Treatment of Vitamin D Deficiency in Special Conditions:Hypertension and Cystic Fibrosis Público

Abstract

ABSTRACT Vitamin D deficiency is common and under treated in the United States because the disease is silent and there are limited evidence based regimens for treatment. Assessing vitamin D status and aggressively treating vitamin D deficiency in model disease populations who are at high risk for vitamin D deficiency could help define a treatment strategy for the population at large. Individuals with hypertension and cystic fibrosis (CF) are model populations since both groups are at risk for vitamin D deficiency. The goals for this thesis project are to define the clinical scope of vitamin D deficiency in individuals with hypertension and CF and to determine the appropriate population specific treatment strategy to restore vitamin D status. We first examined the prevalence of vitamin D deficiency in individuals with CF and hypertension and found both populations have higher rates of vitamin D deficiency compared with non-diseased controls. Further, we found that vitamin D deficiency was sub-optimally treated in both populations. We then examined different strategies to correct vitamin D status in both populations. In the CF population, we examined 600,000 IU of both vitamin D2 and vitamin D3 and UV light and found vitamin D3 to be superior at raising 25- hydroxyvitamin D (25(OH)D), the best marker for vitamin D status. In hypertensive individuals, we examined in a pilot study the effect of calcitriol, the active form of vitamin D, vitamin D3 and placebo on blood pressure, a process thought to be regulated by vitamin D. Although vitamin D3 corrected vitamin D status the best in the three groups, we found that only calcitriol therapy significantly reduced blood pressure. Vitamin D deficiency is common and can be corrected with adequate vitamin D

supplementation. The role of vitamin D in hypertension in humans still needs to be clarified in terms of the correct form and dose of vitamin D to lower blood pressure and the mechanism for vitamin D's anti-hypetensive action.

Table of Contents

TABLE OF CONTENTS Chapter 1: Introduction ................................................................................... 1 Chapter 2 Literature Review ............................................................................... 6 Vitamin D: History, Structure, and Function ........................................................... 6 History ........................................................................................................... 6 Forms and structure ...........................................................................................6 Physiology ........................................................................................................7 Genomic functions..............................................................................................8 Non-genomic functions .......................................................................................9 Assessing and Treating Vitamin D Deficiency .......................................................... 9 Adequate vitamin D status...................................................................................9 Vitamin D intake ................................................................................................11 Correction of vitamin D deficiency ........................................................................12 Co-Morbidities Associated with Vitamin D Deficiency ................................................12 Osteoporosis ....................................................................................................13 Diabetes .........................................................................................................13 Inflammation ....................................................................................................14 Disease Specific Considerations: Cystic Fibrosis ......................................................14 Complications of disease ....................................................................................15 Prevalence of vitamin D deficiency and insufficiency ...............................................15 Management of vitamin D deficiency ....................................................................16 Disease Specific Considerations: Hypertension .......................................................17 Hypertension prevalence ...................................................................................17 Prevention of hypertension ................................................................................18 Hypertension: treatment and complications ..........................................................19 Hypertension: assessment of blood pressure .........................................................19 Hypertension: systems of blood pressure control ...................................................20 Vitamin D and the renin-angiotensin aldosterone axis (RAS) .....................................21 RAS and inflammation .......................................................................................22 1,25(OH)2D and blood pressure ..........................................................................22 Epidemiologic evidence .....................................................................................23 Clinical trials ...................................................................................................23 Summary .......................................................................................................24 Chapter 3 Optimal Vitamin D Status Attenuates the Age-Associated Increase in Systolic Blood Pressure in White Americans: Results from NHANES III ...............25 Chapter 4 Vitamin D and Bone Health in Adults With Cystic Fibrosis ...................26 Chapter 5 Treatment of Vitamin D Insufficiency in Cystic Fibrosis Patients: Evaluation of Ergocalciferol, Cholecalciferol and UV light ...................................27 Abstract .........................................................................................................30 Introduction ....................................................................................................32 Subjects..........................................................................................................34 Design ............................................................................................................34

Analytical methods ............................................................................................35 Statistical methods ...........................................................................................36 Subject demographics ........................................................................................37 Baseline Vitamin D status ................................................................................... 37 Factors associated with increases in 25(OH)D ........................................................ 37 Total Serum 25-hydroxyvitamin D concentrations after D2, D3 or UV light .................... 38 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 concentrations after D2, D3 and UV light ........................................................................................................... 39 Parathyroid hormone concentrations after D2, D3 and UV light ................................... 39 Safety ..............................................................................................................40 Discussion .........................................................................................................41 References ........................................................................................................47 Chapter 6 Hypertension Clinical Trial ................................................................. 64 Evaluation of vitamin D3 and 1,25(OH)2D to lower blood pressure in hypertensive subjects: a pilot study ...................................................................................... 64 Abstract ........................................................................................................ 65 Introduction ....................................................................................................66 Methods: Vitamin D3 treatment in hypertensive subjects: a pilot dose ranging study .... 68 Blood collection and quality assurance .................................................................68 Blood pressure assessment ................................................................................68 Methods: Evaluation of vitamin D3, 1,25(OH)2D or placebo: a pilot randomized controlled trial ................................................................................................70 Participants ....................................................................................................70 Study medication and compliance .......................................................................71 Statistical Analysis ...........................................................................................72 Results ...........................................................................................................73 Blood pressure changes .....................................................................................73 Evaluation of vitamin D3, 1,25(OH)2D or placebo: A pilot randomized controlled trial ............................................................................................................. 74 Blood pressure changes ................................................................................... 74 Biomarkers .................................................................................................... 75 1,25(OH)2D follow-up ...................................................................................... 75 Pooled analysis - plasma renin activity ................................................................ 75 Discussion ..................................................................................................... 77 Conclusion ..................................................................................................... 80 References .................................................................................................... 81 Chapter 7 Expanded Methods ........................................................................ 93 NHANES Analyses ........................................................................................... 93 Sample population ........................................................................................... 93 Blood pressure determination and categorization .................................................... 94 Statistical analysis ........................................................................................... 94 Hypertension Clinical Trial .................................................................................. 96 Identification of study population ........................................................................ 96 Dose identification ............................................................................................ 96 Overview ........................................................................................................ 98 Study population .............................................................................................. 98 Eligibility .......................................................................................................... 99 Study medication ........................................................................................... 100 Randomization and blinding............................................................................... 100 Safety .......................................................................................................... 100 Consent and screening ..................................................................................... 101 Baseline visit .................................................................................................. 102 Final visit ....................................................................................................... 102 Blood Collection .............................................................................................. 103 Quality Assurance ........................................................................................... 103 Blood Pressure Monitor ..................................................................................... 104 Statistical Analysis .......................................................................................... 104 Subject Confidentiality and Privacy ................................................................. 106 Benefits to the Subjects ............................................................................... 107 Study Design - Vitamin D Repletion in Cystic Fibrosis Patients .............................. 108 Background................................................................................................. 108 Overview ................................................................................................... 108 Study population ......................................................................................... 109 Eligibility .................................................................................................... 109 Study medication ........................................................................................ 109 Randomization and blinding............................................................................. 110 Baseline visit ............................................................................................. 110 Final Visit ................................................................................................... 111 Blood collection .............................................................................................. 111 Statistical analysis .......................................................................................... 112 Subject confidentiality and privacy .................................................................... 112 Benefits to subjects ........................................................................................ 113 Chapter 8 Summary and conclusions .............................................................. 114 Key Findings .................................................................................................. 114 Educational Opportunities ................................................................................. 116 Policy Implications ........................................................................................... 118 Next Steps .................................................................................................... 119 Conclusion .................................................................................................... 122 Chapter 9 Literature Cited ............................................................................. 124

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School	Laney Graduate School
Department	Biological and Biomedical Sciences
Degree	PhD
Submission	Dissertation
Language	English
Research Field	Health Sciences, Nutrition
Palavra-chave	cystic fibrosis calcitriol hypertension nutrition vitamin D
Committee Chair / Thesis Advisor	Tangpricha, Vin, Emory University
Committee Members	Bostick, Roberd M, Emory University Nanes, Mark S, Emory University Ziegler, Thomas R, Emory University Wilson, Peter W, Emory University Stein, Aryeh D, Emory University

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