Iron Deficiency Treatment: 5 Pearls Segment

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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)

• • 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 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.

• Prescription and Absorption
  • Prescribe it initially once daily with an adequate bowel regimen.
    • If the patient has GI side effects, try iron every other day.
  • 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 all together.
  • 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 (faraheme)
    • 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 developes 1-2 weeks after infusion: Characterized by high FGF-23 levels, Hyperphosphaturia, Hypophospahtemia, 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.

Contributors

Shreya Trivedi, MD, ACP Member – Author
Nicholas Villano, MD – Host, Editor
Maria Fernandez, MD - Host/Editor
Jason Freed, MD – Guest Expert
Michael Auerbach, MD, FACP – Guest Expert*

Reviewers

Layla Van Doren, MD, MBA*
Jonathan Berry, MD

Layla Van Doren, MD, MBA
Consultant: Pharmacosmos Therapeutics, Inc., Sanofi and Genzyme US Companies
Other: Daiichi Sankyo, Inc, Global Blood Therapeutics, Inc., Pharmacosmos Therapeutics, Inc., Sobi, Inc

Michael Auerbach, MD, FACP
Grant/ Contract: Covis Pharma GmbH
Other: Pharmacosmos Therapeutics, Inc

Those named above, unless otherwise indicated, have no relevant financial relationships to disclose with ineligible companies whose primary business is producing, marketing, selling, re-selling, or distributing healthcare products used by or on patients.  All relevant relationships have been mitigated.

Release Date: March 27, 2024

Expiration Date: March 26, 2027

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