Using Stable Iron Isotopic Techniques and Serum Hepcidin Profiles to Optimize Iron Supplementation

Oral iron supplementation (OIS) is a widely-used strategy to treat iron deficiency anemia. However, absorption of OIS is often low and response is variable. To overcome this, large doses are given but this may reduce compliance due to gastric irritation. Thus, OIS doses should be low, while maximizing absorption. The prevailing serum hepcidin concentration (SHep) is the major determinant of iron absorption and erythrocyte iron utilization. Based on limited data in humans, SHep can be increased by a single OIS dose but the duration of the increase is uncertain: it may be in the range of 24 to 96 hr. Also, there are few data on how the increase in SHep determines the absorption of further doses of oral iron. Is there a threshold SHep at which subsequent iron absorption is sharply reduced? Better understanding of this relationship would be valuable to design more effective and safer OIS regimens.

Objectives: 1) Determine the duration and magnitude of the Fe induced Hepcidin rise form a single iron dose while determining its bioavailability and 2) Compare the bioavailability of a single dose to iron supplements consumed one after the other (two dosages).

Study Overview

• Status: Completed
• Conditions: Anemia; Iron Deficiency Anemia; Iron Deficiency
• Intervention / Treatment: Dietary supplement: Iron Supplement (Ferrous Sulfate Dried)

Detailed Description

Background: Oral iron supplementation (OIS) is a widely-used strategy to treat iron deficiency anemia. However, absorption of OIS is often low and response is variable. To overcome this, large doses are given but this may reduce compliance due to gastric irritation. Thus, OIS doses should be low, while maximizing absorption. The prevailing serum hepcidin concentration (SHep) is the major determinant of iron absorption and erythrocyte iron utilization. Based on limited data in humans, SHep can be increased by a single OIS dose but the duration of the increase is uncertain: it may be in the range of 24 to 96 hr. Also, there are few data on how the increase in SHep determines the absorption of further doses of oral iron. Is there a threshold SHep at which subsequent iron absorption is sharply reduced? Better understanding of this relationship would be valuable to design more effective and safer OIS regimens.

Objectives: 1) Determine the duration and magnitude of the Fe induced Hepcidin rise form a single iron dose while determining its bioavailability and 2) Compare the bioavailability of a single dose to iron supplements consumed one after the other (two dosages). Methods/Subjects: Healthy female subjects will be screened for low iron status. Anemic subjects will be excluded from the study. Thirty two subjects will be included with serum ferritin <20 µg/L, C-reactive protein <5 mg/L and Hemoglobin >117 g/L. Subjects will be randomized in two groups and their Hepcidin (sHep) and iron status markers monitored at day 1 (baseline). Subjects will receive iron supplement dosages of 40, 80, 160 and 240 mg in either single or as two consecutive dosages with stable iron isotopes 54Fe, 57Fe, 58Fe in form of 4 mg of iron sulfate (FeSO4). Prior administration blood samples will be collected at 8:00, 12:00 and 16:00 to monitor sHep and iron status markers, these measurements will be repeated on the days of supplement administration. On the following days, sHep will be measured at 8:00 to quantify the duration of the iron induced hepcidin rise. In the second week, subjects receiving a single Fe dose on week 1 will receive two consecutive dosages and vice versa, while the same sampling scheme as in week one will be applied. On day 23, a last blood sample will be collected and iron incorporation of stable isotopic labels will be measured from the different dosages administered.

Outcome: The combined use of stable iron isotopes and a sensitive SHep assay will allow for better understanding of the iron-hepcidin relationship and this may enable design of more effective OIS regimens.

• Study Type: Interventional
• Enrollment (Actual): 25
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Switzerland
  • Zürich, Switzerland, 8092
    • Laboratory of Human Nutrition

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• BMI 17-25
• No anemia
• Low iron stores defined as Serum Ferritin < 20 micrograms/L
• No blood donation in in the last 4 months
• No intake of vitamin and mineral supplements 2 weeks prior and during the study

Exclusion Criteria:

• Chronic, metabolic, gastrointestinal diseases
• Taking medication
• Participation to clinical trials in the last 30 days.
• Previous participation to iron bio availability studies with stable isotopic labels.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: PREVENTION
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: SINGLE

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: 80 mg FeSO4	Dietary supplement: Iron Supplement (Ferrous Sulfate Dried); Iron supplements of varying concentration will be administered to the four groups in the study. Iron bioavailability from the supplements will be assessed.; Other Names: Ferrous Sulfate (dried)
ACTIVE_COMPARATOR: 40 mg FeSO4	Dietary supplement: Iron Supplement (Ferrous Sulfate Dried); Iron supplements of varying concentration will be administered to the four groups in the study. Iron bioavailability from the supplements will be assessed.; Other Names: Ferrous Sulfate (dried)
ACTIVE_COMPARATOR: 160 mg FeSO4	Dietary supplement: Iron Supplement (Ferrous Sulfate Dried); Iron supplements of varying concentration will be administered to the four groups in the study. Iron bioavailability from the supplements will be assessed.; Other Names: Ferrous Sulfate (dried)
ACTIVE_COMPARATOR: 240 mg FeSO4	Dietary supplement: Iron Supplement (Ferrous Sulfate Dried); Iron supplements of varying concentration will be administered to the four groups in the study. Iron bioavailability from the supplements will be assessed.; Other Names: Ferrous Sulfate (dried)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Iron bio-availability from Oral Iron Supplements (%)	Iron bioavailability will be assessed with stable isotopic labels. The shift in the isotopic ratio in human whole blood 14 days after administration will be measured with Inductively coupled plasma mass spectrometry (ICP-MS).	three weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Hepcidin	Serum Hepcidin levels will be measured in participating subjects in concomitance with iron bioavailability.	three weeks

Collaborators and Investigators

• Sponsor: Swiss Federal Institute of Technology
• Collaborators: University Hospital, Zürich; ETH Zurich

Publications and helpful links

General Publications

• Zimmermann MB, Hurrell RF. Nutritional iron deficiency. Lancet. 2007 Aug 11;370(9586):511-20. doi: 10.1016/S0140-6736(07)61235-5.
• Moretti D, Goede JS, Zeder C, Jiskra M, Chatzinakou V, Tjalsma H, Melse-Boonstra A, Brittenham G, Swinkels DW, Zimmermann MB. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015 Oct 22;126(17):1981-9. doi: 10.1182/blood-2015-05-642223. Epub 2015 Aug 19.

Study record dates

Study Major Dates

• Study Start: February 1, 2013
• Primary Completion (ACTUAL): June 1, 2013
• Study Completion (ACTUAL): June 1, 2013

Study Registration Dates

• First Submitted: February 1, 2013
• First Submitted That Met QC Criteria: February 6, 2013
• First Posted (ESTIMATE): February 7, 2013

Study Record Updates

• Last Update Posted (ESTIMATE): November 11, 2013
• Last Update Submitted That Met QC Criteria: November 8, 2013
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: Hepcidin; Iron absorption; Iron bio availability
• Additional Relevant MeSH Terms: Metabolic Diseases; Hematologic Diseases; Anemia, Hypochromic; Iron Metabolism Disorders; Anemia, Iron-Deficiency; Anemia
• Other Study ID Numbers: EK 2012-N-44