RESUMO
BACKGROUND: Intravenous iron is commonly used in patients with non-dialysis-dependent chronic kidney disease (CKD). Modern intravenous iron compounds (e.g. ferric derisomaltose (FDI), ferric carboxymaltose (FCM)) are increasingly utilized with similar efficacy. A differential effect in terms of hypophosphatemia has been noted following administration of FCM, which may be related to fibroblast growth factor 23 (FGF23). This study was designed to examine the comparative effects of FDI and FCM on FGF23, phosphate and other markers of bone turnover. METHODS: The single-center double-blind randomized controlled trial "Iron and Phosphaturia - ExplorIRON-CKD" primarily assessed the effects of FCM and FDI on intact FGF23 and phosphate, whilst also studying the impact on vitamin D, parathyroid hormone and phosphaturia. Bone markers including alkaline phosphatase, bone-specific alkaline phosphatase, procollagen type 1 N-terminal propeptide and carboxy-terminal collagen cross-linked telopeptide were monitored. Non-dialysis-dependent CKD patients (stage 3a-5) with iron deficiency with/without anemia (serum ferritin < 200 µg/L or transferrin saturation = 20% and serum ferritin 200-299 µg/L) were randomized to receive FDI or FCM in a 1:1 ratio. At baseline 1000 mg of intravenous iron was administered followed by 500-1000 mg at 1 month to achieve replenishment. Measurements were performed at baseline, 1-2 days following iron administration, 2 weeks, 1 month (second iron administration), 1-2 days following second administration, 2 months and 3 months following initial infusion. RESULTS: Twenty-six patients participated in the trial; 14 randomized to FDI and 12 to FCM. Intact FGF23 increased following administration of iron, and the increase was significantly higher with FCM compared to FDI (Baseline to 1-2 days following 1st administration: FDI: 3.0 (IQR: - 15.1 - 13.8) % vs. FCM: 146.1 (IQR: 108.1-203.1) %; p < 0.001 and Baseline to 1-2 days following 2nd administration: FDI: 3.2 (IQR: - 3.5 - 25.4) % vs. FCM: 235.1 (138.5-434.6) %; p = 0.001). Phosphate levels decreased in the FCM group, causing a significant difference versus FDI 2 weeks following administration of the first dose. A significantly greater decrease in 1,25 (OH)2 Vitamin D was noted with FCM. Several markers of bone turnover significantly changed following administration of FCM but not FDI. CONCLUSIONS: The study suggests a differential effect on FGF23 following administration of FCM compared to FDI in non-dialysis-dependent CKD patients, similar to other patient groups. This may lead to changes consistent with hypovitaminosis D and alterations in bone turnover with potential clinical consequences. Further definitive studies are required to understand these differences of intravenous iron compounds. TRIAL REGISTRATION: European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) number: 2019-004370-26 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2019-004370-26/GB ) (First date of trial registration: 03/12/2019).
Assuntos
Anemia Ferropriva , Hipofosfatemia Familiar , Maltose , Insuficiência Renal Crônica , Humanos , Fosfatase Alcalina , Anemia Ferropriva/tratamento farmacológico , Compostos Férricos , Ferritinas , Fator de Crescimento de Fibroblastos 23 , Hipofosfatemia Familiar/tratamento farmacológico , Ferro , Maltose/análogos & derivados , Fosfatos , Insuficiência Renal Crônica/tratamento farmacológico , Método Duplo-CegoRESUMO
CONTEXTO: A hipofosfatemia ligada ao cromossomo X (HLX) é considerada uma doença ultrarrara, cronicamente debilitante e deformante. É uma doença causada por mutações no gene regulador do fosfato com homologia às endopeptidases do cromossomo X (PHEX), que leva a perda de função do mesmo, gerando erros na detecção de fosfato e aumento dos níveis de fator de crescimento de fibroblastos 23 (FGF23). Os maiores achados clínicos na XLH são hipofosfatemia, retardo no crescimento, raquitismo e/ou osteomalácia. Anormalidades esqueléticassão sinais precoces de HLX. Fraturas, perdas auditivas, problemas dentários e osteomalácia podem aparecer além da perda de qualidade de vida associada. O tratamento convencional é realizado com administração de fosfato e vitamina D. Esta não é uma terapia com alvo no mecanismo fisiopatológico da doença, resumindo-se à tentativa de minorar a hipofosfatemia e o excesso de hormônio da paratireoide. A reposição oral de fosfato e vitamina D são insuficientes para atender aos objetivos do tratamento, não logrando alterar a densidade mineral óssea da coluna e quadril em adultos e estão associados a efeitos adversos importantes. Considera-se a possibilidade de inibição da atividade do FGF23 como uma medida terapêutica única para doenças hipofosfatêmicas causadas pelo excesso de FGF23. O burosumabe é um anticorpo monoclonal, sendo o primeiro medicamento desenvolvido para inibir a FGF23 e com isso aumentar a reabsorção de fosfato do rim, para que pela produção de vitamina D, melhore a absorção intestinal de cálcio e fosfato reduzindo os danos causados pela HLX. Agências internacionais aprovaram seu uso inicialmente nas populações pediátricas, em que o benefício clínico na melhora da HLX está mais estabelecido. Alguns países ampliaram o uso para a população adulta. PERGUNTA: O uso de burosumabe para o tratamento da hipofosfatemia ligada ao cromossomo X é eficaz e seguro quando comparado ao tratamento com fosfato e vitamina D ou placebo? TECNOLOGIA: burosumabe (CRYSVITA®). EVIDÊNCIAS CIENTÍFICAS: Em revisão sistemática da literatura, o demandante selecionou seis estudos clínicos que avaliaram o uso do burosumabe no tratamento da HLX. Três destes foram realizados em pacientes pediátricos e três em pacientes adultos. Há algumas limitações inerentes aos estudos de fase 2 e 3 selecionados. Os resultados apresentados demostram benefícios clínicos especialmente na melhora do raquitismo em crianças, da mobilidade e crescimento com tratamento com burosumabe em relação ao tratamento com fosfato e vitamina D. O estudo de Imel, et al., 2019 mostrou melhora do Escore Radiographic Global Impression of Change (RGI-C) global diferença média dos mínimos quadrados em 40 semanas: 1,1 (IC95% 0,8 1,5; p 0,0001) favorecendo o tratamento com burosumabe. O estudo de Carpenter et al., 2018, avaliou o mesmo escore em 40 semanas e obteve os seguintes resultados de acordo com a posologia: burosumabe, duas vezes por mês (+1,66 ± 0,09); burosumabe, uma vez por mês (+1,47 ± 0,14); burosumabe, todos os pacientes (+1,56 ± 0,08). Ao avaliar a gravidade do raquitismo pelo escore Thatcher, a diferença média dos mínimos quadrados em 40 semanas de acordo com a posologia foi: burosumabe, duas vezes por mês: -1,06 ± 0,11; p< 0,0001; burosumabe, uma vez por mês: -0,73 ± 0,10; p<0,0001; burosumabe, todos os pacientes: -0,89 ± 0,0,07. Em adultos também houve benefícios com o uso do medicamento, porém menos consistentes que na população pediátrica. Insogna et al., 2018, avaliaram a cura completa de fraturas ativas ou pseudofraturas em 24 semanas. Os seguintes resultados foram observados: burosumabe (43,1%) versus placebo (7,7%); Odds ratio OR 16,8 (IC95% não reportado); p <0,0001. Os estudos em adultos foram comparados com placebo, logo os resultados favoráveis ao burosumabe foram esperados. Em relação à segurança, tanto na população pediátrica quanto adulta, o burosumabe não acarretou nenhum evento adverso grave nos estudos realizados. AVALIAÇÃO ECONÔMICA: O demandante realizou uma análise de custo-efetividade. O modelo foi construído em uma planilha MS Excel com base em uma estrutura de Markov com horizonte temporal de toda a vida. Dois modelos de custo-efetividade foram apresentados, um considerando a população pediátrica (idades de 1 a 17 anos) e outro a população adulta (idade ≥18 anos). A razão de custo-efetividade incremental (RCEI) do burosumabe em relação ao uso de fosfato e vitamina D em pediatria foi de R$ 2.401.312,64/QALY e para a população adulta de R$ 2.534.873,52 /QALY. Nas análises de sensibilidade univariada para ambas as populações o modelo se mostrou sensível ao custo do burosumabe e idade de início do tratamento. O modelo possui limitações, entre elas a ausência de dados de incidência da HLX na população brasileira e os dados disponíveis no DATASUS relacionados a procedimentos e tratamentos provavelmente estão subestimados em relação a doença. Por tratar-se de doença rara, a falta de registro de dados e suas implicações podem impactar no modelo e suas análises de sensibilidade. AVALIAÇÃO DE IMPACTO ORÇAMENTÁRIO: A análise de impacto orçamentário (AIO) realizada pelo demandante previu população de pacientes elegíveis para o tratamento com burosumabe baseada em referências internacionais pela ausência de dados registrados no Brasil. Foi adotado um horizonte de 5 anos. O demandante apresentou um cenário base com incorporação de burosumabe para 100% dos pacientes. No cenário base os impactos orçamentários em cinco anos foram: R$ 197.249.738,34 para a população pediátrica e R$ 224.968.284,47 para a população adulta. Um outro cenário considerando que 50% seriam diagnosticados e tratados com burosumabe ou fosfato e vitamina D em 5 anos foi apresentado: R$ 98.624.869,17 para a população pediátrica e R$ 67.490.485,34 para a população adulta. O cenário 3 considerou a introdução gradual do burosumabe em 20%, 40%, 50% e 75%, chegando a 100% no quinto ano, assim o impacto em 5 anos foi de: R$ 65.209.976,69 para a população pediátrica R$ 48.026.685,80 para a população adulta. Apesar desse cenário ser o mais próximo do real, a disseminação pode ser maior já que há ausência de tratamento eficaz para a doença. Além disso, a AIO têm provavelmente subestimativas da população por usar uma média internacional e não considerar a incidência da doença ao longo do horizonte temporal. MONITORAMENTO DO HORIZONTE TECNOLÓGICO: De acordo com os critérios adotados nessa análise, não foram localizados medicamentos em desenvolvimento clínico para a doença. DISCUSSÃO: A análise da evidência clínica apresentada sugere que a tecnologia proposta apresenta efetividade superior à única alternativa disponível atualmente para tratamento da HLX no SUS, com confiabilidade moderada, corroborando atuais recomendações para seu uso em diretrizes internacionais. Por ser uma doença rara, com limitações de dados brasileiros disponibilizados, as análises econômicas submetidas pelo demandante indicam limitações metodológicas, reduzindo a confiabilidade das conclusões a respeito de custo-efetividade e impacto orçamentário no cenário brasileiro podendo ter os valores subestimados. RECOMENDAÇÃO PRELIMINAR DA CONITEC: Os membros do plenário não consideraram como robustas as evidências científicas de eficácia e segurança do borusomabe. Além disso, foi considerado elevado o valor de custo-efetividade incremental, assim como o impacto orçamentário. Sendo assim, no dia 7 de outubro de 2020, em sua 91ª reunião de plenário, os membros da Conitec foram desfavoráveis à recomendação de incorporação no SUS do "Burosumabe para o tratamento de hipofosfatemia ligada ao cromossomo X em adultos e crianças". CONSULTA PÚBLICA: a Consulta Pública nº 56 foi realizada entre os dias 04/11/2020 e 30/11/2020. Foram recebidas 619 contribuições, sendo 103 pelo formulário para contribuições técnico-científicas e 516 pelo formulário para contribuições sobre experiência ou opinião. Após apreciação das contribuições recebidas, o Plenário da Conitec entendeu que houve argumentação suficiente para mudança de entendimento acerca de sua recomendação preliminar. A maioria das contribuições foram contra recomendação e se concentraram nos seguintes benefícios do medicamento: eficácia do tratamento; melhora dos sintomas; melhora dos níveis de fosfato e qualidade de vida. Desse modo, a Comissão mudou a recomendação inicial. RECOMENDAÇÃO FINAL DA CONITEC: Os membros da Conitec presentes na 94ª reunião ordinária, no dia 04 de fevereiro de 2021, consideraram que os benefícios clínicos do tratamento foram mais acentuados na população pediátrica apresentando desfechos consistentes. Diante do exposto, os membros presentes deliberaram, por unanimidade, a recomendação do burosumabe para o tratamento de hipofosfatemia ligada ao cromossomo X em crianças conforme protocolo Clínico e Diretrizes Terapêuticas (PCDT) e recomendar a não incorporação do burosumabe para o tratamento de hipofosfatemia ligada ao cromossomo X em adultos. Assim, foi assinado o Registro de Deliberação nº 589/2021. DECISÃO: incorporar o burosumabe para o tratamento da hipofosfatemia ligada ao cromossomo X em crianças conforme Protocolo Clínico e Diretrizes Terapêuticas (PCDT) e não incorporar o burosumabe para o tratamento da hipofosfatemia ligada ao cromossomo X em adultos, do Sistema Único de Saúde - SUS, conforme Portaria nº 01, publicada no Diário Oficial da União nº 34, seção 1, página 93, em 22 de fevereiro de 2021.
Assuntos
Hipofosfatemia Familiar/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , Avaliação da Tecnologia Biomédica , Análise Custo-Eficiência , Sistema Único de SaúdeRESUMO
OBJECTIVE: Hereditary hypophosphatemias (HH) are rare monogenic conditions characterized by decreased renal tubular phosphate reabsorption. The aim of this study was to explore the prevalence, genotypes, phenotypic spectrum, treatment response, and complications of treatment in the Norwegian population of children with HH. DESIGN: Retrospective national cohort study. METHODS: Sanger sequencing and multiplex ligand-dependent probe amplification analysis of PHEX and Sanger sequencing of FGF23, DMP1, ENPP1KL, and FAM20C were performed to assess genotype in patients with HH with or without rickets in all pediatric hospital departments across Norway. Patients with hypercalcuria were screened for SLC34A3 mutations. In one family, exome sequencing was performed. Information from the patients' medical records was collected for the evaluation of phenotype. RESULTS: Twety-eight patients with HH (18 females and ten males) from 19 different families were identified. X-linked dominant hypophosphatemic rickets (XLHR) was confirmed in 21 children from 13 families. The total number of inhabitants in Norway aged 18 or below by 1st January 2010 was 1,109,156, giving an XLHR prevalence of â¼1 in 60,000 Norwegian children. FAM20C mutations were found in two brothers and SLC34A3 mutations in one patient. In XLHR, growth was compromised in spite of treatment with oral phosphate and active vitamin D compounds, with males tending to be more affected than females. Nephrocalcinosis tended to be slightly more common in patients starting treatment before 1 year of age, and was associated with higher average treatment doses of phosphate. However, none of these differences reached statistical significance. CONCLUSIONS: We present the first national cohort of HH in children. The prevalence of XLHR seems to be lower in Norwegian children than reported earlier.
Assuntos
Transtornos do Crescimento , Hipofosfatemia Familiar , Nefrocalcinose , Sistema de Registros , Adolescente , Criança , Pré-Escolar , Raquitismo Hipofosfatêmico Familiar/complicações , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/epidemiologia , Raquitismo Hipofosfatêmico Familiar/genética , Feminino , Fator de Crescimento de Fibroblastos 23 , Genótipo , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/epidemiologia , Transtornos do Crescimento/etiologia , Transtornos do Crescimento/genética , Humanos , Hipofosfatemia Familiar/complicações , Hipofosfatemia Familiar/tratamento farmacológico , Hipofosfatemia Familiar/epidemiologia , Hipofosfatemia Familiar/genética , Lactente , Masculino , Nefrocalcinose/tratamento farmacológico , Nefrocalcinose/epidemiologia , Nefrocalcinose/etiologia , Nefrocalcinose/genética , Noruega/epidemiologia , Linhagem , Fenótipo , Fósforo/uso terapêutico , Prevalência , Estudos Retrospectivos , Fatores Sexuais , Vitamina D/uso terapêuticoRESUMO
Oncogenic osteomalacia is a rare paraneoplastic syndrome induced by mesenchymal tumors. Just over 100 cases have been reported for this rare disorder, and only seven instances were caused by phosphaturic mesenchymal tumors of the spine. The authors present an illustrative case of a 61-year-old woman with oncogenic osteomalacia induced by a tumor of the spine, and review the literature describing the clinical presentation, surgical treatment, and follow-up of this syndrome.
Assuntos
Hipofosfatemia Familiar/complicações , Mesenquimoma/patologia , Neoplasias de Tecido Conjuntivo/patologia , Síndromes Paraneoplásicas/patologia , Neoplasias da Coluna Vertebral/patologia , Vértebras Torácicas/patologia , Feminino , Fatores de Crescimento de Fibroblastos/metabolismo , Humanos , Hipofosfatemia Familiar/tratamento farmacológico , Mesenquimoma/cirurgia , Pessoa de Meia-Idade , Neoplasias de Tecido Conjuntivo/cirurgia , Procedimentos Ortopédicos/métodos , Osteomalacia , Síndromes Paraneoplásicas/cirurgia , Neoplasias da Coluna Vertebral/cirurgia , Vértebras Torácicas/cirurgia , Resultado do TratamentoRESUMO
A case of young man with low back ache and heel pains who was examined in a rheumatology outpatient and diagnosed as familial hypophosphatemia (FH), probably X-linked (XL), is presented. FH is most commonly transmitted as XL. The role of PHEX gene and fibroblast growth factor 23 is also described.
Assuntos
Calcanhar , Hipofosfatemia Familiar/diagnóstico , Dor Lombar/diagnóstico , Limitação da Mobilidade , Dor/diagnóstico , Adulto , Conservadores da Densidade Óssea/administração & dosagem , Cálcio da Dieta/administração & dosagem , Humanos , Hipofosfatemia Familiar/tratamento farmacológico , Masculino , Vitamina D/administração & dosagemRESUMO
BACKGROUND: Hypophosphataemic rickets (HR) is a rare cause of short stature associated with limb deformities. OBJECTIVE: To report the clinical and laboratory features of HR in two siblings and their father. METHODS: Following the diagnosis of HR in a 4-year-old girl, her siblings and parents were screened using clinical, laboratory, and radiological parameters. RESULTS: Short stature, lower limb deformities, frontal bossing and hypophosphataemia were present in all three patients. Serum alkaline phosphatase (ALP) was markedly elevated in both siblings who were aged two and 11 years but only minimally raised in their 43-year-old father. While spontaneous mutation is the presumed aetiology in the father, X linked dominant inheritance is the likely cause in both daughters. CONCLUSIONS: Hypophosphataemic rickets should be considered in the differential diagnosis of short stature associated with limb deformities regardless of a family history of HR. Serum ALP may not be remarkably elevated when the diagnosis is made in adulthood.
Assuntos
Fosfatase Alcalina/sangue , Hipofosfatemia Familiar/diagnóstico , Deformidades Congênitas dos Membros/diagnóstico por imagem , Raquitismo/genética , Adulto , Criança , Pré-Escolar , Diagnóstico Diferencial , Pai , Feminino , Predisposição Genética para Doença , Humanos , Hipofosfatemia Familiar/tratamento farmacológico , Hipofosfatemia Familiar/genética , Hipofosfatemia Familiar/metabolismo , Masculino , Núcleo Familiar , Fosfatos/administração & dosagem , Radiografia , Raquitismo/complicações , Raquitismo/tratamento farmacológico , Resultado do TratamentoRESUMO
Tenofovir disoproxil fumarate (TDF) is a first-line drug used in patients with highly active retroviral disease; however, it can cause renal failure associated with many tubular anomalies that may be due to down regulation of a variety of ion transporters. Because rosiglitazone, a peroxisome proliferator-activated receptor-gamma agonist induces the expression of many of these same transporters, we tested if the nephrotoxicity can be ameliorated by its use. High doses of TDF caused severe renal failure in rats accompanied by a reduction in endothelial nitric-oxide synthase and intense renal vasoconstriction; all of which were significantly improved by rosiglitazone treatment. Low-dose TDF did not alter glomerular filtration rate but produced significant phosphaturia, proximal tubular acidosis, polyuria and a reduced urinary concentrating ability. These alterations were caused by specific downregulation of the sodium-phosphorus cotransporter, sodium/hydrogen exchanger 3 and aquaporin 2. A Fanconi's-like syndrome was ruled out as there was no proteinuria or glycosuria. Rosiglitazone reversed TDF-induced tubular nephrotoxicity, normalized urinary biochemical parameters and membrane transporter protein expression. These studies suggest that rosiglitazone treatment might be useful in patients presenting with TFV-induced nephrotoxicity especially in those with hypophosphatemia or reduced glomerular filtration rate.
Assuntos
Adenina/análogos & derivados , Nefropatias/tratamento farmacológico , Organofosfonatos/efeitos adversos , Tiazolidinedionas/uso terapêutico , Adenina/efeitos adversos , Animais , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/tratamento farmacológico , Taxa de Filtração Glomerular/efeitos dos fármacos , Hipoglicemiantes/farmacologia , Hipofosfatemia/tratamento farmacológico , Hipofosfatemia Familiar/tratamento farmacológico , Nefropatias/induzido quimicamente , Masculino , Proteínas de Membrana Transportadoras/efeitos dos fármacos , Ratos , Ratos Wistar , Inibidores da Transcriptase Reversa/efeitos adversos , Rosiglitazona , Tenofovir , Tiazolidinedionas/farmacologiaRESUMO
OBJECTIVE: To evaluate the outcome of 1-(OH) vitamin D and oral phosphate treatment on dentin structure in patients with familial hypophosphatemic rickets, and expression of SIBLINGs (a family of non-collagenous proteins involved in dentinogenesis) and osteocalcin. PATIENTS AND METHODS: Seven patients with familial hypophosphatemic rickets (age 3-16 years) were studied before or during treatment. Deciduous and permanent teeth were prepared for scanning electron microscopy (SEM) analysis and immunohistochemistry. RESULTS: Untreated or inadequately treated patients had necrotic teeth with impaired dentin mineralization including unmerged calcospherites and accumulation of non-collagenous proteins in wide interglobular spaces. Most of the primary incisors analyzed displayed fissures linking enamel subsurface to pulp horn. These elements may explain the bacterial penetration and dental abscesses despite the absence of carious lesions. Well-treated patients had healthy teeth with good dentin mineralization and little evidence of calcospherites. CONCLUSION: Treatment of hypophosphatemic children with 1-(OH) vitamin D and oral phosphate insures good dentin development and mineralization, and prevents clinical anomalies such as the dental necrosis classically associated with the disease. Starting treatment during early childhood and good adherence to the therapy are mandatory to observe these beneficial effects.
Assuntos
Dentina/efeitos dos fármacos , Hipofosfatemia Familiar/tratamento farmacológico , Fosfatos/uso terapêutico , Vitamina D/uso terapêutico , Vitaminas/uso terapêutico , Adolescente , Estudos de Casos e Controles , Criança , Pré-Escolar , Necrose da Polpa Dentária/tratamento farmacológico , Necrose da Polpa Dentária/prevenção & controle , Dentina/patologia , Feminino , Humanos , Hipofosfatemia Familiar/complicações , Masculino , Fosfatos/farmacologia , Vitamina D/farmacologia , Vitaminas/farmacologiaRESUMO
Although increased circulating levels of PTH with mild hypocalcemia has been reported in Hyp mice, hyperparathyroidism in X-linked hypophosphatemic rickets is postulated to arise from the standard use of phosphate salts, which induce chronic stimulation of PTH secretion. In this study, we sought to examine the role of PTH in the metabolic derangements associated with Hyp by generating hemizygous hypophosphatemic (Hyp/Y) mice homozygous for the Pth-null allele (Pth(-/-);Hyp/Y). Early postnatal lethality was observed in the Pth(-/-);Hyp/Y mice. Within the first 6 h, postpartum serum phosphorus increased to levels comparable to those in the Pth(-/-) mice, whereas in Hyp mice, it decreased during the first 48 h after birth. Serum calcium concentration started low after birth and remained reduced in both Pth(-/-);Hyp/Y and Pth(-/-) mice although more profoundly so in the former group, whereas in Hyp/Y mice, the levels were initially lower than but reached wild-type levels by 24 h. Circulating PTH levels in Hyp/Y mice were higher than wild-type levels throughout the first 48 h after birth and continued to be so well into adulthood. Twice-daily administration of PTH 1-34 to Pth(-/-);Hyp/Y newborn mice increased serum calcium levels and prevented their early demise. The findings here indicate that the cause of death in the Pth(-/-);Hyp/Y mice is severe hypocalcemia. A potential role for fibroblast growth factor 23 in promoting secondary hyperparathyroidism by suppressing renal 25-hydroxyvitamin D(3)-1alpha-hydroxylase (Cyp27b1) activity while increasing that of renal 25-hydroxyvitamin D(3) 24-hydroxylase (Cyp24) is proposed. Hyperparathyroidism, therefore, is an integral component in the pathophysiology of Hyp, and likely X-linked hypophosphatemic rickets and serves to prevent severe hypocalcemia in mice and perhaps in patients afflicted with the disorder.
Assuntos
Deleção de Genes , Hipofosfatemia Familiar/genética , Hipofosfatemia Familiar/mortalidade , Hormônio Paratireóideo/genética , Animais , Animais Recém-Nascidos , Feminino , Hipocalcemia/genética , Hipocalcemia/mortalidade , Hipocalcemia/fisiopatologia , Hipofosfatemia Familiar/tratamento farmacológico , Hipofosfatemia Familiar/patologia , Masculino , Camundongos , Camundongos Knockout , Hormônio Paratireóideo/uso terapêutico , Fragmentos de Peptídeos/uso terapêutico , Fenótipo , Terapia de Salvação , Índice de Gravidade de Doença , Fatores SexuaisRESUMO
Growth failure appears frequently in children with X-linked hypophosphatemic rickets (XLHR) due to hypophosphatemia, disease severity, body disproportion, and primary bone abnormality. Recombinant human growth hormone (rhGH) increases phosphate tubular reabsorption and phosphate level in blood and, thus, constitutes an attractive but controversial therapy in short children with XLHR, those efficacy was demonstrated in small uncontrolled series. Our aim was to report our experience regarding growth in XLHR. Twenty-seven children with XLHR--20 girls, seven boys--diagnosed at a median (md) of 1.46 years of age, (range 0.39-8.5 years), were studied at 10.12 years of age (1.58-18.56), md (range). All received oral treatment with phosphate and calcitriol. At the first visit, grouped Z-height was -1; (-4.58; 0.54) md (range). After 5 years' follow-up (0.92-15.6), Z-height was -0.91 (- 4.56; 0.17), not different from that at baseline (P = 0.465). In 16 children entirely controlled in our program upon presentation, a "catch up" phenomenon after the rickets had healed (P = 0.823) or throughout the long-term was not observed (P = 0.995). Eight patients had a Z-height = -2SD at the last visit, and impaired linear growth was associated with age >2 years at diagnosis, male gender and non-adherence to treatment. Four children, all boys, received rhGH, and in two cases with sufficient follow up stature normalized. No rhGH side effects were observed, and phosphate and calcitriol doses remained stable. Linear growth failure appeared in a third of XLHR children. Efforts need to be made to reduce the age of diagnosis and to improve adherence to treatment. Treatment with rhGH should be considered early, after the rickets has been controlled, in those patients with impaired growth or delayed diagnosis.
Assuntos
Estatura/efeitos dos fármacos , Transtornos do Crescimento/tratamento farmacológico , Transtornos do Crescimento/fisiopatologia , Crescimento/efeitos dos fármacos , Hormônio do Crescimento Humano/uso terapêutico , Hipofosfatemia Familiar/tratamento farmacológico , Hipofosfatemia Familiar/fisiopatologia , Adolescente , Criança , Pré-Escolar , Feminino , Transtornos do Crescimento/etiologia , Humanos , Hipofosfatemia Familiar/complicações , Lactente , Masculino , Estudos Retrospectivos , Resultado do TratamentoRESUMO
A 45-year-old man was admitted to our hospital because of bone pain and hypophosphatemia. He had undergone surgery 2 years previously for a "benign unclassified mesenchymal tumor" in the skull, but there were no clinical symptoms related to osteomalacia. His laboratory examination revealed low serum phosphate, high alkaline phosphatase, and normal calcium levels. The diagnosis of tumor-induced osteomalacia due to phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT) was made by re-examining the pathologic specimens. Oral supplementation with phosphate and 1-25-dihydroxyvitamin D relieved his clinical symptoms and laboratory values returned to normal. However, subcutaneous administration of octreotide had no clinical effect. Clinicians and pathologists should be aware of the existence of PMTMCT especially nonphosphaturic or asymptomatic variants of this disorder.
Assuntos
Fossa Craniana Posterior/patologia , Hipofosfatemia Familiar/etiologia , Mesenquimoma/complicações , Osteomalacia/etiologia , Neoplasias da Base do Crânio/complicações , Fossa Craniana Posterior/cirurgia , Fraturas Espontâneas/etiologia , Humanos , Hipofosfatemia Familiar/tratamento farmacológico , Imageamento por Ressonância Magnética , Masculino , Mesenquimoma/cirurgia , Mesenquimoma/urina , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/complicações , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/cirurgia , Octreotida/administração & dosagem , Octreotida/uso terapêutico , Osteomalacia/tratamento farmacológico , Osteomalacia/urina , Fosfatos/uso terapêutico , Radiocirurgia , Neoplasias da Base do Crânio/cirurgia , Neoplasias da Base do Crânio/urina , Vitamina D/análogos & derivados , Vitamina D/uso terapêuticoRESUMO
OBJECTIVE: To report a rare case of tertiary hyperparathyroidism (HPT) as a result of long-term oral phosphate therapy. METHODS: We present a case report, with a focus on clinical manifestations and biochemical findings during the course of tertiary HPT, and discuss the pathophysiologic features of this disorder and the therapeutic strategies. RESULTS: A 35-year-old woman, 22 years after the initial diagnosis of familial hypophosphatemic rickets and initiation of treatment with phosphate and vitamin D, underwent assessment for recurrent symptomatic kidney stones, bone pain, and fatigue. Laboratory studies performed 10 months before this presentation showed findings consistent with secondary HPT. Examination was notable for short stature, and pertinent laboratory results were as follows: intact parathyroid hormone 602 pg/mL, calcium 10.9 mg/dL, and phosphorus 3.6 mg/dL. Tertiary HPT was diagnosed, and she underwent subtotal parathyroidectomy and transcervical thymectomy. Postoperatively, she had hypocalcemia and was treated with calcitriol, phosphate, and calcium carbonate; the last agent was discontinued when the serum calcium normalized. Despite multiple dosage alterations in the phosphate and calcitriol therapy, the patient had recurrent tertiary HPT and another kidney stone (treated by lithotripsy). Three years after the subtotal parathyroidectomy, treatment consisted of cinacalcet, calcitriol, and elemental phosphate. CONCLUSION: Long-term follow-up of patients with tertiary HPT is critical, with careful dosage adjustments in phosphate and vitamin D therapy and monitoring of serum levels of phosphorus, calcium, and parathyroid hormone.
Assuntos
Hiperparatireoidismo/induzido quimicamente , Fosfatos/administração & dosagem , Fosfatos/efeitos adversos , Administração Oral , Adulto , Calcitriol/administração & dosagem , Cálcio/sangue , Feminino , Humanos , Hiperparatireoidismo/prevenção & controle , Hipofosfatemia Familiar/tratamento farmacológico , Hormônio Paratireóideo/sangue , Fósforo/análiseRESUMO
In order to examine the etiology of refractory rickets, we evaluated the case records of patients presenting between 1990 and 2002. Subjects with impaired renal functions were excluded. Of 131 patients, 25.9 % each had hypophosphatemic rickets and distal renal tubular acidosis (RTA), 19.6 %vitamin D dependent rickets (VDDR), 11.3 % proximal RTA, 9.1 % liver disease and 6.1 % malabsorption. A significant proportion of patients with VDDR and proximal RTA showed deformities in the first year of life, whereas those with distal RTA and hypophosphatemic rickets presented later. Patients with hypophosphatemic rickets had predominant involvement of lower limbs; hypercalciuria was found in 4. Distal RTA was associated with marked rickets and normal levels of alkaline phosphatase. Hypophosphatemia and low tubular reabsorption of phosphate, though characteristic of hypophosphatemic rickets, was also seen in patients with VDDR (19.2%) and distal RTA (17.6 %). Our findings suggest that application and interpretation of appropriate investigations are useful in determining the cause of non-azotemic refractory rickets allowing initiation of specific therapy.
Assuntos
Acidose Tubular Renal , Hipofosfatemia Familiar/tratamento farmacológico , Raquitismo/tratamento farmacológico , Resultado do Tratamento , Vitamina D/uso terapêutico , Criança , Pré-Escolar , Feminino , Humanos , Hipofosfatemia Familiar/fisiopatologia , Índia , Lactente , Masculino , Recidiva , Estudos Retrospectivos , Raquitismo/fisiopatologiaRESUMO
BACKGROUND: Conventional treatment of X-linked hypophosphatemia with oral phosphate and calcitriol can heal rickets, but it does not always raise serum phosphate concentrations significantly, nor does it always normalize linear growth. Some clinical trials suggest that combining recombinant human growth hormone therapy with conventional treatment improves growth velocity, phosphate retention, and bone mineral density, but some clinical trials suggest that it appears to aggravate the pre-existent disproportionate stature of such children. OBJECTIVES: To determine whether recombinant human growth hormone therapy for children with X-linked hypophosphatemia is associated with changes in longitudinal growth, mineral metabolism, endocrine function, renal function, bone mineral density, body proportions, and also with any adverse effects. SEARCH STRATEGY: Relevant trials were identified from searching the Cochrane Central Register of Controlled Trials Issue 3, 2003 and Ovid MEDLINE 1966 to September 2003. Additional trials were identified from the reference lists of identified trials and other reviews. We also searched the Journal of Bone and Mineral Research (1986 to 2003) and proceedings of the American Society for Bone and Mineral Research Annual Meeting (1st to 24th). Date of most recent search: November 2003. SELECTION CRITERIA: All randomized controlled trials or quasi-randomized controlled trials comparing growth hormone (alone or combined with conventional treatment) with either placebo or conventional treatment alone in children with X-linked hypophosphatemia. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trials for methodological quality and extracted data from eligible trials. MAIN RESULTS: The searches identified five trials, of which one met the inclusion criteria, including a total of five participants. In this trial, rhGH therapy improved the height standard deviation score (z score), and transiently increased serum phosphate and tubular maximum for phosphate reabsorption. AUTHORS' CONCLUSIONS: We have found no conclusive evidence to indicate that the use of recombinant human growth hormone therapy in children with XLH is associated with changes in longitudinal growth, mineral metabolism, endocrine, renal function, bone mineral density, body proportions, but it does not appear to have any adverse effects.
Assuntos
Doenças Genéticas Ligadas ao Cromossomo X/tratamento farmacológico , Hormônio do Crescimento/uso terapêutico , Hipofosfatemia Familiar/tratamento farmacológico , Criança , Humanos , Hipofosfatemia Familiar/genética , Ensaios Clínicos Controlados Aleatórios como Assunto , Proteínas Recombinantes/uso terapêuticoRESUMO
BACKGROUND: X-linked hypophosphatemic rickets (XLH) is characterized by rickets, disproportionate short stature, and impaired renal phosphate reabsorption and vitamin D metabolism. Despite oral phosphate and vitamin D treatment, most children with XLH demonstrate reduced adult height. OBJECTIVE: To determine the beneficial effects of recombinant human growth hormone (rhGH) therapy on body proportions and adult height among patients with XLH. METHODS: Three initially prepubertal short children (age, 9.4-12.9 years) with XLH were treated with rhGH for 3.1 to 6.3 years until adult height was attained. RESULTS: rhGH treatment led to sustained increases in standardized height for all children. The median adult height was 0.9 SD (range: 0.5-1.3 SD) greater than that at the initiation of rhGH treatment and exceeded the predicted adult height by 6.2 cm (range: 5.3-9.8 cm). However, longitudinal growth of the trunk was stimulated more than leg growth. During rhGH treatment, the standardized sitting height increased by 1.6 SD (range: 1.1-2.7 SD), compared with baseline values. In contrast, the median subischial leg length did not change consistently (median change: 0.3 SD; range: -0.1 to 0.6 SD). CONCLUSION: The increase in final height after rhGH treatment is of potential benefit for children with XLH. However, the exaggeration of disproportionate truncal growth observed for our prepubertal patients is a potential negative effect of treatment and should be confirmed with additional studies.
Assuntos
Estatura/efeitos dos fármacos , Transtornos do Crescimento/tratamento farmacológico , Hormônio do Crescimento Humano/uso terapêutico , Hipofosfatemia Familiar/tratamento farmacológico , Criança , Feminino , Crescimento/efeitos dos fármacos , Transtornos do Crescimento/etiologia , Humanos , Hipofosfatemia Familiar/complicações , MasculinoRESUMO
In this report we describe different forms of clinical presentation of an autosomal dominant hypophosphatemic rickets (ADHR) in 4 members of the same family as well as the treatment used in these patients and their response to it. Patient No 1: a 60 year old female who consulted for bone pain: Bone densitometry showed osteoporosis. Laboratory assays showed hypophosphatemia with low renal phosphate threshold, high total alkaline phosphatase, normal intact PTH and normal serum calcium. With neutral phosphate and calcitriol, the biochemical parameters normalized and bone densitometry improved significantly in less than a year. Patient No 2 her grand daughter consulted at 1 year and 8 months of age for growth retardation (height at percentile 3) and genu varum. Laboratory assays showed low serum phosphate and high total alkaline phosphatase; thickening and irregular epiphyseal borders of the wrists were observed radiologically. She began treatment with calcitriol and phosphorus with normalization of laboratory parameters and increase in growth (height increasing to percentile 50 after 20 months of therapy). Patient No 3: mother of patient No 2, she had no clinical manifestations and normal densitometry but presented low serum phosphate (1.9 mg/dl) that normalized with neutral phosphate therapy. Patient No 4: he was the youngest son of Patient No 1, who had had hypophosphatemic rickets, by age 5; his serum phosphate normalized without treatment At age 29, he presented normal serum phosphate and bone densitometry. Genomic DNA analysis performed in patient No 3, showed missense mutation with substitution of arginine at position 179 for glutamine. The family was catalogued as having autosomal dominant hypophosphatemic rickets/osteomalacia.
Assuntos
Fatores de Crescimento de Fibroblastos/genética , Hipofosfatemia Familiar/genética , Mutação , Raquitismo/genética , Adulto , Fosfatase Alcalina/sangue , Criança , Feminino , Fator de Crescimento de Fibroblastos 23 , Humanos , Hipofosfatemia Familiar/diagnóstico , Hipofosfatemia Familiar/tratamento farmacológico , Lactente , Masculino , Pessoa de Meia-Idade , Osteomalacia/complicações , Osteomalacia/diagnóstico , Osteomalacia/genética , Linhagem , Fosfatos/uso terapêutico , Raquitismo/complicações , Raquitismo/diagnósticoRESUMO
In this report we describe different forms of clinical presentation of an autosomal dominant hypophosphatemic rickets (ADHR) in 4 members of the same family as well as the treatment used in these patients and their response to it. Patient No 1: a 60 year old female who consulted for bone pain: Bone densitometry showed osteoporosis. Laboratory assays showed hypophosphatemia with low renal phosphate threshold, high total alkaline phosphatase, normal intact PTH and normal serum calcium. With neutral phosphate and calcitriol, the biochemical parameters normalized and bone densitometry improved significantly in less than a year. Patient No 2 her grand daughter consulted at 1 year and 8 months of age for growth retardation (height at percentile 3) and genu varum. Laboratory assays showed low serum phosphate and high total alkaline phosphatase; thickening and irregular epiphyseal borders of the wrists were observed radiologically. She began treatment with calcitriol and phosphorus with normalization of laboratory parameters and increase in growth (height increasing to percentile 50 after 20 months of therapy). Patient No 3: mother of patient No 2, she had no clinical manifestations and normal densitometry but presented low serum phosphate (1.9 mg/dl) that normalized with neutral phosphate therapy. Patient No 4: he was the youngest son of Patient No 1, who had had hypophosphatemic rickets, by age 5; his serum phosphate normalized without treatment At age 29, he presented normal serum phosphate and bone densitometry. Genomic DNA analysis performed in patient No 3, showed missense mutation with substitution of arginine at position 179 for glutamine. The family was catalogued as having autosomal dominant hypophosphatemic rickets/osteomalacia.
Describimos distintas formas de presentación clínica de un raquitismo hipofosfatémico autosómicodominante en 4 miembros de una misma familia y su respuesta al tratamiento. Paciente N° 1: de sexofemenino de 60 años que consultó por dolores costales y pélvicos, con osteoporosis densitométrica, hipofosfatemia con bajo umbral renal de fósforo, PTH intacta normal y calcemia normal. Tratada con fósforo neutro y calcitriol logró la normalización bioquímica y una notable mejoría de la densitometría en menos de un año. Paciente N° 2: su nieta, consultó al año y ocho meses de edad por presentar talla en percentil 3 y genu varum. En el laboratorio mostró hipofosfatemia y fosfatasa alcalina total muy elevada y en la Rx de mano, ensanchamiento y deflecamiento epifisario compatible con raquitismo. Tratada con fósforo neutro y calcitriol, normalizó los parámetros bioquímicos y logró un ascenso en el percentil de talla de 3 a 50 a los 20 meses de tratamiento. Paciente N° 3: la madre de la paciente N° 2, quien sin ninguna manifestación clínica y con densitometría ósea normal presentó hipofosfatemia que se normalizócon tratamiento con fosfato neutro. Paciente N° 4: el tío de la paciente N° 2, tuvo raquitismo hipofosfatémico de niño,y luego de los 5 años normalizó el fósforo sin tratamiento. Estudiado a los 29 años presentó fósforo normal y densitometría ósea normal. El análisis del ADN genómico de la paciente N° 3 mostró una mutación con sentido erróneo en el gen del factor de crecimiento fifroblástico 23 (sustitución de arginina por una glutamina en posición 179). Por lo tanto se llegó al diagnóstico de raquitismo/osteomalacia hipofosfatémico autosómico dominante.
Assuntos
Criança , Feminino , Humanos , Lactente , Masculino , Pessoa de Meia-Idade , Adulto , Fatores de Crescimento de Fibroblastos/genética , Hipofosfatemia Familiar/genética , Mutação , Raquitismo/genética , Fosfatase Alcalina/sangue , Fosfatos/uso terapêutico , Hipofosfatemia Familiar/diagnóstico , Hipofosfatemia Familiar/tratamento farmacológico , Osteomalacia/complicações , Osteomalacia/diagnóstico , Osteomalacia/genética , Linhagem , Raquitismo/complicações , Raquitismo/diagnósticoRESUMO
A 17 year-old girl with polyostotic fibrous dysplasia and hypophosphatemia had inappropriately low tubular reabsorption of phosphate. She had radiological evidence of rickets and osteomalacia. The patient showed clinical improvement after treatment with phosphate supplementation, active vitamin D (calcitriol) and alendronate. It is postulated that either a phosphaturic substance elaborated from the dysplastic bone or target-organ (kidney) unresponsiveness may interfere with phosphate reabsorption in the renal tubule.