20% | • Higher risk of all-cause mortality# |
Yeh et al. (2019) [71] | HD-CKD with/without PKD (evaluated iron profiles) | TSAT ≤ 20% | • Higher risk of mortality‡ |
Mehta et al. (2021) [65] | ID/iron status in CKD | ID: serum ferritin 4.85–82.48 µg/L + TSAT 1.28–17.24% FID: serum ferritin 157.7–3769.0 µg/L + TSAT 1.28–17.24% Iron-replete: serum ferritin 82.49–284.4 µg/L + TSAT 17.25–28.018% Mixed ID: serum ferritin 82.49–157.6 µg/L + TSAT 1.28–17.24% High iron: serum ferritin 284.4–3769.0 µg/L + TSAT 28.019–87.12% Nonclassified: serum ferritin 4.85–82.48 µg/L + TSAT 17.25–87.12 or serum ferritin 82.49–284.4 µg/L + TSAT 28.019–87.12% or serum ferritin 284.4–3769.0 µg/L + TSAT 17.25–28.018% | • ID independently associated with mortality and heart failure • Mixed ID associated with mortality and ESKD • High iron associated with mortality, heart failure and ESKD • FGF23 mediated the risks of mortality and heart failure conferred by ID |
Guedes et al. (2021) (45) | ID and ND-dependent CKD | AID: serum ferritin < 50 µg/L + TSAT < 20% FID: serum ferritin > 300 µg/L + TSAT < 20% | • Worse physical HRQoL |