Assessing the role of inflammation on serum folate, red blood cell folate, vitamin B-12, vitamin D, and zinc in adolescents and school-age children Restricted; Files Only
Zeiler, Madeleine (Spring 2023)
Abstract
Objectives: Knowledge gaps remain on the role of inflammation on micronutrient biomarker concentrations among school age children (SAC) and adolescents (ADL). Children and WRA are particularly vulnerable, with at least half of PSC and around two-thirds of non-pregnant WRA experiencing a micronutrient deficiency in some form.1 Associations between concentrations of inflammation biomarkers C-reactive protein (CRP) and α1-acid glycoprotein (AGP) and serum folate (SFO), red blood cell folate (RBC folate), vitamin B-12, vitamin D, and zinc were examined.
Methods: This study analyzed cross-sectional data from nutrition surveys in multiple countries from 2006-2016 in SAC and ADL. Survey eligibility criteria were as follows: inclusion of either SAC (5-9 years) or ADL (10-19 years), AGP or CRP and ≥ 1 micronutrient of interest, and n > 100. Micronutrient deficiencies were defined as SFO < 10 nmol/L, RBC folate < 340 nmol/L, vitamin B-12 < 150 pmol/L, vitamin D < 25 nmol/L, and zinc < 57 µg/dL – 74 µg/dL depending on specified conditions. Inflammation was defined as AGP > 1 g/L and CRP > 5 mg/L. Prevalence estimates were adjusted for complex survey design, and associations were assessed by rank correlation coefficient.
Results: Correlations between AGP or CRP and SFO, RBC folate, vitamin B-12, vitamin D, and zinc were weak, with no clear pattern of association. Of the 50 observations recorded 11 were statistically significant (p < 0.05). 10 of these were negative: 3 between SFO and CRP (r = -0.08 to -0.06); 2 between vitamin B-12 and CRP (r = -0.18 to -0.09); 1 between vitamin D and CRP (r = -0.06); 1 between zinc and AGP (r = -0.18); and 3 between zinc and CRP (r = -0.19 to -0.06). 1, vitamin B-12 and CRP (r = 0.10 to 0.13), was statistically significant and positive. Decile plots showed no clear pattern across biomarkers.
Conclusions: Due to weak and inconsistent correlations between the inflammation biomarkers and micronutrient biomarkers, there is no rationale to adjust for inflammation when estimating population prevalence SFO, RBC folate, vitamin B-12, vitamin D or zinc deficiencies in SAC or ADL.
Table of Contents
CHAPTER 1: INTRODUCTION 1
Introduction and Rationale 1
Problem Statement 2
Purpose Statement 2
Research Question 3
Significance Statement 3
Definition of Terms 3
CHAPTER 2: LITERATURE REVIEW 6
Micronutrient Overview 6
Folate 6
Vitamin B-12 8
Vitamin D 10
Zinc 12
Deficiency Cutoffs 15
Inflammation Overview 15
α1-Acid glycoprotein (AGP) 16
C-reactive protein (CRP) 17
Laboratory Analysis 18
The Public Health Implications of Micronutrient Deficiency 21
Past/Related Findings 22
The Case for Adjusting for Inflammation 24
Bidirectional Associations of Inflammation and Micronutrients 26
Biological Plausibility for B Vitamins (SFO, RBC folate, and Vitamin B-12) 26
Biological Plausibility for Vitamin D 27
Biological Plausibility for Zinc 28
Methods of Inflammation Adjustment 28
Potential Confounders 30
CHAPTER 3: MANUSCRIPT 33
Introduction 34
Methods 37
Study Design and Data Sources 37
Lab Methods 37
Statistical Methods 38
Results 39
Primary Analysis 39
Sensitivity Analysis 42
Discussion 45
CHAPTER 4: DISCUSSION 48
Overview 48
Biological Rationale 49
Next Steps 50
Suggested Cutoffs 50
Clinical Trial Design 51
Study Strengths 52
Study Limitations 52
Conclusions 53
SUPPLEMENTARY MATERIALS 56
Table 1: Prevalence of deficiency for each country included in the analysis for PSC and non-pregnant women* 56
Table 2: Prevalence of people with deficiencies in one more of three core micronutrients from 2003-2019* 57
Figure 1: Study Inclusion and Exclusion Criteria 58
Table 3: Age, AGP, and CRP status in adolescents and school-age children 59
Table 4: Serum folate, RBC folate, vitamin B-12, vitamin D, and zinc status in adolescents and school-age children 60
Table 5: Rank correlation coefficient between serum folate, red blood cell folate, vitamin B-12, vitamin D, and zinc and AGP or CRP in adolescents and school-age children 61
Figure 3: Estimated geometric means of (A) serum folate by AGP, (B) serum folate by CRP, (C) vitamin B12 by AGP, (D) vitamin B12 by CRP, (E) RBC folate by AGP and (F) RBC folate by CRP in school-age children by sex and age group 62
Figure 4: Estimated geometric means of (A) serum folate by AGP, (B) serum folate by CRP, (C) vitamin B12 by AGP, (D) vitamin B12 by CRP, (E) RBC folate by AGP and (F) RBC folate by CRP in school-age children by sex and age group. AGP, α1-Acid glycoprotein; CRP, C-reactive protein 63
Table 6: Age, AGP, and CRP status in school-age children by age 64
Table 7: Serum folate, RBC folate, vitamin B-12, vitamin D, and zinc status in school-age children by age group 65
Table 8: Rank correlation coefficient between serum folate, red blood cell folate, vitamin B-12, vitamin D, and zinc and AGP or CRP in school-age children by age group 66
Figure 5: Estimated geometric means of (A) serum folate by AGP, (B) serum folate by CRP, (C) vitamin B12 by AGP, (D) vitamin B12 by CRP, (E) RBC folate by AGP and (F) RBC folate by CRP in school-age children by sex and age group. AGP, α1-Acid glycoprotein; CRP, C-reactive protein 67
Figure 6: Estimated geometric means of (A) vitamin D by AGP, (B) vitamin D by CRP, (C) zinc by AGP, (D) zinc by CRP in school-age children by age group and sex. AGP, α1-Acid glycoprotein; CRP, C-reactive protein 68
Table 9: Data Sources and Availability 69
Table 10: Suggested lower* cutoffs for the assessment of serum zinc** 72
Table 11: Laboratory methods by biomarker and age group 72
Table 12: When to apply the BRINDA inflammation adjustment method and by AGP and/or CRP 72
REFERENCES 73
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