Replacement Therapy in Nutritional Deficiency Anemias: A Practical Approach

Educational Objectives

The goal of this program is to improve management of various nutritional deficiency anemias. After hearing and assimilating this program, the clinician will be better able to:

1. Select appropriate replacement therapy for iron deficiency.
2. Administer appropriate dosing regimens for treatment of vitamin B₁₂ deficiency.

Summary

Iron Deficiency

Iron deficit: the Ganzoni equation [total iron (mg) = weight (kg) x (desired hemoglobin – observed hemoglobin) x 2.4 + 500] can be used to calculate a patient’s iron deficit

Oral iron therapy: most products are available over the counter; ferrous sulfate, ferrous fumarate, and ferrous gluconate have very high bioavailability (BA); carbonyl irons and iron sugars have variable BA and are not as effective at repletion of iron stores; products have variable elemental iron content (20–30% BA of elemental iron); often causes gastrointestinal distress and constipation; the best BA is achieved on an empty stomach ≥1 hr before meals; whole grains inhibit iron absorption; ascorbic acid (contained in, eg, orange juice) has a dose-dependent effect on enhancement of iron absorption; chewable vitamin C tablets (500 mg) can be taken with oral iron to improve absorption; taking iron with a meal rich in ascorbic acid can prevent gastrointestinal issues

Pathophysiology: ferric iron undergoes conversion into ferrous iron to be absorbed in the gut; can be stored as ferritin or transported across the basolateral membrane by ferroportin; increased absorption of ferrous iron leads to increases in hepcidin levels and downregulates ferroportin availability to stop further absorption; Moretti et al (2015) found that twice-daily iron intake leads to a higher hepcidin level, causing quick downregulation of iron absorption; once-daily or alternate-day oral iron administration attenuates the increase in hepcidin level and provides more stable iron absorption

Recommendations: in 2016, the World Health Organization recommended iron supplementation in menstruating women and adolescent girls; 30 to 60 mg elemental iron daily for 3 consecutive months each year is recommended

Intravenous (IV) iron therapies: increasingly being prescribed for patients who cannot tolerate or absorb oral iron therapy (due to, eg, gastric bypass surgery); iron dextran (InFeD) — contains 50 mg/mL of elemental iron (≤2500 mg can be administered in a single dose); particularly useful for patients with severe iron deficiency (ID); the actual dose takes 2 to 3 hr to administer; iron sucrose (Venofer) — contains 20 mg/mL of elemental iron; administered as a 200 mg dose over 15 min (weekly) or a 500 mg dose over 2 to 3 hr (usually every other week); ferumoxytol (Feraheme) — contains 30 mg/mL of elemental iron; 500 mg can be administered in one dose and repeated in 3 days; ferric carboxymaltose — contains 50 mg/mL of elemental iron; 750 mg can be administered in a single dose; sodium ferric gluconate complex in sucrose (Ferrlecit) — contains the lowest concentration of elemental iron; a single dose is limited to 200 mg

ID in heart failure: iron replacement is considered reasonable to improve functional status and quality of life (QOL) for patients with heart failure with reduced ejection fraction and ID (with or without anemia); indications for iron supplementation are serum ferritin <100 ng/mL, or 100 to 300 ng/mL with transferrin saturation <20%; studies have shown IV iron improves exercise capacity, QOL, 5-min walking test, and New York Heart Association classification; two meta-analyses have suggested reductions in cardiovascular-related hospitalizations and deaths following IV iron therapy; 2022 guidelines recommend against the administration of erythropoietin-stimulating agents to patients with heart failure to improve morbidity and mortality; Swedberg et al (2013) demonstrated no benefit to patients with heart failure following supplementation with darbepoietin alfa, which caused increased risks for thrombosis and stroke

Vitamin B₁₂ Deficiency

Diagnosis: complete blood count shows pancytopenia with macrocytosis and reticulocytopenia, plus low hemoglobin levels; elevated methylmalonic acid can help confirm the diagnosis of vitamin B₁₂ deficiency in patients with reported vitamin B₁₂ level between 180 and 300 pg/mL

Treatment: prior to administering the first vitamin B₁₂ injection, check for antiparietal cell and anti-intrinsic factor antibodies to assess for pernicious anemia; parenteral replacement with 1000 mcg biweekly for 6 wk, then 1000 mg once a month is recommended; data show people with vitamin B₁₂ deficiency can absorb enough vitamin B₁₂, because vitamin B₁₂ stores usually last for years and are slowly depleted over time; Nyholm et al (2003) found that oral B₁₂ therapy can successfully replete patients with B₁₂ levels in the lower 25^th percentile previously receiving parenteral therapy; data suggest that oral replacement can achieve high serum levels of vitamin B₁₂, making it possible to achieve sufficient levels to obviate the need for parenteral supplementation; administer 1000 mcg oral vitamin B₁₂ daily to patients previously receiving parenteral replacement, and monitor for sufficient repletion

Copper Deficiency

Clinical manifestations: mimic vitamin B₁₂ deficiency; hematologic manifestations include macrocytic anemia and leukopenia, though thrombocytopenia is less severe vs vitamin B₁₂ deficiency; neurologic manifestations include gait disturbances, posterior column signs, spasticity, and sensory ataxia; cutaneous manifestations include alopecia, hair pigment issues, and wound healing issues

Etiology: gastric bypass is a classic cause; can be seen with high-dose zinc supplementation and long-term total parenteral nutrition; infections with Cryptosporidium spp. and Giardia spp. may cause copper deficiency

Treatment: start with 2 to 4 mg of IV copper chloride (slowly administered over 3-4 hr) weekly for 4 to 6 wk; start 2 mg oral copper (copper gluconate, copper sulfate, or copper chloride) daily; hematologic manifestations will resolve in 4 to 6 wk; neurologic symptoms may take 6 mo to resolve, and patients may have some residual effects

Readings

Carmel R. Subclinical cobalamin deficiency. Curr Opin Gastroenterol. 2012;28(2):151–158. doi:10.1097/MOG.0B013E3283505852. View article; Das SN, Devi A, Mohanta BB, et al. Oral versus intravenous iron therapy in iron deficiency anemia: an observational study. J Family Med Prim Care. 2020;9(7):3619–3622. View article; Devalia V, Hamilton MS, Molloy AM. Guidelines for the diagnosis and treatment of cobalamin and folate disorders. Br J Haematol. 2014;166(4):496–513. doi:10.1111/BJH.12959. View article; Gletsu-Miller N, Broderius M, Frediani JK, et al. Incidence and prevalence of copper deficiency following roux-en-y gastric bypass surgery. Int J Obes (Lond). 2012;36(3):328–335. doi:10.1038/IJO.2011.159. View article; Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2022;145(18):e895-e1032. doi:10.1161/CIR.0000000000001063. Erratum in: Circulation. 2022 May 3;145(18):e1033. Erratum in: Circulation. 2022 Sep 27;146(13):e185. Erratum in: Circulation. 2023 Apr 4;147(14):e674. View article; Marumo A, Yamamura T, Mizuki T, et al. Copper deficiency-induced pancytopenia after taking an excessive amount of zinc formulation during maintenance hemodialysis. J Res Med Sci. 2021;26(1):42. doi:10.4103/JRMS.JRMS_25_19. View article; Nyholm E, Turpin P, Swain D, et al. Oral vitamin B12 can change our practice. Postgrad Med J. 2003;79(930):218-20. doi:10.1136/pmj.79.930.218. View article; Swedberg K, Young JB, Anand IS, et al. Treatment of anemia with darbepoetin alfa in systolic heart failure. N Engl J Med. 2013;368(13):1210-9. doi:10.1056/NEJMoa1214865. View article.

Disclosures

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

Acknowledgements

Dr. Liles was recorded at the 35th Annual Recent Developments in Internal Medicine, held August 24-26, 2023, in Atlantic Beach, NC, and presented by the Brody School of Medicine at East Carolina University, in association with the Eastern Area Health Education Center. For information on future CME activities from this presenter, please visit https://cme.ecu.edu. 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 0.75 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 0.75 CE contact hours.

Lecture ID:

FP714502

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.