Tom Wade MD

Today, I review, link to and excerpt from CoreIM‘s Iron Deficiency Treatment: 5 Pearls Segment.

All that follows is from the above resource.

Posted: March 27, 2024
By: Dr. Maria J. Fernandez Turizo, Dr. Nick Villano, Dr. Michael Auerbach, Dr. Jason A. Freed and Dr. Shreya P. Trivedi
Graphic: Dr. Dexter Nwachukwu
Audio: Daksh Bhatia
Peer Review: Dr. Jonathan Berry, Dr. Layla Van Doreen

Iron Deficiency Treatment: 5 Pearls Segment

Podcast: Play in new window | Download

Time Stamps Behind The Scenes YouTube Interview CME-MOC Show Notes Transcript References

Time Stamps

• 02:09 Pearl 1: Spaced repetition from the last Core IM Gray Matters Episode
• 05:29 Pearl 2: Choosing between oral and IV iron
• 11:17 Pearl 3: Considerations with oral iron repletion
• 24:02 Pearl 4: Considerations with IV iron repletion
• 32:36 Pearl 5: Complications and side effects of IV iron

Behind The Scenes YouTube Interview

Subscribe to Core IM’s YouTube Channel for more behind the scenes, whiteboard animations and more!

Treatment of Iron Deficiency

IV Iron Infusion Reactions

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Show Notes

Pearl 1: Spaced repetition from our Gray Matters Episode. 

Iron deficiency diagnosis and workup

• Iron deficiency diagnosis
  • The absence of iron stores in the bone marrow remains the gold standard for diagnosis; however, its high invasiveness renders it less favorable.
  • Iron deficiency  (ID) is the most common cause of microcytic anemia but can also present with normocytic anemia.
  • Ferritin is the most cost-effective, practical, and non-invasive marker.
  • Low serum ferritin levels are the hallmark of absolute ID.
    • As a rule of thumb, a ferritin cut-off <50 can be used to diagnose ID in a patient without inflammation.
• Iron deficiency in chronic inflammatory disorders
  • Patients with chronic inflammation have elevated cytokines and acute-phase reactants.
    • As hepcidin levels rise, ferroportin degradation occurs in duodenal enterocytes.
    • Iron remains trapped within enterocytes and is also sequestered in macrophages.
  • A decrease in circulating iron leads to a lower saturation of the iron carrier protein, transferrin.
  • Thus, a low transferrin saturation (TSAT) (TSAT = (Serum Fe/TIBC) × 100) can aid with the diagnosis of ID in chronic inflammatory disorders.
  • Instead of using established diagnostic cut-offs for ID, cut-off parameters for ferritin and TSAT should be individualized for every patient, considering underlying inflammatory disorders and comorbidities.
    • TSAT <20% and ferritin 100-300 in inflammatory conditions (but this is largely from HF, CHF, CKD population)In a therapeutic trial of iron, a rise in hemoglobin > 1 g/dl over 2-4 weeks is highly sensitive for absolute ID.
  • A time-limited therapeutic trial of iron can help interpret diagnostic cut-offs in patients with active inflammation.
  • In a therapeutic trial of iron, a rise in hemoglobin > 1 g/dl over 2-4 weeks is highly sensitive for absolute ID.

Pearl 2: Oral vs IV iron repletion

• Oral iron therapy is recommended for:
  • Patients who can tolerate oral iron
  • Patients without active bleeding
  • No evidence of severe symptomatic anemia
  • Patients without absorption disorders that are known to be unresponsive to oral iron
  • Patients who do not have chronic inflammatory disorders.
• IV iron therapy is recommended for:
  • Patients who were unable to tolerate oral iron despite adequate management of side effects
  • Patients with active bleeding or blood losses
  • Patients with severe symptomatic anemia
  • Patients with limited ability to absorb oral iron
  • Patients with chronic comorbidities, such as CKD and heart failure, and rheumatologic disorders, among others.
  • Conditions in which the administration of oral iron may be potentially harmful such as IBD.
  • 2nd and 3rd trimester of pregnancy

Pearl 3: Considerations with oral iron repletion

• Oral Iron Formulations
  • In terms of efficacy, all compounds are essentially equivalent.
  • The most important component of a formulation is the amount of elemental iron.
    • Be aware of formulations that claim to have fewer side effects. They often have a lower amount of elemental iron and may not be as effective.
  • Common formulations include
    • Ferrous sulfate (65 mg  elemental iron per tablet-325 mg)
    • Ferrous gluconate (37.5 mg  elemental iron per tablet-325 mg)
    • Ferrous fumarate (106 mg elemental iron per tablet-325 mg).
  • Choose an affordable formulation.
• Frequency: Is once a day best or every other day?
  • The most quoted study was a study of two prospective, open-label, RCT assessing iron absorption. It included pre-menopausal iron-depleted women (ferritin <25 μg/L) who received consecutive vs. alternate-day iron dosing.
    • Higher cumulative fractional iron absorption in the alternate-day group (21.8% vs. 16.3%).
    • Higher cumulative total iron absorption in the alternate-day group (175.3 mg vs. 131.0 mg).
    • Lower serum hepcidin in alternate-day group
  • Criticism of the study:
    • May not be generalized to patients with anemia since most women had iron deficiency without anemia
    • Outcomes were assessed at day 14 for the consecutive-day group and day 28 for the alternate-day group.
      • It would helpful to know iron markers if study design had been set up such that consecutive group received daily iron for 28 days and checked labs on day 28, similar to the alternate-day group
• A more recent study found that administering iron 3 times per week was non-inferior to 3 times per day.
  • Criticisms of the study:
    • Small study
    • While it was non-inferior, after four weeks, patients who received iron 3 times per day exhibited an about average hemoglobin level that was 1g/dl higher than those in the 3 times per week group (10.8 vs. 9.9 g/dL, respectively, p = 0.040).
• Takeaway: Frequency can be individualized the patient depending on how you rapidly you want iron depletion to improve (with more frequent iron) vs. potential iron side effect
• Prescription and Absorption
  • For better absorption, iron should be ingested
    • at least 30 minutes before a meal
    • 1 to 2 hours before taking additional medications.
    • Avoid taking iron with milk, calcium, caffeine, anti-acids, and tea.
      • Tailor patient instructions. Too many instructions may lead some patients to forget to take their iron altogether.
  • Oral iron therapy should be continued for 6-12 months to replenish iron stores.
• Effect of Vitamin C and Orange Juice on Oral Iron Absorption
  • A study evaluating the effect of Vitamin C supplementation, in 1994 on 25 women who were not anemic but had iron deficiency anemia, found a slightly increased serum ferritin in patients who received vitamin C supplementation.
  • In 2020, a JAMA RCT that included 440 adults with iron deficiency anemia showed no difference in the mean change in hemoglobin level after 2 weeks, for patients using oral iron supplementation alone versus a vitamin C-supplemented oral iron regimen.
  • Orange juice is often enriched with calcium, which can compete with iron absorption.
• Post-treatment Labs
  • Post-treatment labs can be checked 6 months after initiating treatment.
  • Post-treatment target levels depend on how anemic the patient was to begin with but in general, we should target:
    • Ferritin levels above 30-50 
    •  TSAT levels above 20.

Pearl 4: Considerations with IV iron repletion

• IV iron Formulations: # of Infusion Sitting to get 1g of iron
  • 1 infusion sitting:
    • Low-molecular-weight iron dextran
    • Ferumoxytol (feraheme)
      • can be 1-2 visits
    • Iron desiromaltose (monoferic)
  • 2 infusion sittings:
    • Ferric carboxymaltose comes in 2 different  presentations
  • 5 or more infusion sittings:
    • Ferrous gluconate and Iron sucrose
• Formulations are similar in efficacy.
• The side effect profile appears to be similar for all formulations, but further head-to-head comparisons are needed.
• However, there is a higher incidence of hypophosphatemia, one of the features of the 6H syndrome, with ferric carboxymaltose.
  • 6H syndrome develops 1-2 weeks after infusion: Characterized by high FGF-23 levels, Hyperphosphaturia, Hypophosphatemia, Hypovitaminosis D, Hypocalcemia, and secondary Hyperparathyroidism
  • Ferric carboxymaltose induces FGF23 to increase, which leads to renal phosphate wasting, calcitriol deficiency, and secondary hyperparathyroidism.
  • Complications from the 6H syndrome include osteomalacia, bone fractures, muscle weakness, and respiratory failure.
• Dose calculation
  • The optimal IV iron dose can be estimated or calculated using the Ganzoni formula. 
  • A practical approach is using 1 gram of iron without calculating the dose.
  • However, the Ganzoni formula is available online, easy to use, and can be helpful to avoid underdosing patients.
• Post-treatment Laboratories:
  • Post-treatment labs should be checked 6 weeks after infusion.
  • Checking before 6 weeks can be associated with falsely high levels of ferritin.
    • Repeat doses are indicated if the ferritin level is not above 30-50 and TSAT above 20%.
  • During pregnancy, iron parameters should be checked every trimester and repeat doses should be given if patients remain iron deficient.

Pearl 5: Complications and side effects of IV iron

• IV iron is a safe treatment option.
• Severe reactions with IV iron are rare after the withdrawal of high-molecular-weight-dextran from the market.
  • Anaphylaxis in particular is estimated to occur in less than 1 per 250,000 administrations
• Inpatient treatment considerations.
  • Recent evidence has demonstrated IV iron is safe and does not confer a higher risk of infections. It can be administered in patients with mild infections that are resolving.
  • Avoid IV iron in patients with active bacteremia. 
• Fishbane reactions are minor and self-limited infusion reactions.
  • Described by Dr. Fishbane, a nephrologist.
  • Occurs in approximately 1 in 100 patients.
  • Characterized by flushing, arthralgias, myalgias, back and chest pain
  • Absence of anaphylactic symptoms.
    • Fishbane is not an allergic reaction. Not IgE mediated. The mechanism is suspected to be related to labile iron.
    • No increase in serum tryptase
  • Symptoms recover spontaneously and quickly after stopping the infusion
    • Infusion should be restarted at a slower rate.
    • Symptoms do not recur after restarting the infusion at a slower rate.
  • Do NOT administer EPINEPHRINE OR ANTIHISTAMINES (BENADRYL) as there is a high risk for circulatory collapse.