Iron Replacement: The Promise and Peril of Current Options

Educational Objectives

The goal of this program is to improve administration of iron replacement therapy. After hearing and assimilating this program, the clinicians will be able to:

1. Differentiate between absolute and functional iron deficiency.
2. Analyze the risks and benefits associated with use of different oral and intravenous iron formulations.

Summary

Iron absorption: oral Fe²⁺ (ferrous iron) is converted to Fe³⁺ (ferric iron) by gastric acid; N,N-Dimethyltryptamine-1 and associated intestinal coenzymes then convert Fe³⁺ into Fe²⁺, which enters the basolateral membrane and blood; Fe³⁺ does not require gastric acid (or an empty stomach) for absorption, causes less dyspepsia, and is compatible with chronic proton-pump inhibitor therapy

Oral Fe³⁺ supplementation: ferric citrate — a phosphate binder; good for patients with chronic kidney disease (CKD) or end-stage renal disease (ESRD) not currently receiving intravenous (IV) iron therapy; ferric maltol — approved by the United States Food and Drug Administration (FDA); available by prescription as 30 mg twice daily; sucrosomial iron (SI) — Fe³⁺ bound to sugar moieties; available over-the-counter; administered once daily

Hepcidin: regulates release of Fe to red blood cells (RBCs) through ferroportins on duodenal enterocytes, hepatocytes, and macrophages; levels increase following administration of a bolus of iron, in the presence of inflammatory cytokines, or in patients with iron-refractory iron deficiency anemia (IRIDA; hepcidin cannot be downregulated, due to a genetic defect in matriptase-2, impairing regulation of Fe; suspected in families of patients who are nonresponsive to oral Fe supplementation; caused by a defect in matriptase-2); hepcidin levels decline in patients with IDA, thalassemia, or sideroblastic anemia

Iron-restricted erythropoiesis

Presentation: absolute iron deficiency (AID) — characterized by reduced or absent Fe stores; seen in patients with pregnancy, gastrointestinal (GI) bleeding, gastric bypass, celiac sprue, menorrhagia, or intravascular hemolysis (typically seen in patients who develop a paravalvular leak in a prosthetic heart valve); functional iron deficiency (FID) — inability to mobilize Fe stores; occurs secondary to inflammation; notable in patients taking erythropoiesis-stimulating agents (ESAs)

Diagnosis and treatment: AID — diagnosed if ferritin <30 μg/L with normal renal function and without inflammation, ferritin <50 μg/L in the presence of microcytic anemia in a patient >65 yr old (trial oral Fe supplementation), ferritin <50 μg/L during pregnancy, or ferritin <100 μg/L and transferrin saturation (TSAT) <20% in a patient with CKD (treat with epoietin alfa); patients receiving dialysis are usually not treated for AID, as they generally receive IV Fe³⁺ supplementation; FID — ideally, ferritin levels should remain ≤700 μg/L (to avoid accumulation); diagnosed if ferritin >200 μg/L and TSAT <20% in a patient with CKD receiving dialysis or ferritin >100 μg/L and TSAT <20% in a patient with CKD not receiving dialysis; ferritin >100 μg/L and TSAT <20% may also indicate presence of anemia of inflammation (trial ESA plus Fe supplementation); concurrent AID and IDA — usually indicated by ferritin >100 μg/L, TSAT <20%, and normal total iron-binding capacity

Oral iron supplementation

Dosing: Moretti et al (2015) demonstrate that oral iron absorption is blocked with administration of a second pill within 24 hr of the initial dose; once-daily dosing is ideal, as bioavailability decreases with additional doses (which also increase adverse GI effects); Stoffel et al (2017) showed best absorption and least toxicity with alternate-day dosing, compared with daily dosing

Assessment of response: meta-analysis by Okam et al (2016) showed that most women with postpartum anemia have a 2g/dL increase in serum hemoglobin (Hb) levels by day 56 of oral Fe²⁺ therapy; with proper absorption, serum Hb levels should increase 1 hr following administration of oral Fe²⁺ to a fasting patient and by ≈1 g/dL by day 14 of therapy; oral Fe²⁺ is less effective in patients with continued bleeding, compared with IV Fe³⁺; TSAT, ferritin level, and reticulocyte counts at day 14 are not predictive of response; per Okam et al (2016), switch to IV Fe³⁺ therapy if no response seen after 14 days of oral Fe²⁺ therapy

IV iron supplementation

Indications: include intolerance or nonresponse to oral iron, continued significant blood loss (especially with inflammatory bowel disease), in combination with ESAs in the presence of CKD (with or without dialysis), perioperative administration with ESAs in patients who identify as a Jehovah’s Witness, or in patients with congestive heart failure or pulmonary hypertension

Preparations: iron dextran — previously associated with hypersensitivity (ie, fatal anaphylaxis); the current formulation contains a greater proportion of chains of low molecular weight and significantly reduces the risk for anaphylaxis to ≈1%; ≤2,000 mg can be administered, though over a long, slow period to monitor for anaphylaxis (possible at the time of administration, rather than days later); iron gluconate — 250 mg is infused over 1 hr; approved for any patients, though return to clinic is necessary; associated with release of free iron ions; iron sucrose — effective, though multiple doses are needed; ferumoxytol — 510 mg dose approved by the FDA; iron carboxymaltose — can be administered as one 1,000 mg injection or as two 750 mg injections separated by one week; each infusion takes 15 min

Hypophosphatemia (ie, 6H syndrome): a severe side effect which can occur with any form of iron supplementation, especially with ferric carboxymaltose; can last ≤6 mo in ≈5% of patients; weekly IV phosphorus infusions are necessary for resolution; symptoms include fatigue, nausea, and bone pain; severe profound hypophosphatemia can lead to diaphragmatic paralysis; risk for development increased in patients with IDA (who have elevated levels of fibroblast growth factor-23 [FGF-23]), baseline vitamin D deficiency or hypophosphatemia (notable in patients taking cyclosporine), or African-American ethnicity; not seen in patients with CKD or ESRD (who have lower levels of FGF-23)

Daprodustat: an oral hypoxia-inducible factor prolyl hydroxylase enzyme inhibitor which recently received FDA approval for treatment of anemia of CKD; permits natural secretion of erythropoietin by the kidney; an alternative to injectable ESAs; Singh et al (2022) showed noninferiority of daprodustat vs darbopoietin alfa for treatment of patients with anemia of CKD; like other ESAs, daprodustat carries a black box warning for increased cardiovascular events, in addition to potential for promotion of cancer progression (because many tumors have surface erythropoietin receptors)

Readings

Auerbach M, Adamson J. How we diagnose and treat iron deficiency anemia. Am J Hematol. 2016;91(1):31-38. doi:10.1002/ajh.24201. View article; Bhandari S. Iron therapy in patients with chronic kidney disease. Transfus Altern Transfus Med. 2012;12:115-121. doi:10.1111/j.1778-428X.2012.01156.x. View article; DeLoughery TG. Safety of oral and intravenous iron. Acta Haematol. 2019;142:8-12. doi:10.1159/000496966. View article; Fishbane S, Kowalski EA. The comparative safety of intravenous iron dextran, iron saccharate, and sodium ferric gluconate. Semin Dial. 2000;13:381-384. doi:10.1046/j.1525-139x.2000.00104.x. View article; Jefferds ME, Mei Z, Addo Y, et al. Iron deficiency in the United States: limitations in guidelines, data, and monitoring of disparities. Am J Public Health. 2022;112:S826-35. doi:10.2105/AJPH.2022.306998. View article; Moretti D. Novel approaches to oral iron treatment. HemaSphere. 2019;3:109-111. Doi:10.1097/HS9.0000000000000235. View article; Singh AK, Cizman B, Carroll K, et al. Efficacy and safety of daprodustat for treatment of anemia of chronic kidney disease in incident dialysis patients: a randomized clinical trial. JAMA Intern Med. 2022;182(6):592-602. Doi:10.1001/jamainternmed.2022.0605. View article; Snook J, Bhala N, Beales ILP, et al. British Society of Gastroenterology guidelines for the management of iron deficiency anaemia in adults. Gut. 2021;70(11):2030-2051. Doi:10.1136/gutjnl-2021-325210. View article; Zoller H, Schaefer B, Glodny B. Iron-induced hypophosphatemia: an emerging complication. Curr Opin Nephrol Hyperten. 2017;26:266-275. doi:10.1097/MNH.0000000000000329. View article.

Disclosures

For this program, members of the faculty and planning committee reported nothing relevant to disclose.

Acknowledgements

Dr. O’Connell was recorded at 50th Annual USC Internal Medicine for PCPs and Subspecialists, held April 17-20, 2023, on Maui, HI, and presented by Keck School of Medicine of the University of Southern California. For more information about upcoming CME activities from this presenter, please visit https://www.keck.usc.edu/cme. Audio Digest thanks the speakers and presenters for their cooperation in the production of this program.

CME/CE INFO

Accreditation:

The Audio- Digest Foundation is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Audio- Digest Foundation designates this enduring material for a maximum of 1.00 AMA PRA Category 1 Credits™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Audio Digest Foundation is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center's (ANCC's) Commission on Accreditation. Audio Digest Foundation designates this activity for 1.00 CE contact hours.

Lecture ID:

FP712802

Expiration:

This CME course qualifies for AMA PRA Category 1 Credits™ for 3 years from the date of publication.

Instructions:

To earn CME/CE credit for this course, you must complete all the following components in the order recommended: (1) Review introductory course content, including Educational Objectives and Faculty/Planner Disclosures; (2) Listen to the audio program and review accompanying learning materials; (3) Complete posttest (only after completing Step 2) and earn a passing score of at least 80%. Taking the course Pretest and completing the Evaluation Survey are strongly recommended (but not mandatory) components of completing this CME/CE course.

Estimated time to complete this CME/CE course:

Approximately 2x the length of the recorded lecture to account for time spent studying accompanying learning materials and completing tests.