Kvachenyuk D. Growth hormone deficiency: effects of vitamin D on the growth hormone/growth factor system in children and adolescents

Українська версія

Thesis for the degree of Doctor of Philosophy (PhD)

State registration number

0823U101119

Applicant for

Specialization

  • 222 - Медицина

Specialized Academic Board

2872

State Institution "V.P. Komissarenko Institute of Endocrinology and Metabolism of the National academy of medical science of Ukraine"

Essay

The goal of study is to increase the treatment efficacy in children with growth hormone deficiency based on the study of the relationship between the GH /growth factors axis, vitamin D level and the vitamin D receptor gene polymorphisms. Clinical evaluation was performed in the Department of Pediatric Endocrine Pathology VP Komisarenko Institute of Endocrinology and Metabolism; 226 children with short stature were enrolled in the study. When conducting the research, general clinical, hormonal and biochemical methods were used: determination of thyroid-stimulating hormone TSH, free thyroxine, insulin-like growth factor-1 (IGF-1), basal and stimulated GH levels, vit D content, ghrelin (Ghr), parathyroid hormone, vitamin D-binding protein (VD-BP), biochemical blood analysis; molecular genetics methods; instrumental; statistical research methods. In patients with GHD, a positive correlation between the 25(OH)D plasma levels and IGF-1 level was shown, an inverse relationship between vit D and BA was established, as well as direct correlations between IGF-1 level, stimulated GH level, PTH level and BA. It was established that reduced IGF-1 levels, basal and stimulated GH levels and hypovitaminosis D associated with normal levels of Ghr, PTH and increased indicators of VD-BP in the majority of patients with GHD. Ghr level has an inverse correlation with VD-BP and directly correlates with the basal and stimulated levels of GH and IGF-1 level. It was found that most GHD patients with the BsmI polymorphism and COLIA1 have the G allele. With the BsmI polymorphism, 53,57% of the examinees were carriers of the GA genotype, and 25% of the GG genotype; with COLІA1 - carriers of the GG genotype were 53,57%, GT genotype – 39,29% of individuals. The ApaI polymorphism was dominated by the AC genotype. Medium strength between TS TaqI genotype and the low plasma level of 25(OH)D was established. The presence of the AC ApaI genotype increases the chances of hypovitaminosis D by 8,43 times. It was determined that BsmI and ApaI polymorphisms of the VDR gene are significant clinical and diagnostic factors for risk assessing of developing GHD. Presence of G allele BsmI and allele A ApaI is reliably associated with a high risk of developing GH deficiency, both with homo- and heterozygous genotypes. The presence of homozygous genotype AA BsmI VDR and homozygous genotype CC ApaI VDR can be considered as protective polymorphisms for GHD. It has been established that the vit D supplementation leads to an increase in the effectiveness of treatment with rhGH. Vit D supplementation to the treatment regimen inhibits the growth rate decrease that occurs after the first year of monotherapy with rhGH, and thereafter the growth velocity remains stable and acceptable for achieving satisfactory growth rates. The scientific novelty of the study is that, for the first time, a comprehensive study of the GH/IGF-1 axis status was conducted in prepubertal GHD children in conditions of different supply of vit D. The indicators of the growth factor - ghrelin - in prepubertal GHD children were studied. For the first time in Ukraine, a study of the genotypic characteristics of GHD children was conducted, namely the study of the distribution of allele frequencies and genotypes of the polymorphic loci BsmI, TaqI, ApaI of the vit D receptor gene and polymorphism of the type 1 collagen gene COLІA1. Presence of G BsmI and allele A ApaI is reliably associated with a high risk of developing GHD, both with homo- and heterozygous genotypes. The presence of homozygous genotype AA BsmI VDR and homozygous genotype CC ApaI VDR can be considered as protective polymorphisms for the development GHD. For the first time in Ukraine, the advisability and effectiveness of vit D supplementation in complex therapy with rhGH was determined. The inclusion of vit D in the complex therapy of such patients leads to a reliably increase in growth velocity. The practical significance of the obtained results is as follows: A significant vit D imbalance has been established in the majority of GHD children, regardless of the form of the disease, which implies a mandatory study of the vit D content before and during the use of rhGH in children with this pathology, as well as the normalization of its level before the start of rhGH therapy. It has established that due to the obvious decrease in the efficacy of rhGH therapy after the first years of treatment, it is recommended to use combined therapy of GHD children with rhGH and vit D. It was established that the carrier of the allele G BsmI VDR, and the carrier of the allele A ApaI VDR is reliably associated with the risk of GH development, which can be an additional diagnostic test. Keywords: vitamin D, vitamin D receptor gene polymorphism, growth hormone, insulin-like growth factor-1, ghrelin, parathyroid hormone, vitamin D-binding protein, growth hormone deficiency, recombinant human growth hormone children, adolescents, treatment.

Research papers

Bolshova  OV,  Ryznychuk  MA,  Kvachenyuk  DA. Аnalysis  of  the  vitamin  D  receptor BsmI gene polymorphism in children with growth hormone deficiency.  WiadLek. 2021;74(3p.I):498­503, DOI: 10.36740/WLek202103121.

Большова О. В., Спринчук Н. А.,Кваченюк Д. А., Музь Н. М., Ризничук М.  О., Лукашук І.  В., Маліновська Т.  М., Самсон О.  Я., Вишневська О.  А.,  Пахомова ВГ. Взаємозв’язок системи гормон росту/інсуліноподібний чинник росту­1 та вітаміну D  у дітей із низькорослістю. Репродуктивна ендокринологія. 2022;1­2(63­64):34­38.  DOI:  http://dx.doi.org/10.18370/2309­ 4117.2022.63.34­38.

Ryznychuk M, Bolshova O, Kvachenyuk D, Sprinchuk N, Malinovska T. Genetic  features of children with idiopathic short stature. Wiad Lek. 2023;76(02):320­325.  DOI:  10.36740/WLek202302111.

Большова О. В., Ризничук М. О., Кваченюк Д. А., Спринчук Н. А., Лукашук І. В., Пахомова В. Г., Маліновська Т. М., Вишневська О. А., Самсон О. Я. Оцінка ризику розвитку соматотропної недостатності залежно від розподілу частот алелей і генотипів поліморфного локусу rs1544410  BsmI  гена рецептора віт D.  Сучасна педіатрія. 2023, 1(129):16­22.  DOI:  10.15574/SP.2023.129.16.

Большова О.  В., Ризничук М.  О., Кваченюк Д.  А. Участь гена рецептора вітаміну D в ідіопатичній низькорослості. Міжнародний ендокринологічний журнал. 2023; 19(1):21­26.  DOI:  https://doi.org/10.22141/2224­ 0721.19.1.2023.1236.

Большова О.  В., Кваченюк Д.  А., Ризничук М.  О. Система гормон росту/ інсуліноподібний чинник росту­1 та вміст вітаміну D у дітей із соматотропною недостатністю. Ендокринологія.  2023;28(1):67­74.  DOI:  10.31793/1680­1466.2023.28­1.67.

Кваченюк Д. А., Большова О. В. Оцінка ефектривності комбінованої терапії препаратами рекомбінантного гормону росту та вітаміну D  дітей препубертатного віку із соматотропною недостатністю. Сучасна педіатрія. Україна. 2023;3(131): 31­36. doi 10.15574/SP.2023.131.31

Bolshova  O,  Ryznychuk  M,  &  Kvachenyuk  D. Поліморфізм TaqI гена рецептора вітаміну D у дітей із соматотропною недостатністю. Міжнародний ендокринологічний журнал ­ Mìžnarodnij endokrinologìčnij žurnal, 2023; 19(4),  249–253.  https://doi.org/10.22141/2224­0721.19.4.2023.1280

Большова О.  В., Ризничук М.  О., Кваченюк Д.  А. Метаболізм вітаміну D  у дітей із затримкою зросту. Сучасна педіатрія. 2019; 7(103): 50­57.  DOI:   10.15574/SP.2019.103.50.

Большова О. В., Музь Н. М., Кваченюк Д. А., Ризничук М. О. Рівень вітаміну D  у дітей з затримкою внутрішньоутробного розвитку на тлі нормосоматотропінемії.  Міжнародний ендокринологічний журнал  2020;  2(16): 30­36, DOI: 10.22141/2224­0721.16.2.2020.201294

Большова О. В., Музь Н. М., Кваченюк Д. А., Ризничук М. О. Взаємозв’язок стану системи гормон росту/ростові фактори, рівнів вітаміну D та показників зросту в дітей із затримкою внутрішньоутробного розвитку. Ендокринологія. 2021;26(1):21­30.  DOI:  10.31793/1680­1466.2021.26­1.2

Большова О.  В., Музь Н.  М.,  Кваченюк Д.  А.,  Ризничук М.  О.  Патент. Большова О.В., Музь Н.М., Кваченюк Д.А., Ризничук М.О. Cпосіб лікування низькорослості у осіб препубертатного віку із затримкою внутрішньоутробного розвитку: пат. 143159 Україна. No u202001200; заявл. 24.02.2020; опубл. 10.07.2020, Бюл. № 13

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