What are the implications of low iron saturation, also known as Hypoferremia?

From the Guidelines

Low iron saturation is a condition that requires prompt attention to prevent fatigue, weakness, and other complications, and I strongly recommend taking an oral iron supplement such as ferrous sulfate (325 mg) once or twice daily, as supported by the British Society of Gastroenterology guidelines 1. To address low iron saturation, it is essential to understand that iron deficiency can be absolute or functional, and serum ferritin is the most specific test for iron deficiency in the absence of inflammation, with a level of <15 μg/L indicating absent iron stores 1. The treatment of low iron saturation typically involves oral iron supplementation, and ferrous sulfate is a commonly recommended formulation, which should be taken on an empty stomach with vitamin C to enhance absorption, and avoided with calcium, dairy products, coffee, tea, or antacids that can reduce absorption 1. In addition to oral supplements, increasing dietary iron by consuming lean red meat, beans, lentils, spinach, and fortified cereals can help replenish iron stores, and it is crucial to continue treatment for 3-6 months, even after symptoms improve, to ensure that iron stores are fully replenished 1. If oral supplements cause digestive issues, trying a different formulation like ferrous gluconate or taking the supplement with food, despite slightly reduced absorption, may be necessary, and severe cases may require intravenous iron therapy, as recommended by the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines 1. It is also important to note that intravenous iron replacement may be reasonable to improve functional status and quality of life in patients with heart failure and iron deficiency, as suggested by the 2017 ACC/AHA/HFSA focused update of the 2013 ACCF/AHA guideline for the management of heart failure 1. Overall, addressing low iron saturation requires a comprehensive approach that includes oral iron supplementation, dietary changes, and, in some cases, intravenous iron therapy, and it is essential to consult with a healthcare provider to determine the best course of treatment.

From the FDA Drug Label

Transferrin saturation also increased at endpoint of study from baseline in the Venofer-treated population (8.8 ± 1.6%) compared to this historical control population (-5.1 ± 4.3%). Increases from baseline in mean hemoglobin (1. 7 g/dL), hematocrit (5%), serum ferritin (434.6 ng/mL), and serum transferrin saturation (14%) were observed at week 2 of the observation period and these values remained increased at week 4 of the observation period. Patients with PDD-CKD, stable erythropoietin for 8 weeks, hemoglobin of ≤ 11. 5 g/dL, TSAT ≤ 25%, ferritin ≤ 500 ng/mL were randomized to receive either no iron or Venofer (300 mg in 250 mL 0.9% NaCl over 1.5 hours on Day 1 and 15 and 400 mg in 250 mL 0.9% NaCl over 2.5 hours on Day 29).

Low iron saturation is addressed in the studies as patients with low transferrin saturation (TSAT) were included in the studies.

• The studies showed that Venofer treatment increased transferrin saturation in patients with low iron saturation.
• The target TSAT levels are not explicitly stated in the label, but the studies included patients with TSAT ≤ 25% and ≤ 20%.
• Treatment with Venofer resulted in increased TSAT levels, with mean increases ranging from 8.7% to 14% in different studies 2, 2, 2.

From the Research

Low Iron Saturation: Treatment Options

• Low iron saturation can be treated with oral iron supplementation, which is usually the first line of treatment 3, 4.
• Oral iron supplements can be in the form of ferrous salts, such as ferrous sulfate, or ferric complexes with polysaccharides or succinylated milk proteins 3.
• Novel iron formulations, such as lipophilic iron donor ferric maltol or nanoparticle encapsulated sucrosomial iron, have also been developed 3.

Dosage and Frequency of Oral Iron Supplementation

• The optimal dosage and frequency of oral iron supplementation are still being researched, but studies suggest that doses of 60-120 mg of elemental iron per day may be effective 5, 6.
• Giving oral iron doses on alternate days, rather than daily, may help maximize fractional iron absorption and reduce side effects 5.
• Morning doses of iron may be more effective than afternoon or evening doses, due to the circadian increase in plasma hepcidin 5.

Comparison of Oral Iron Supplements

• Different oral iron supplements, such as ferrous sulfate and iron protein succinylate, have been compared in terms of efficacy and tolerability 6.
• Studies have shown that iron protein succinylate may have a better tolerability profile than ferrous sulfate, with minimal iron depositions in the intestinal tissue and no increase in serum hepcidin 6.

Intravenous Iron Therapy

• Intravenous iron therapy may be necessary when oral iron supplementation is contraindicated or ineffective 3, 7.
• Intravenous iron preparations can facilitate rapid iron repletion in one or two doses, and may be indicated for the treatment of iron deficiency in certain clinical contexts, such as chronic inflammatory conditions or perioperative settings 7.