Contribuições para o entendimento do papel do fator de crescimento fibroblástico 23 na fisiologia e fisiopatologia do metabolismo ósseo e mineral
Data
2022-09-22
Autores
Pallone, Sthefanie Giovanna 
Orientadores
Lazaretti-Castro, Marise
Tipo
Tese de doutorado
Título da Revista
ISSN da Revista
Título de Volume
Resumo
Introdução: O FGF23 é um hormônio regulador da homeostase do fósforo e da vitamina D. Embora sua função na doença renal crônica seja bem descrita, suas atribuições em outros contextos ainda não estão bem estabelecidas. O objetivo desta tese é avaliar o papel do FGF23 em diferentes cenários clínicos: na indução de fosfatúria pelo PTH em uma paciente com calcinose tumoral familiar hiperfosfatêmica (CTFH), no hiperparatireoidismo primário (HPP) e na suplementação de vitamina D3. Métodos: Manuscrito 1: Foi reportado o uso de teriparatida (PTH 1-34) 40 mcg/dia em uma paciente com diagnóstico de CTFH secundária à mutação no gene GALNT3. Foram avaliadas tanto a resposta da fosfatúria e da fosfatemia quanto a segurança da intervenção. Manuscrito 2: Foi realizado um ensaio clínico não randomizado em que pacientes com HPP e controles receberam 14.000 UI/semana de vitamina D3 por 12 semanas. No início e após 12 semanas de intervenção, amostras de sangue e urina foram coletadas para avaliar FGF23, 1,25(OH)2vitamina D (1,25(OH)2D), 25- hidroxivitamina D (25OHD), PTH, cálcio total (tCa) e outros parâmetros bioquímicos do metabolismo ósseo e mineral. A 1,25(OH)2D foi medida por cromatografia líquida e espectrometria de massas (LC-MS/MS).
Resultados: Manuscrito 1: No início do estudo a concentração do fósforo (P) sérico era de 6,2 mg/dL e, após 28 dias de teriparatida 40 mcg/dia, reduziu para 5,2 mg/dL. Houve elevação de 34% nas concentrações de 1,25(OH)2D e aumento da calciúria. Manuscrito 2: 70 indivíduos com HPP e 75 controles foram incluídos no início do estudo. 55 indivíduos com HPP e 64 controles completaram o protocolo de 12 semanas. Após a intervenção, tCa e PTH não se alteraram, mesmo havendo um aumento significativo de 25OHD em ambos os grupos. As concentrações de FGF23 aumentaram significativamente (HPP: de 47,9±27,1 para 76,3±33,3; controles: de 40,5±13,9 para 59,8±19,8 pg/mL), enquanto os níveis de 1,25(OH)2D diminuíram nos dois grupos (HPP: de 94,8±34,6 para 68,9 ±25,3; controles: de 68,7±23,5 para 56,4±20,7 pg/mL). A queda da 1,25(OH)2D apresentou correlação com a elevação do FGF23 e o delta do FGF23 foi o fator preditor para a redução da 1,25(OH)2D com a intervenção.
Conclusões: Manuscrito 1: A teriparatida é capaz de induzir fosfatúria na ausência de ação biológica do FGF23. Porém, apesar de eficaz, não é uma droga segura em pacientes com CTFH. Isso ocorre provavelmente pela ausência do efeito regulador do FGF23 sobre a enzima 1α-hidroxilase. Manuscrito 2: A suplementação de vitamina D3 leva à elevação do FGF23 e à queda da 1,25(OH)2D, quando avaliada por LC-MS/MS. A segurança da suplementação de vitamina D3 relacionada ao excesso de vitamina D ativa parece estar associada à redução da 1,25(OH)2D secundária ao aumento do FGF23. Os dois trabalhos ressaltam a importância do controle do FGF23 sobre o metabolismo da vitamina D.
Introduction:FGF23 is a hormone that regulates phosphorus and vitamin D homeostasis. Although its role in chronic kidney disease is well described, its attributions in other contexts are not yet well established. This thesis aims to evaluate the role of FGF23 in different clinical scenarios: in the induction of phosphaturia by PTH in a patient with hyperphosphatemic familial tumor calcinosis (HFTC), in primary hyperparathyroidism (PHPT), and in vitamin D3 supplementation. Methods: Manuscript 1: The use of teriparatide (PTH 1-34) 40 mcg/day was reported in a patient diagnosed with HFTC secondary to a mutation in the GALNT3 gene. We evaluated the phosphaturia and phosphataemia response and the safety of the intervention. Manuscript 2: This is a nonrandomized clinical trial in which PHPT patients and controls received 14,000 IU/week of vitamin D3 for 12 weeks. At baseline and after 12 weeks of intervention, blood and urine samples were collected to assess FGF23, 1,25(OH)2vitamin D (1,25(OH)2D), 25-hydroxyvitamin D (25OHD), PTH, and total calcium (tCa). The 1,25(OH)2D was measured by liquid chromatography and mass spectrometry (LC-MS/MS). Results: Manuscript 1: At the beginning of the study, the concentration of serum phosphorus (P) was 6.2 mg/dL, and after 28 days of teriparatide 40 mcg/day, it reduced to 5.2 mg/dL. There was a 34% increase in 1,25(OH)2D concentrations and an increase in calciuria. Manuscript 2: 70 subjects with active PHPT and 75 controls were included at baseline. 55 PHPT and 64 controls completed the 12-week protocol. After the intervention, tCa and PTH did not change, with a significant increase in 25OHD in both groups. FGF23 concentrations increased significantly (PHPT: from 47.9±27.1 to 76.3±33.3; controls: from 40.5±13.9 to 59.8±19.8 pg/mL), while 1.25(OH)2D levels decreased in both groups (PHPT: from 94.8±34.6 to 68.9 ±25.3; controls: from 68.7±23.5 to 56.4± 20 .7 pg/mL). The drop in 1.25(OH)2D correlated with the increase in FGF23, and the delta of FGF23 was the predictor factor for the reduction in 1.25(OH)2D with the intervention. Conclusions: Manuscript 1: Teriparatide can induce phosphaturia without the biological action of FGF23. However, despite being effective, it is not a safe drug in patients with HFTC. The hypercalciuria is probably due to the absence of the regulatory effect of FGF23 on 1α-hydroxylase. Manuscript 2: Vitamin D3 supplementation leads to an increase in FGF23 and a decrease in 1,25(OH)2D when evaluated by LC-MS/MS. The safety of vitamin D3 supplementation related to excess active vitamin D appears to be associated with a reduction in 1,25(OH)2D secondary to an increase in FGF23. Both studies emphasize the importance of the FGF23 control over the vitamin D metabolism.
Introduction:FGF23 is a hormone that regulates phosphorus and vitamin D homeostasis. Although its role in chronic kidney disease is well described, its attributions in other contexts are not yet well established. This thesis aims to evaluate the role of FGF23 in different clinical scenarios: in the induction of phosphaturia by PTH in a patient with hyperphosphatemic familial tumor calcinosis (HFTC), in primary hyperparathyroidism (PHPT), and in vitamin D3 supplementation. Methods: Manuscript 1: The use of teriparatide (PTH 1-34) 40 mcg/day was reported in a patient diagnosed with HFTC secondary to a mutation in the GALNT3 gene. We evaluated the phosphaturia and phosphataemia response and the safety of the intervention. Manuscript 2: This is a nonrandomized clinical trial in which PHPT patients and controls received 14,000 IU/week of vitamin D3 for 12 weeks. At baseline and after 12 weeks of intervention, blood and urine samples were collected to assess FGF23, 1,25(OH)2vitamin D (1,25(OH)2D), 25-hydroxyvitamin D (25OHD), PTH, and total calcium (tCa). The 1,25(OH)2D was measured by liquid chromatography and mass spectrometry (LC-MS/MS). Results: Manuscript 1: At the beginning of the study, the concentration of serum phosphorus (P) was 6.2 mg/dL, and after 28 days of teriparatide 40 mcg/day, it reduced to 5.2 mg/dL. There was a 34% increase in 1,25(OH)2D concentrations and an increase in calciuria. Manuscript 2: 70 subjects with active PHPT and 75 controls were included at baseline. 55 PHPT and 64 controls completed the 12-week protocol. After the intervention, tCa and PTH did not change, with a significant increase in 25OHD in both groups. FGF23 concentrations increased significantly (PHPT: from 47.9±27.1 to 76.3±33.3; controls: from 40.5±13.9 to 59.8±19.8 pg/mL), while 1.25(OH)2D levels decreased in both groups (PHPT: from 94.8±34.6 to 68.9 ±25.3; controls: from 68.7±23.5 to 56.4± 20 .7 pg/mL). The drop in 1.25(OH)2D correlated with the increase in FGF23, and the delta of FGF23 was the predictor factor for the reduction in 1.25(OH)2D with the intervention. Conclusions: Manuscript 1: Teriparatide can induce phosphaturia without the biological action of FGF23. However, despite being effective, it is not a safe drug in patients with HFTC. The hypercalciuria is probably due to the absence of the regulatory effect of FGF23 on 1α-hydroxylase. Manuscript 2: Vitamin D3 supplementation leads to an increase in FGF23 and a decrease in 1,25(OH)2D when evaluated by LC-MS/MS. The safety of vitamin D3 supplementation related to excess active vitamin D appears to be associated with a reduction in 1,25(OH)2D secondary to an increase in FGF23. Both studies emphasize the importance of the FGF23 control over the vitamin D metabolism.
Descrição
Citação
PALLONE, S G. Contribuições para o entendimento do papel do fator de crescimento fibroblástico 23 na fisiologia e fisiopatologia do metabolismo ósseo e mineral. São Paulo, 2022. 122 f. Tese (Doutorado em Endocrinologia e Metabologia) - Escola Paulista de Medicina (EPM), Universidade Federal de São Paulo (UNIFESP). São Paulo, 2022.