Therapy for persistent hypercalcemic hyperparathyroidism post-renal transplant: cinacalcet versus parathyroidectomy / Tratamento do hiperparatireoidismo hipercalcêmico persistente pós-transplante renal: cinacalcete versus paratireoidectomia

ABSTRACT Background: Persistent hyperparathyroidism post-transplant is associated with increases in the incidence of cardiovascular events, fractures, and deaths. The aim of this study was to compare both therapeutic options available: parathyroidectomy (PTX) and the calcimimetic agent cinacalcet. Methods: A single center retrospective study including adult renal transplant recipients who developed hypercalcemia due to persistent hyperparathyroidism. Inclusion criteria: PTH > 65 pg/mL with serum calcium > 11.5 mg/dL at any time after transplant or serum calcium persistently higher than 10.2 mg/dL one year after transplant. Patients treated with cinacalcet (n=46) were compared to patients treated with parathyroidectomy (n=30). Follow-up period was one year. Clinical and laboratory data were analyzed to compare efficacy and safety of both therapeutic modalities. Results: PTX controlled calcemia faster (month 1 x month 6) and reached significantly lower levels at month 12 (9.1±1.2 vs 9.7±0.8 mg/dL, p < 0.05); PTX patients showed significantly higher levels of serum phosphate (3.8±1.0 vs 2.9±0.5 mg/dL, p < 0.05) and returned PTH to normal levels (45±51 pg/mL). Cinacalcet, despite controlling calcium and phosphate in the long term, decreased but did not correct PTH (197±97 pg/mL). The proportion of patients that remained with PTH above normal range was 95% in the cinacalcet group and 22% in the PTX group. Patients treated with cinacalcet had better renal function (creatinine 1.2±0.3 vs 1.7±0.7 mg/dL, p < 0.05). Conclusions: Surgical treatment was superior to cinacalcet to correct the metabolic disorders of hyperparathyroidism despite being associated with worse renal function in the long term. Cinacalcet proved to be a safe and well tolerated drug.

RESUMO Introdução: O hiperparatireoidismo persistente pós-transplante está associado a aumento na incidência de eventos cardiovasculares, fraturas e óbitos. O objetivo deste estudo foi comparar as opções terapêuticas disponíveis: paratireoidectomia (PTX) e o agente calcimimético cinacalcete. Métodos: Estudo retrospectivo de um único centro incluiu pacientes transplantados renais adultos que desenvolveram hipercalcemia devido a hiperparatireoidismo persistente. Critérios de inclusão: PTH > 65 pg/mL com cálcio sérico > 11,5 mg/dL a qualquer momento após o transplante, ou cálcio sérico persistentemente superior a 10,2 mg/dL um ano após o transplante. Os pacientes tratados com cinacalcete (n = 46) foram comparados aos pacientes tratados com paratireoidectomia (n = 30). O período de acompanhamento foi de um ano. Dados clínicos e laboratoriais foram analisados para comparar a eficácia e a segurança de ambas as modalidades terapêuticas. Resultados: a PTX controlou a calcemia mais rapidamente (mês 1 x mês 6) e atingiu níveis significativamente mais baixos no mês 12 (9,1 ± 1,2 v.s. 9,7 ± 0,8 mg/dL, p < 0,05); pacientes submetidos à PTX apresentaram níveis significativamente mais altos de fósforo sérico (3,8 ± 1,0 v.s. 2,9 ± 0,5 mg/dL, p < 0,05) e retornaram aos níveis normais de PTH (45 ± 51 pg/mL). O cinacalcete, apesar de controlar o cálcio e o fósforo no longo prazo, diminuiu, mas não corrigiu o PTH (197 ± 97 pg/mL). A proporção de pacientes que permaneceram com PTH acima da faixa normal foi de 95% no grupo cinacalcete e 22% no grupo PTX. Os pacientes tratados com cinacalcete apresentaram melhor função renal (creatinina 1,2 ± 0,3 v.s. 1,7 ± 0,7 mg/dL, p < 0,05). Conclusões: O tratamento cirúrgico foi superior ao cinacalcete para corrigir os distúrbios metabólicos do hiperparatireoidismo, apesar de estar associado a pior função renal no longo prazo. Cinacalcete provou ser um medicamento seguro e bem tolerado.

Association between hypocalcemia and rivaroxaban in coagulation disorders: a case report / Associação entre hipocalcemia e rivaroxaban em distúrbios de coagulação: relato de caso

ABSTRACT We describe a patient with tertiary hyperparathyroidism with history of three episodes of deep vein thrombosis and on rivaroxaban. The patient underwent a subtotal parathyroidectomy, developing cervical hematoma with airway compression. Therefore, emergency surgical decompression was necessary. Later, on the ninth postoperative day, the serum ionized calcium levels were low. Medical team knowledge about preexisting diseases and their implication in the coagulation state are essential conditions to reduce morbidity and mortality of surgeries. However, no reports were found in literature about the association of hypocalcemia with the use of the new class of anticoagulants, which act as factor X inhibitors (Stuart-Prower factor), predisposing to increased bleeding in the immediate postoperative period.

RESUMO Descrevemos um paciente com hiperparatireoidismo terciário com história de três episódios de trombose venosa profunda e em uso de rivaroxabana. O paciente foi submetido a uma paratireoidectomia subtotal, desenvolvendo hematoma cervical com compressão das vias aéreas. Foi necessária descompressão cirúrgica de emergência. No nono dia de pós-operatório, os níveis séricos de cálcio iônico estavam baixos. O conhecimento da equipe médica sobre doenças preexistentes e de sua implicação no estado de coagulação é condição indispensável para a redução da morbimortalidade do procedimento cirúrgico. No entanto, não há relatos na literatura associando hipocalcemia com o uso da nova classe de anticoagulantes que atuam como inibidores do fator X (fator de Stuart-Prower), predispondo ao aumento do sangramento no pós-operatório imediato.

Disparity between Preoperative and Pre-Excisional Intraoperative Parathyroid Hormone in Parathyroid Surgery

Abstract Introduction Intraoperative parathyroid hormone (ioPTH) testing is a widely accepted standard for assessing the parathyroid gland function. A decline of preoperative parathyroid hormone (PTH) levels by more than 50% is one accepted measure of parathyroid surgery adequacy. However, there may be a variation between preoperative PTH levels obtained at a clinic visit and pre-excisional ioPTH. Objective Our study explores the differences between preoperative PTH and pre-excisional ioPTH levels, and the potential impact this difference has on determining the adequacy of parathyroid surgery. Methods A retrospective study that consisted of 33 patients that had undergone parathyroid resection between September 2009 and March 2016 at a tertiary academic center was performed. Each subject's preoperative PTH levels were obtained from clinic visits and pre-excisional ioPTH levels were recorded along with the time interval between the measurements. Results There was a significant difference between the mean preoperative PTH and the pre-excisional ioPTH levels of 147 pg/mL (95% confidence interval [CI] 11.43 to 284.47; p= 0.0396). The exclusion of four outliers revealed a further significant difference with a mean of 35.09 pg/mL (95% CI 20.27 to 49.92; p< 0.0001). The average time interval between blood draws was 48 days + 32 days. A weak correlation between the change in PTH values and the time interval between preoperative and pre-excision blood draws was noted (r2 = 0.15). Conclusion Our study reveals a significant difference between the preoperative PTH levels obtained at clinic visits and the pre-excisional intraoperative PTH levels. We recommend routine pre-excisional intraoperative PTH levels, despite evidence of elevated preoperative PTH levels, in order to more accurately assess the adequacy of surgical resection.

Hypocalcemia development in patients operated for primary hyperparathyroidism: Can it be predicted preoperatively?

ABSTRACT Objective Primary hyperparathyroidism (PHP) is a common endocrine disease, and its most effective treatment is surgery. Postoperative hypocalcemia is a morbidity of parathyroid surgeries, and it may extend hospitalization durations. The purpose of this study is to determine the predictive factors related to the development of hypocalcemia and hungry bone syndrome (HBS) in patients who underwent parathyroidectomy for PHP. Materials and methods Laboratory data comprising parathyroid hormone (PTH), calcium, phosphate, 25-OHD, albumin, magnesium, alkaline phosphatase (ALP), blood urea nitrogen (BUN), and thyroid stimulating hormone (TSH) of the patients were recorded preoperatively, on the 1st and 4th days postoperatively, and in the 6th postoperative month, and their neck ultrasound (US) and bone densitometry data were also recorded. Results Hypocalcemia was seen in 63 patients (38.4%) on the 1st day after parathyroidectomy. Ten patients (6.1%) had permanent hypocalcemia in the 6th month after surgery. Out of the patients who underwent parathyroidectomy for PHP, 22 (13.4%) had HBS. The incidence of postoperative hypocalcemia was higher in patients who underwent parathyroidectomy for PHP, who had parathyroid hyperplasia, and who had osteoporosis. Preoperative PTH, ALP, and BUN values were higher in those patients who developed HBS. Furthermore, HBS was more common in patients who had osteoporosis, who had parathyroid hyperplasia, and who underwent thyroidectomy simultaneously with parathyroidectomy. Conclusions As a result, patients who have the risk factors for development of hypocalcemia and HBS should be monitored more attentively during the perioperative period.

The history of the parathyroid surgery / A história da cirurgia das paratireoides

ABSTRACT The authors conducted a review of the major aspects of progression of knowledge about the surgical treatment of hyperparathyroidism. Through literature review, we analyzed articles on the history of the evolution of anatomical, physiological, pathological and surgical knowledge of the parathyroid glands. Because of their unique anatomical features, the parathyroid glands were the last of the endocrine glands to be discovered, which greatly hindered proper treatment until the first decades of the twentieth century. Technological developments in the last 30 years greatly facilitated the location of the glands and hyperparathyroidism surgery. However, an experienced and dedicated surgeon is still essential to the excellence of treatment.

RESUMO Os autores fizeram uma revisão dos principais aspectos históricos da progressão do conhecimento sobre o tratamento cirúrgico do hiperparatireoidismo. Por meio de revisão bibliográfica, foram analisados artigos selecionados sobre a história da evolução do conhecimento anatômico, fisiológico, patológico e cirúrgico das glândulas paratireoides. Devido às suas características anatômicas peculiares, as paratireoides foram as últimas das glândulas endócrinas a serem descobertas, o que dificultou sobremaneira seu tratamento adequado até as primeiras décadas do Século XX. A evolução tecnológica ocorrida nos últimos 30 anos facilitou sobremaneira a localização das glândulas e a cirurgia do hiperparatireoidismo. Contudo, um cirurgião experiente e dedicado ao tratamento dessa enfermidade ainda é fundamental para a excelência do tratamento.

Localizacao de glandulas paratireoides ectopicas e supranumerarias em pacientes com hiperparatireoidismo secundario e terciario: descricao cirurgica e correlacao com ultrassonografia e cintilografia Tc99m-Sestamibi pre-operatorios / Localization of ectopic and supernumerary parathyroid glands in patients with secondary and tertiary hyperparathyroidism: surgical description and correlation with preoperative ultrasonography and Tc99m-Sestamibi scintigraphy

Introdução: O hiperparatireoidismo é uma consequência metabólica esperada na doença renal crônica (DRC). Paratireoides (PT) ectópicas e/ou supranumerárias podem ser causa de falha cirúrgica nos pacientes submetidos à paratireoidectomia total (PTX). Objetivo: Definir cirurgicamente a localização das PT, em pacientes com hiperparatireoidismo associado à DRC, e correlacionar esses achados com os exames pré-operatórios. Materiais e métodos: Foi conduzido um estudo retrospectivo com 166 pacientes submetidos à PTX. A localização das PT no intraoperatório foi registrada, sendo classificada como tópica ou ectópica. A localização pré-operatória, definida pela ultrassonografia (USG) e pela cintilografia Tc99m-Sestamibi (MIBI), foi comparada com aos achados cirúrgicos. Resultados: Nos 166 pacientes, foram identificadas 664 PT. Foram classificadas como tópicas e ectópicas 577 (86,4%) e 91(13,6%) glândulas, respectivamente. Oito PT supranumerárias foram encontradas (7 tópicas e 1 ectópica). As localizações mais comuns de PT ectópicas foram as regiões retroesofágica e tímica. Associadas, a USG e a MIBI não identificaram 56 glândulas (61,5%) ectópicas. Entretanto, a MIBI foi positiva para 69,7% daquelas localizadas nas regiões tímicas e mediastinal. Conclusão: A presença de glândulas ectópicas e supranumerárias em pacientes com hiperparatireoidismo associado à DRC é significativa. Os exames de imagem pré-operatórios não localizaram a maioria das glândulas ectópicas. A MIBI pode ter importância na identificação de PT nas regiões tímica e mediastinal. .

Introduction: Hyperparathyroidism is an expected metabolic consequence of chronic kidney disease (CKD). Ectopic and/or supernumerary parathyroid glands (PT) may be the cause of surgical failure in patients undergoing total parathyroidectomy (PTX). Aim: To define the locations of ectopic and supernumerary PT in patients with renal hyperparathyroidism and to correlate intraoperative findings with preoperative tests. Materials and methods: A retrospective study was conducted with 166 patients submitted to PTX. The location of PT during surgery was recorded and classified as eutopic or ectopic. The preoperative localizations of PT found by ultrasonography (USG) and Tc99m-Sestamibi scintigraphy (MIBI) were subsequently compared with intraoperative findings. Results: In the 166 patients studied, 664 PT were found. Five-hundred-seventy-seven (86.4%) glands were classified as eutopic and 91(13.6%) as ectopic. Eight supernumerary PT were found. The most common sites of ectopic PT were in the retroesophageal and thymic regions. Taken together, USG and MIBI did not identify 56 (61.5%) ectopic glands. MIBI was positive for 69,7% of all ectopic glands located in the mediastinal and thymic regions. Conclusion: The presence of ectopic and supernumerary PT in patients with renal hyperparathyroidism is significant. Although preoperative imaging tests did not locate most of ectopic glands, MIBI may be important for identifying ectopic PT in the mediastinal and thymic regions. .

Diagnosis and management of primary hyperparathyroidism: a scientific statement from the Department of Bone Metabolism, the Brazilian Society for Endocrinology and Metabolism / Diagnóstico e manejo do hiperparatireoidismo primário: uma posição científica do Departamento de Metabolismo Ósseo, a Sociedade Brasileira de Endocrinologia e Metabolismo

OBJECTIVE: To conduct a literature review on the diagnosis and management of primary hyperparathyroidism including the classical hipercalcemic form as well as the normocalcemic variant. MATERIALS AND METHODS: This scientific statement was generated by a request from the Brazilian Medical Association (AMB) to the Brazilian Society for Endocrinology as part of its Clinical Practice Guidelines program. Articles were identified by searching in PubMed and Cochrane databases as well as abstracts presented at the Endocrine Society, Brazilian Society for Endocrinology Annual Meetings and the American Society for Bone and Mineral Research Annual Meeting during the last 5 years. Grading quality of evidence and strength of recommendation were adapted from the first report of the Oxford Centre for Evidence-based Medicine. All grades of recommendation, including "D", are based on scientific evidence. The differences between A, B, C and D, are due exclusively to the methods employed in generating evidence. CONCLUSION: We present a scientific statement on primary hyperparathyroidism providing the level of evidence and the degree of recommendation regarding causes, clinical presentation as well as surgical and medical treatment.

OBJETIVO: Conduzir uma atualização das últimas evidências científicas a respeito da apresentação, do diagnóstico e do manejo clínico e cirúrgico do hiperparatireoidismo primário clássico e normocalcêmico. MATERIAIS E MÉTODOS: Este documento foi concebido pelo Departamento de Metabolismo Ósseo da Sociedade Brasileira de Endocrinologia e Metabologia (SBEM) a partir daquele oriundo do Programa de Diretrizes da Associação Médica Brasileira (AMB) da SBEM. Realizamos uma revisão dos artigos mais relevantes obtidos nos bancos de dados PubMed e Cochrane, além de abstracts apresentados nos encontros anuais da Endocrine Society, da Sociedade Brasileira de Endocrinologia e da American Society for Bone and Mineral Research dos últimos cinco anos, e classificamos as evidências em níveis de recomendações de acordo com a força científica por tipo de estudo, adaptando o primeiro relato do "Oxford Centre for Evidence-based Medicine". Todos os graus de recomendação, incluindo-se o "D", foram basea-dos em evidência científica, sendo as diferenças entre o A, B, C e D devidas exclusivamente ao desenho empregado na geração da evidência. CONCLUSÃO: Apresentamos uma atualização científica a respeito do hiperparatireoidismo primário, classificando e graduando em níveis de recomendações as principais evidências científicas sobre as suas causas, as variadas formas de apresentação, seu diagnóstico e tratamento.

New mutation in the CASR gene in a family with familial hypocalciuric hypercalcemia (FHH) and neonatal severe hyperparathyroidism (NSHPT) / Nova mutação no gene CASR em uma família com hipercalcemia hipocalciúrica familiar (HHF) e hiperparatireoidismo neonatal grave (HPTNG)

A loss of calcium-sensing receptor (CASR) function due to inactivating mutations can cause familial hypocalciuric hypercalcemia (FHH) or neonatal severe hyperparathyroidism (NSHPT). NSHPT represents the most severe expression of FHH and courses as a life-threatening condition. The aim of this study was to identify and characterize a CASR mutation in a female infant brought to the health service due to dehydration, apathy, lack of breast feeding and severe hypercalcemia. Molecular analysis was performed on genomic DNA of the index case and her parents. A novel homozygous mutation (p.E519X) in CASR was identified in the proband; both mother and father had the same mutation in heterozygous state, confirming their FHH condition. The mutation results in a truncated and inactive protein due to the lack of transmembrane and intracellular domains. The identification of this novel CASR gene mutation established the basis of hypercalcemia in this family and allowed a genetic counseling.

Mutações inativadoras no gene do sensor do cálcio (CASR) podem causar hipercalcemia hipocalciúrica familiar (HHF) ou hiperparatireoidismo neonatal grave (HPTNSG). A HPTNS representa a forma mais grave da HHF cursando com risco de vida. O objetivo deste estudo foi identificar e caracterizar uma mutação no gene CASR de uma criança do sexo feminino levada ao hospital em decorrência de desidratação, apatia, dificuldade para mamar e hipercalcemia grave. A análise molecular foi realizada a partir do DNA genômico do caso índice e de seus pais. Uma nova mutação em homozigose (p.E519X) foi identificada no caso índice; ambos, mãe e pai, apresentaram a mesma mutação em heterozigose, o que os caracteriza como portadores de HHF. Essa alteração resulta em uma proteína truncada e inativa devido à falta dos domínios transmembrana e intracelular. A identificação dessa nova mutação estabeleceu a causa da hipercalcemia na família e permitiu o aconselhamento genético.

Assessment of targeted parathyroidectomy for solitary adenoma without intra-operative parathyroid hormone monitoring

Minimally invasive parathyroidectomy has become the first surgical option for patients with primary hyperparathyroidism [HPT]. Preoperative localization study using Technetium-99m sestamibi [MIBI] scan is mandatory. The present study was conducted to analyze our series of targeted parathyroidectomies for solitary adenoma without the use of intraoperative parathyroid hormone monitoring [IPHM]. In a 5-year period [2005-2010], 50 patients underwent unilateral neck exploration for HPT at Ahmadi hospital, Kuwait. After biochemical diagnosis, a technetium 99m sestamibi scan and cervical ultrasonography were performed preoperatively for all patients. Histopathologic examination was used to confirm parathyroid tissue in all patients. Data regarding patient demographics, surgical details, results, and complications were analyzed. Patients were followed-up regularly for a mean of 48.5 months [range 6-66 months]. There were 37 women and 13 men, with a mean age of 52 years [range 25-71 years]. Mean preoperative calcium was 12.3 mg/dL [range 11.0-15.1 mg/dL], and PTH was 352 pg/mL [range 115-2,131 pg/mL]. Mean operative time was 47 minutes [range 35-90 minutes], and the mean parathyroid weight was 1.1 g[range 0.21-1.8 g]. Mean hospital stay was 2 days [range 1-7 days]. MIBI scan correctly localized the abnormal gland in 47 patients [94%] and three patients [6%] required contralateral exploration. There were no operative mortalities or complications. Postoperatively, there was two operative hematomas [4%]. All patients became normo-calcemic, at 24 hours postoperatively and 46 patients [92%] were asymptomatic at one year. Based on the data presented, it may be concluded that selected patients with solitary parathyroid adenomas, localized preoperatively by MIBI scan be safely and successfully treated with targeted parathyroidectomy without the use of IPHM

Utilidad de la PTH intraoperatoria como predictor de curación quirúrgica en hiperparatiroidismo primario / Usefulness of intraoperative parathormone measurement to predict surgical cure in primary hyperparathyroidism

Background: The aim of the surgical treatment of primary hyperparathyroidism (PHPT) is to achieve its complete cure, evidenced by normal serum calcium in the postoperative period. Measurement of intraoperative serum parathormone (PTH) can be useful to predict complete cure of the disease. Aim: To assess the usefulness of intraoperative PTH measurement to predict complete cure of PHPT Material and methods: Serum PTH was measured to all patients operated for PHPT between 2003 and 2008, before and five and ten minutes after the excision of the parathyroid gland causing the disease. The criteria for complete cure were normal serum calcium at 24 hours and 6 months after surgery and the pathological confirmation of parathyroid gland excision. Results: Eighty-eight operated patients, aged 58±15 years (72 females) were studied. Sixty four percent were asymptomatic and their preoperative serum calcium was 11.6± 1.2 mg/dl. A normal serum calcium was achieved in 86 patients (98 percent) at 24 hours and 50 of 52 patients followed for six months (96 percent). The pathological study disclosed an adenoma in 69 (78 percent), and multiglandular disease in 16 (18 percent), a parathyroid cancer in one and a normal gland in one patient. Intraoperative PTH predicted early and definitive cure in 97 percent and 100 percent of patients with a single adenoma, respectively. Among patients with multiglandular disease, the predictive figures were 94 percent and 100 percent, respectively. Conclusions: Intraoperative PTH measurement efficiently predicts early and definitive surgical cure of PHPT.

Neoplasia endocrina múltiple tipo 1 / Multiple endocrine neoplasia type 1

Multiple endocrine neoplasia type 1 (NEM1) is an uncommon autosomal dominant disease caused by an alteration of menin, a tumor suppression protein and is characterized by the presence of primary tumors in at least two different endocrine tissues. It is described as the “three P disease”since it involves mainly the pituitary, parathyroid and pancreas. However more than 20 different tumor locations have been described. Most tumors are benign and primary hyperparathyroidism is the first manifestation of the disease in 90 percent of cases enteropancreatic tumors appear in approximately 60 percent of patients and pituitary adenomas, usually prolactinomas, in 30 percent. Skin lesions, non functional adrenal adenomas and neuroendocrine tumors such as carcinoid are also part of the disease. We describe the pathogenesis, clinical presentation, diagnosis and treatment of NEM1.

Minimally invasive radionuclide-guided parathyroidectomy using [99m] Tc-Sestamibi in patients with primary hyperparathyroidism: a single-instituion experience

To evaluate the efficacy and usefulness of [99m]Tc- sestambi sccintigraphy and gamma probe localization of parathyroid glands in patients with primary hyperparathyroidism and establish radio-guided minimally invasive parathyroidectomy at Hussain Makki Al Jumma Center for Specialized Surgery, Kuwait. Twelve patients with primary hyperparathyroidism [mean age: 48 +/- 14 years; median age: 46 years; age range-29-68 years] were evaluated. The diagnosis of hyperparathyroidism was established by elevated serum calcium and parathyroid hormone levels. All patients had a well-defined parathyroid lesion on previous standard [99m]Tc-sestambi scintigraphy with or without ultrasound study. All had a normal thyroid gland, no history of familial hyperparathyroidism or multiple endocrine neoplasia nor any history of previous neck irradiation. On the day of surgery, patients were injected with 740 MBq [20mCi] of [99m]Tc-sestamibi followed by a half-hour-delayed single standard pinhole view of the neck. A skin marker was placed on the basis of maximum count intensity during gamma probe localization. Patients were then sent for radio-guided minimally invasive parathyroidectomy. The preoperative localization of the affected gland was successful in all cases using a gamma probe and [99m]Tc-sestamibi scintigraphy. The pathological parathyroid tissue was localized and successfully removed with the gamma probe. The histopathological diagnosis was parathyroid adenoma in 11 cases and hyperplasia in the remaining one. All patients remained disease and symptom free at 12-month follow-up. Our initial experience with intraoperative use of a gamma probe to carry out minimally invasive parathyroidectomy was a useful, easy and safe procedure for treating patients with primary hyperparathyroidism

HRPT2-related familial isolated hyperparathyroidism: could molecular studies direct the surgical approach? / Formas familiares de hiperparatireoidismo relacionadas a mutações no gene HRPT2: estudos moleculares poderiam direcionar procedimentos cirúrgicos?

It is still debatable which is the best management to familial forms of hyperparathyroidism. Conservative, minimally invasive or aggressive surgical approaches have been proposed from different groups around the world. Our objective was to study the gene mutation, expression of HRPT2 and the clinical outcome after 32 years of follow-up in one Brazilian kindred with familial isolated hyperparathyroidism (FIHP). Clinical and biochemical data, direct sequencing of the HRPT2 gene, analysis of parafibromin expression using RT-PCR, and immunohistochemistry were done. A nonsense mutation was found in exon 1 (c.96G>A)(p.Trp32X) in all affected members studied. Using RT-PCR, mRNA transcription was altered with complete absence of both transcripts in tumor tissue. Immunohistochemical analysis of tumors showed loss of parafibromin immunoreactivity. In this kindred there was a high prevalence of recurrence (75 percent), or persistence after less than subtotal parathyroidectomy that led us to consider a more aggressive surgical approach should be discussed among the affected family members, once surgical criteria was met. We concluded that it is necessary to individualize the surgical approach for HRPT2-related hyperparathyroidism until we can gather a better phenotype-genotype correlation in larger series, to best define their treatment.

A melhor conduta nas formas familiares de hiperparatireoidismo relacionadas a mutações no gene HRPT2 ainda é controvertida. Cirurgias conservadoras, minimamente invasivas ou mais agressivas já foram propostas por diferentes grupos. Objetivamos estudar a seqüência e a expressão do gene HRPT2, além do desfecho clínico, após seguimento de até 32 anos de uma família brasileira com hiperparatireodismo familiar isolado (FIHP). Utilizamos dados clínicos e bioquímicos, seqüenciamento direto do HRPT2 além de análise da expressão da parafibromina através da RT-PCR e imunohistoquímica. Foi identificada mutação nonsense no éxon 1 (c.96G>A)(p.Trp32X) em todos os membros afetados que foram estudados. A análise do mRNA transcrito, através da RT-PCR, demonstrou ausência do transcrito no tecido tumoral. A imunohistoquímica também evidenciou ausência da parafibromina. Nessa família houve alta (75 por cento) prevalência de recorrência ou persistência da doença após paratireoidectomia parcial o que nos levou a considerar fundamental discutir uma abordagem cirúrgica mais agressiva com os outros familiares portadores da mutação caso critérios de indicação cirúrgica sejam atingidos. Dessa maneira, até que estudos mais amplos estabeleçam uma correlação genótipo-fenótipo no hiperparatireoidismo familiar relacionado a mutações no HRPT2, a abordagem cirúrgica deverá ser individualizada.

Analysis of the diagnostic presentation profile, parathyroidectomy indication and bone mineral density follow-up of Brazilian patients with primary hyperparathyroidism

Primary hyperparathyroidism is an endocrine disorder with variable clinical expression, frequently presenting as asymptomatic hypercalcemia in Western countries but still predominantly as a symptomatic disease in developing countries. The objective of this retrospective study was to describe the diagnostic presentation profile, parathyroidectomy indication and post-surgical bone mineral density follow-up of patients with primary hyperparathyroidism seen at a university hospital. We found 115 patients (92 women, median age 56 years) with primary hyperparathyroidism diagnosed during the last 20 years. We defined symptomatic patients based on the presence of any classical symptom affecting bone, kidney or the neuromuscular system. Surgical criteria followed the guidelines of the National Institutes of Health regarding asymptomatic primary hyperparathyroidism. Symptomatic patients and patients meeting surgical criteria for parathyroidectomy were 66 and 93 percent of the sample, respectively. Median calcium and parathyroid hormone values were 11.9 mg/dL and 189 pg/mL, respectively. After surgical treatment, 97 percent of patients were cured, with increases in bone mineral density of 19.4 percent in the lumbar spine and 15.7 percent in the femoral neck 3 years after surgery. Greater bone mass increases were detected in pre-menopausal women, men, and in symptomatic and younger patients, both in the lumbar spine and femoral neck. Our results support the previous findings of a predominantly symptomatic disease with a presentation profile that could be mainly related to a delayed diagnosis. Nevertheless, genetic and racial backgrounds, and nutritional factors such as calcium and vitamin D deficiency may play a role in the clinical presentation of primary hyperparathyroidism of Brazilian patients.

Hiperparatireoidismo associado à osteomalacia hipofosfatêmica do adulto: relato de caso e revisão da literatura / Hyperparathyroidism associated with hypophosphatemic osteomalacia: case report and review of the literature

A osteomalacia hipofosfatêmica é uma doença rara caracterizada por hipofosfatemia, níveis elevados de fosfatase alcalina e diminuição da densidade óssea. O tratamento é realizado com suplementação oral com fosfato e vitamina D e, nos casos de osteomalacia oncogênica, com a ressecção do tumor. Relatamos o caso de uma paciente que apresentou quadro de osteomalácia hipofosfatêmica de causa indeterminada. Apesar de extensivamente procurado, nenhum tumor produtor de substância hipofosfatêmica foi localizado. A paciente foi tratada como suplementação de fosfato e vitamina D por longo período, evoluindo com quadro de hiperparatireoidismo terciário. A retirada de três paratireóides não normalizou os níveis de PTH e a paciente recusou-se a continuar a investigação e o tratamento. Após dez anos de tratamento irregular, foi internada por insuficiência respiratória causada por colabamento do arcabouço costal e múltiplas fraturas, evoluindo para o óbito. Os autores discutem a relação entre osteomalácia e hiperparatireoidismo e o curso agressivo da doença.

Clinical suspicion and parathyroid carcinoma management

CONTEXTO E OBJETIVO: A abordagem adequada do carcinoma de paratireóide parece relacionada à capacidade de identificação pelo cirurgião na primeira operação. O objetivo do estudo foi avaliar o papel da suspeita clínica pré-operatória na abordagem do carcinoma de paratireóide. TIPO DE ESTUDO E LOCAL: Análise retrospectiva realizada no Departamento de Cirurgia de Cabeça e Pescoço, da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brasil. MÉTODOS: De 1995 a 2000, 143 pacientes foram operados por hiperparatireoidismo. Esses casos foram revistos para verificar se a suspeita clínica pré e intra-operatória de carcinoma de paratireóide foi útil para a realização de operação mais extensa e quais fatores melhor se relacionaram com a suspeita de carcinoma. RESULTADOS: Entre 66 casos de hiperparatireoidismo primário, houve quatro casos de carcinoma de paratireóide (6,1%), e um caso foi encontrado em hiperparatireoidismo secundário (1,3%). Nódulos palpáveis foram observados em cinco pacientes com hiperparatireoidismo primário, quatro deles com carcinoma de paratireóide. Os níveis pré-operatórios da calcemia nos casos de carcinoma de paratireóide de hiperparatireoidismo primário variaram entre 12,0 mg/dl e 18,2 mg/dl. Em dois pacientes, o tumor tinha invasão macroscópica de estruturas adjacentes. Com exceção de um caso, com doença extensa, houve ressecção completa em monobloco dos tumores. No hiperparatireoidismo secundário, o carcinoma de paratireóide foi identificado numa quinta glândula mediastinal. Houve um caso de adenoma atípico. CONCLUSÕES: O nível de calcemia muito elevado, o tumor palpável e a aderência a estruturas próximas são comuns no carcinoma de paratireóide. Esses sinais clínicos podem ser úteis na tomada de decisão nas operações sobre a glândula paratireóide.