Iron Absorption and Utilization During Tuberculosis and After Treatment

The Effects of Tuberculosis on Dietary Iron Absorption and Systemic Iron Utilization: a Double Stable Isotope Study in Bagamoyo, Tanzania

Background: The disease burden of tuberculosis (TB), second only to HIV/AIDS among infectious diseases, is a major public health problem in developing countries. Accumulating evidence suggests that iron status is a primary determinant of TB progression. Anaemia is prevalent in patients with TB, particularly in sub-Saharan Africa, and associated with increased mortality. Anaemia in TB may be due to inflammation, dietary iron deficiency, or both, and distinguishing among these aetiologies is difficult. Iron supplementation is commonly used to treat anaemia in TB patients, but may be unnecessary if inflammation is the cause. Body iron sequestered by TB inflammation can be mobilized during treatment and used to correct the anaemia. Moreover, supplemental iron may be retained within macrophages, potentially increasing susceptibility to TB and leading to a poorer clinical outcome. Thus, better understanding of iron metabolism during TB and the aetiology of TB-related anaemia would clarify the potential role of iron in pathogenesis and optimal management of the disease.

The investigators hypothesize that: a) TB will increase circulating hepcidin and thereby impair dietary iron absorption and systemic utilization of iron, resulting in iron sequestration and anaemia; b) TB treatment and resolution of inflammation over 6 months will decrease circulating hepcidin, correcting these impairments and improving iron status and hemoglobin; c) the majority of iron utilized to replenish hemoglobin during recovery from TB will come from mobilization of sequestered iron stores rather than from iron absorption.

Objectives: Use iron stable isotopes to characterize iron balance over six months of TB treatment, and specifically to: a) quantify oral and intravenous iron incorporation (oral absorption and systemic iron utilization) at three time points during TB treatment (acute disease, after the intensive treatment phase and at completion of the continuation treatment phase); and b) determine the effect of treatment on iron mobilization from stores to replenish hemoglobin.

Methods/Subjects: Using a triple stable-isotope technique, iron absorption from labelled test meals (57Fe) and systemic iron utilization after labelled intravenous doses (54Fe, 58Fe) will be determined in 18 Tanzanian subjects with newly diagnosed pulmonary TB. The subjects will be studied at three time points (i) the day after TB diagnosis while infected, (ii) after 8 weeks of intensive phase treatment, and (iii) after another 16 weeks of continuation phase treatment. Iron status, hemoglobin, hepcidin and inflammation indexes will be measured at each time point. Isotope enrichment during the two treatment phases will be measured to estimate the relative rates of iron absorption and mobilization from stores during the intensive and continuation phases to determine the relative contributions of iron absorption and iron mobilization from stores during TB treatment and recovery.

Outcome: These studies will provide important new insights into the aetiology of anaemia and iron metabolism in TB patients. The results will provide essential data for evidence-based recommendations on the timing, administration route and efficacy of iron therapy in patients with TB, making possible, a safer and more effective treatment of anaemia in TB while decreasing morbidity and mortality from the disease.

Study Overview

• Status: Completed
• Conditions: Tuberculosis
• Intervention / Treatment: Other: Stable iron isotopes, non-drug intervention

• Study Type: Observational
• Enrollment (Actual): 19

Contacts and Locations

Study Locations

• Tanzania
  • Pwani
    • Bagamoyo, Pwani, Tanzania, 0601
      • Tb-clinic, Bagamoyo Research and Training Centre

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Probability Sample

Study Population

18 tuberculosis cases recruited at the Bagamoyo District Hospital and surrounding TB diagnostic centres.

Description

Inclusion Criteria:

• Females and males 18-45 years of age
• Sputum smear-positive, and confirmed by polymerase chain reaction and culture
• Obtained informed consent

Exclusion Criteria:

• Pregnancy or Lactating (assessed by pregnancy test)
• Body weight <40 kg
• Severe anaemia (Hb <70 g/L)
• HIV positive (assessed by HIV test)
• Positive rapid malaria antigen test
• Intake of mineral/vitamin supplements 2 weeks before and during the study
• Diagnosed metabolic or gastrointestinal disorders, eating disorders or food allergy
• Blood transfusion, blood donation or significant blood loss (accident, surgery) over the past 6 months
• Subject who cannot be expected to comply with study protocol (e.g. non-residents to the Bagamoyo Coast region, or subjects who plan to travel or move)

Study Plan

How is the study designed?

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Tuberculosis, no HIV and severe anemia	Other: Stable iron isotopes, non-drug intervention

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in iron absorption of stable isotope tracers at week 8	Stable iron isotopes will be orally administered under standardized conditions and close supervision. Iron absorption will be calculated from the shift in the normal isotopic abundance in red blood cells; 8 weeks = end of first treatment phase	baseline, 8 weeks
Change from baseline in iron incorporation of stable isotope tracers at week 8	Stable iron isotopes will be infused under standardized conditions and close supervision. Iron incorporation will be calculated from the shift in the normal isotopic abundance in red blood cells; 8 weeks = end of first treatment phase.	baseline, 8 weeks
Change from baseline in iron absorption of stable isotope tracers at week 24	Stable iron isotopes will be orally administered under standardized conditions and close supervision. Iron absorption will be calculated from the shift in the normal isotopic abundance in red blood cells; 24 weeks = end of second treatment phase	baseline, 24 weeks
Change from baseline in iron incorporation of stable isotope tracers at week 24	Stable iron isotopes will be infused under standardized conditions and close supervision. Iron incorporation will be calculated from the shift in the normal isotopic abundance in red blood cells; 24 weeks = end of second treatment phase.	baseline, 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in serum hepcidin at week 2	As a determinant of iron metabolism, serum hepcidin will be measured several times during the study.	baseline, 2 weeks
Change from baseline in serum hepcidin at week 4	As a determinant of iron metabolism, serum hepcidin will be measured several times during the study.	baseline, 4 weeks
Change from baseline in serum hepcidin at week 6	As a determinant of iron metabolism, serum hepcidin will be measured several times during the study.	baseline, 6 weeks
Change from baseline in serum hepcidin at week 8	As a determinant of iron metabolism, serum hepcidin will be measured several times during the study.	baseline, 8 weeks
Change from baseline in serum hepcidin at week 10	As a determinant of iron metabolism, serum hepcidin will be measured several times during the study.	baseline, 10 weeks
Change from baseline in serum hepcidin at week 12	As a determinant of iron metabolism, serum hepcidin will be measured several times during the study.	baseline, 12 weeks
Change from baseline in serum hepcidin at week 14	As a determinant of iron metabolism, serum hepcidin will be measured several times during the study.	baseline, 14 weeks
Change from baseline in serum hepcidin at week 16	As a determinant of iron metabolism, serum hepcidin will be measured several times during the study.	baseline, 16 weeks
Change from baseline in serum hepcidin at week 18	As a determinant of iron metabolism, serum hepcidin will be measured several times during the study.	baseline, 18 weeks
Change from baseline in serum hepcidin at week 20	As a determinant of iron metabolism, serum hepcidin will be measured several times during the study.	baseline, 20 weeks
Change from baseline in serum hepcidin at week 22	As a determinant of iron metabolism, serum hepcidin will be measured several times during the study.	baseline, 22 weeks
Change from baseline in serum hepcidin at week 24	As a determinant of iron metabolism, serum hepcidin will be measured several times during the study.	baseline, 24 weeks
Change from baseline in serum hepcidin at week 26	As a determinant of iron metabolism, serum hepcidin will be measured several times during the study.	baseline, 26 weeks

Collaborators and Investigators

• Sponsor: Swiss Federal Institute of Technology
• Collaborators: Swiss Tropical & Public Health Institute; Ifakara Health Institute

Publications and helpful links

General Publications

• Cercamondi CI, Stoffel NU, Moretti D, Zoller T, Swinkels DW, Zeder C, Mhimibra F, Hella J, Fenner L, Zimmermann MB. Iron homeostasis during anemia of inflammation: a prospective study of patients with tuberculosis. Blood. 2021 Oct 14;138(15):1293-1303. doi: 10.1182/blood.2020010562.

Study record dates

Study Major Dates

• Study Start: April 1, 2015
• Primary Completion (Actual): January 1, 2017
• Study Completion (Actual): January 1, 2017

Study Registration Dates

• First Submitted: June 23, 2014
• First Submitted That Met QC Criteria: June 26, 2014
• First Posted (Estimate): June 27, 2014

Study Record Updates

• Last Update Posted (Actual): June 5, 2017
• Last Update Submitted That Met QC Criteria: June 2, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Infections; Bacterial Infections; Bacterial Infections and Mycoses; Gram-Positive Bacterial Infections; Actinomycetales Infections; Mycobacterium Infections; Tuberculosis
• Other Study ID Numbers: Fe_TB_Study_TZ