Oral Iron and Vitamin C

Introduction

Vitamin C (ascorbic acid) enhances the absorption of non-heme iron from the gastrointestinal tract by reducing ferric (Fe³⁺) to ferrous (Fe²⁺) iron, the form more readily absorbed in the duodenum. This effect is particularly important in individuals with low dietary iron or increased iron needs. While many iron supplements now contain vitamin C or are taken with juice or vitamin C tablets, the clinical impact of this combination on long-term outcomes remains modest. Nonetheless, for patients with iron deficiency, especially those with impaired absorption or on plant-based diets, co-administration of vitamin C with oral iron remains a simple and potentially helpful strategy.

Physiology

• Vitamin C increases iron absorption by chemically transforming iron into a form that is easier to absorb and by preventing it from forming insoluble compounds as it moves through the digestive tract:
  • Reduction of iron: Most dietary iron from plant sources is in the ferric (Fe³⁺) form, which is poorly absorbed by the gut. Vitamin C acts as an electron donor (a reducing agent): it reduces ferric iron (Fe³⁺) to ferrous iron (Fe²⁺), the specific form transported into intestinal cells by the Divalent Metal Transporter-1 (DMT-1).
  • Chelation and solubility: At the low pH of the stomach, vitamin C binds to (chelates) the ferric iron, keeping it soluble. As the pH rises in the duodenum (the first part of the small intestine), this chelate remains soluble, preventing iron from precipitating out as insoluble compounds (like iron phosphates or tannates) that the body cannot absorb. This chelation keeps iron soluble and bioavailable in the alkaline environment of the small intestine.
  • Transport into cells: The enzyme duodenal cytochrome b (Dcytb) on the gut lining uses vitamin C to help transfer electrons to Fe³⁺, making more Fe²⁺ available to be transported into the cells by DMT-1.
  • Overcoming inhibitors: Vitamin C can counteract the effects of common dietary inhibitors like phytates and polyphenols, which otherwise limit nonheme iron absorption.
• Step-by-step summary:
  • Iron enters the stomach, mostly as Fe³+ (ferric), which is not easily absorbed.
  • Vitamin C (ascorbic acid) is present in the diet or supplements.
  • In the acidic stomach environment, vitamin C reduces Fe³⁺ to Fe²⁺ (ferrous) and forms a soluble complex with ferric iron.
  • As iron moves into the more alkaline duodenum, this complex remains soluble and bioavailable.
  • At the surface of enterocytes (gut cells), duodenal cytochrome b (Dcytb) and vitamin C further facilitate the reduction and stabilization of iron.
  • The transport protein DMT-1 moves the Fe²⁺ into the cells for absorption into the bloodstream.
• Vitamin C thus serves a dual role: it is both a chemical reducing agent and a chelator, making dietary iron more absorbable, especially from plant foods.

Primary Studies

• Li et al. 2020
  • Goal: Directly compare adults with iron deficiency anemia (IDA) taking oral iron supplements alone versus those taking oral iron plus vitamin C.
  • Participants: 440 adults with IDA; most were women with anemia due to menstrual bleeding.
  • Interventions: Iron alone vs. iron plus vitamin C, three times daily for 3 months.
  • Outcomes:
    • Hemoglobin recovery was equivalent in both groups at 2, 4, 6, and 8 weeks.
    • Iron stores (ferritin) and other blood parameters showed no significant additional benefit from adding vitamin C.
    • Adverse effects (mostly mild gastrointestinal symptoms) were similar in both groups.
  • Conclusion: Taking vitamin C with oral iron does not improve hemoglobin recovery or iron stores compared to iron alone in people with IDA.
  • Implications:
    • Vitamin C is not necessary for effective treatment of iron deficiency anemia with oral iron supplements.
    • Pairing vitamin C with iron-rich meals may still help vegetarians or those with diets high in iron absorption inhibitors, but routine high-dose vitamin C alongside iron tablets offers no significant benefit for treating iron deficiency anemia.
• Deng et al., 2024
  • Objective: To determine whether adding vitamin C to oral iron improves blood outcomes in people with iron deficiency anemia.
  • What They Did:
    • Systematic review & meta-analysis of 11 studies (10 RCTs, 1 cohort; 1,930 patients).
    • Outcomes: Hemoglobin, ferritin, reticulocyte % change, and side effects.
  • Key Findings:
    • Adding vitamin C to iron caused a small but statistically significant increase in:
      • Hemoglobin (mean difference +0.14 g/dL)
      • Ferritin (+3.23 µg/L)
      • Reticulocyte percentage (+0.22%)
    • However, these increases were small, likely not clinically important.
    • No increase in overall side effects; possible reduction in GI irritation, but data limited.
    • Considerable study heterogeneity (differences in age, severity, formulations, and dosages)
  • Conclusion:
    • Although lab values increased slightly with vitamin C, the effect is so small that it does not support routine addition of vitamin C to oral iron for treatment of IDA.
    • Taking iron alone is enough for almost all patients.
  • Bottom line:
    • Adding vitamin C to oral iron may cause a minor lab improvement, but it’s not clinically meaningful. Most guidelines and this latest evidence suggest vitamin C is not routinely needed with oral iron for iron deficiency anemia.

Iron Absorption: The Psychological Benefit of Vitamin C

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