Biochemical, bone and renal patterns in hyperparathyroidism associated with multiple endocrine neoplasia type 1

Primary hyperparathyroidism associated with multiple endocrine neoplasia type I (hyperparathyroidism/multiple endocrine neoplasia type 1) differs in many aspects from sporadic hyperparathyroidism, which is the most frequently occurring form of hyperparathyroidism. Bone mineral density has frequently been studied in sporadic hyperparathyroidism but it has very rarely been examined in cases of hyperparathyroidism/multiple endocrine neoplasia type 1. Cortical bone mineral density in hyperparathyroidism/multiple endocrine neoplasia type 1 cases has only recently been examined, and early, severe and frequent bone mineral losses have been documented at this site. Early bone mineral losses are highly prevalent in the trabecular bone of patients with hyperparathyroidism/multiple endocrine neoplasia type 1. In summary, bone mineral disease in multiple endocrine neoplasia type 1related hyperparathyroidism is an early, frequent and severe disturbance, occurring in both the cortical and trabecular bones. In addition, renal complications secondary to sporadic hyperparathyroidism are often studied, but very little work has been done on this issue in hyperparathyroidism/multiple endocrine neoplasia type 1. It has been recently verified that early, frequent, and severe renal lesions occur in patients with hyperparathyroidism/multiple endocrine neoplasia type 1, which may lead to increased morbidity and mortality. In this article we review the few available studies on bone mineral and renal disturbances in the setting of hyperparathyroidism/multiple endocrine neoplasia type 1. We performed a meta-analysis of the available data on bone mineral and renal disease in cases of multiple endocrine neoplasia type 1-related hyperparathyroidism.

Total parathyroidectomy in a large cohort of cases with hyperparathyroidism associated with multiple endocrine neoplasia type 1: experience from a single academic center

Most cases of sporadic primary hyperparathyroidism present disturbances in a single parathyroid gland and the surgery of choice is adenomectomy. Conversely, hyperparathyroidism associated with multiple endocrine neoplasia type 1 (hyperparathyroidism/multiple endocrine neoplasia type 1) is an asynchronic, asymmetrical multiglandular disease and it is surgically approached by either subtotal parathyroidectomy or total parathyroidectomy followed by parathyroid auto-implant to the forearm. In skilful hands, the efficacy of both approaches is similar and both should be complemented by prophylactic thymectomy. In a single academic center, 83 cases of hyperparathyroidism/ multiple endocrine neoplasia type 1 were operated on from 1987 to 2010 and our first surgical choice was total parathyroidectomy followed by parathyroid auto-implant to the non-dominant forearm and, since 1997, associated transcervical thymectomy to prevent thymic carcinoid. Overall, 40% of patients were given calcium replacement (mean intake 1.6 g/day) during the first months after surgery, and this fell to 28% in patients with longer follow-up. These findings indicate that several months may be needed in order to achieve a proper secretion by the parathyroid auto-implant. Hyperparathyroidism recurrence was observed in up to 15% of cases several years after the initial surgery. Thus, long-term follow-up is recommended for such cases. We conclude that, despite a tendency to subtotal parathyroidectomy worldwide, total parathyroidectomy followed by parathyroid auto-implant is a valid surgical option to treat hyperparathyroidism/multiple endocrine neoplasia type 1. Larger comparative systematic studies are needed to define the best surgical approach to hyperparathyroidism/multiple endocrine neoplasia type 1.

Primary hyperparathyroidism in multiple endocrine neoplasia type 1: when to perform surgery?

Primary hyperparathyroidism is a common endocrinological disorder. In rare circumstances, it is associated with familial syndromes, such as multiple endocrine neoplasia type 1. This syndrome is caused by a germline mutation in the multiple endocrine neoplasia type 1 gene encoding the tumor-suppressor protein menin. Usually, primary hyperparathyroidism is the initial clinical expression in carriers of multiple endocrine neoplasia type 1 mutations, occurring in more than 90% of patients and appearing at a young age (20-25 years). Multiple endocrine neoplasia type 1/primary hyperparathyroidism is generally accompanied by multiglandular disease, clinically manifesting with hypercalcemia, although it can remain asymptomatic for a long time and consequently not always be recognized early. Surgery is the recommended treatment. The goal of this short review is to discuss the timing of surgery in patients when primary hyperparathyroidism is associated with multiple endocrine neoplasia type 1.

Surgical treatment of pancreatic endocrine tumors in multiple endocrine neoplasia type 1

Surgical approaches to pancreatic endocrine tumors associated with multiple endocrine neoplasia type 1 may differ greatly from those applied to sporadic pancreatic endocrine tumors. Presurgical diagnosis of multiple endocrine neoplasia type 1 is therefore crucial to plan a proper intervention. Of note, hyperparathyroidism/multiple endocrine neoplasia type 1 should be surgically treated before pancreatic endocrine tumors/multiple endocrine neoplasia type 1 resection, apart from insulinoma. Non-functioning pancreatic endocrine tumors/multiple endocrine neoplasia type 1 >1 cm have a high risk of malignancy and should be treated by a pancreatic resection associated with lymphadenectomy. The vast majority of patients with gastrinoma/multiple endocrine neoplasia type 1 present with tumor lesions at the duodenum, so the surgery of choice is subtotal or total pancreatoduodenectomy followed by regional lymphadenectomy. The usual surgical treatment for insulinoma/multiple endocrine neoplasia type 1 is distal pancreatectomy up to the mesenteric vein with or without spleen preservation, associated with enucleation of tumor lesions in the pancreatic head. Surgical procedures for glucagonomas, somatostatinomas, and vipomas/ multiple endocrine neoplasia type 1 are similar to those applied to sporadic pancreatic endocrine tumors. Some of these surgical strategies for pancreatic endocrine tumors/multiple endocrine neoplasia type 1 still remain controversial as to their proper extension and timing. Furthermore, surgical resection of single hepatic metastasis secondary to pancreatic endocrine tumors/multiple endocrine neoplasia type 1 may be curative and even in multiple liver metastases surgical resection is possible. Hepatic trans-arterial chemo-embolization is usually associated with surgical resection. Liver transplantation may be needed for select cases. Finally, pre-surgical clinical and genetic diagnosis of multiple endocrine neoplasia type 1 syndrome and localization of multiple endocrine neoplasia type 1related tumors are crucial for determining the best surgical strategies in each individual case with pancreatic endocrine tumors.

Surgical approach in patients with hyperparathyroidism in multiple endocrine neoplasia type 1: total versus partial parathyroidectomy

Usually, primary hyperparathyroidism is the first endocrinopathy to be diagnosed in patients with multiple endocrine neoplasia type 1, and is also the most common one. The timing of the surgery and strategy in multiple endocrine neoplasia type 1/hyperparathyroidism are still under debate. The aims of surgery are to: 1) correct hypercalcemia, thus preventing persistent or recurrent hyperparathyroidism; 2) avoid persistent hypoparathyroidism; and 3) facilitate the surgical treatment of possible recurrences. Currently, two types of surgical approach are indicated: 1) subtotal parathyroidectomy with removal of at least 3-3 K glands; and 2) total parathyroidectomy with grafting of autologous parathyroid tissue. Transcervical thymectomy must be performed with both of these procedures. Unsuccessful surgical treatment of hyperparathyroidism is more frequently observed in multiple endocrine neoplasia type 1 than in sporadic hyperparathyroidism. The recurrence rate is strongly influenced by: 1) the lack of a pre-operative multiple endocrine neoplasia type 1 diagnosis; 2) the surgeon's experience; 3) the timing of surgery; 4) the possibility of performing intra-operative confirmation (histologic examination, rapid parathyroid hormone assay) of the curative potential of the surgical procedure; and, 5) the surgical strategy. Persistent hyperparathyroidism seems to be more frequent after subtotal parathyroidectomy than after total parathyroidectomy with autologous graft of parathyroid tissue. Conversely, recurrent hyperparathyroidism has a similar frequency in the two surgical strategies. To plan further operations, it is very helpful to know all the available data about previous surgery and to undertake accurate identification of the site of recurrence.

Post-surgical follow-up of primary hyperparathyroidism associated with multiple endocrine neoplasia type 1

The bone mineral density increments in patients with sporadic primary hyperparathyroidism after parathyroidectomy have been studied by several investigators, but few have investigated this topic in primary hyperparathyroidism associated with multiple endocrine neoplasia type 1. Further, as far as we know, only two studies have consistently evaluated bone mineral density values after parathyroidectomy in cases of primary hyperparathyroidism associated with multiple endocrine neoplasia type 1. Here we revised the impact of parathyroidectomy (particularly total parathyroidectomy followed by autologous parathyroid implant into the forearm) on bone mineral density values in patients with primary hyperparathyroidism associated with multiple endocrine neoplasia type 1. Significant increases in bone mineral density in the lumbar spine and femoral neck values were found, although no short-term (15 months) improvement in bone mineral density at the proximal third of the distal radius was observed. Additionally, short-term and medium-term calcium and parathyroid hormone values after parathyroidectomy in patients with primary hyperparathyroidism associated with multiple endocrine neoplasia type 1 are discussed. In most cases, this surgical approach was able to restore normal calcium/parathyroid hormone levels and ultimately lead to discontinuation of calcium and calcitriol supplementation.

Surgical management of pancreatico-duodenal tumors in multiple endocrine neoplasia syndrome type 1

Pancreatico-duodenal tumors are the second most common endocrinopathy in multiple endocrine neoplasia syndrome type 1, and have a pronounced effect on life expectancy as the principal cause of disease-related death. Previous discussions about surgical management have focused mainly on syndromes of hormone excess and, in particular, the management of multiple endocrine neoplasia syndrome type 1-related Zollinger-Ellison syndrome. Since hormonal syndromes tend to occur late and indicate the presence of metastases, screening with biochemical markers and endoscopic ultrasound is recommended for early detection of pancreatico-duodenal tumors, and with early surgery before metastases have developed. Surgery is recommended in patients with or without hormonal syndromes in the absence of disseminated liver metastases. The suggested operation includes distal 80% subtotal pancreatic resection together with enucleation of tumors in the head of the pancreas, and in cases with Zollinger-Ellison syndrome, excision of duodenal gastrinomas together with clearance of regional lymph node metastases. This strategy, with early and aggressive surgery before metastases have developed, is believed to reduce the risks for tumor recurrence and malignant progression.

Application of genetic testing to define the surgical approach in a sporadic case of multiple endocrine neoplasia type 1 / Aplicação de teste genético para definição da conduta cirúrgica num caso esporádico de neoplasia endócrina múltipla do tipo 1

We report the use of a genetic test for therapeutic decision making in a case of primary hyperparathyroidism associated with Cushing's disease (CD). A 20-year-old woman was evaluated for gradual weight gain, asthenia, muscle pain, and hypertension. Biochemical and radiologic tests confirmed CD and she underwent transsphenoidal surgery. Immunohistochemistry of the microadenoma was positive for adrenocorticotropic hormone (ACTH). On follow-up, hypercalcemia with high parathyroid hormone (PTH) levels was detected, associated with nephrolithiasis and low bone mineral density in the spine and hip. Parathyroid scintigraphy showed tracer uptake in the inferior region of the left thyroid lobe, and cervical ultrasound showed a heterogeneous nodule in the same area, suggestive of a parathyroid adenoma (PA). Genetic testing detected mutation in the MEN 1 gene and total parathyroidectomy with the implantation of a fragment of one gland in the forearm was performed. Pathology showed a PA and 3 normal parathyroid glands, without hyperplasia, despite the diagnosis of MEN 1. This case illustrates the role of genetic testing in defining the therapeutic approach for sporadic MEN 1.

Relatamos o uso de teste genético para decisão terapêutica em um caso de hiperparatireoidismo primário associado com doença de Cushing (DC). Uma jovem de 20 anos foi avaliada por ganho de peso gradual, astenia, mialgias e hipertensão. Os exames complementares confirmaram DC e ela foi submetida à cirurgia transesfenoidal. A análise imuno-histoquímica do microadenoma foi positiva para hormônio adrenocorticotrófico (ACTH). No seguimento, a paciente apresentou hipercalcemia com níveis elevados de hormônio de paratireoide (PTH), nefrolitíase e densidade mineral óssea baixa em coluna e fêmur. A cintilografia de paratireoide mostrou captação do traçador em região inferior do lobo esquerdo da tireoide e a ecografia cervical revelou nódulo heterogêneo na mesma área, sugestivo de adenoma da paratireoide (AP). O teste genético detectou mutação no gene MEN 1 e ela foi submetida à paratireoidectomia total com implante de fragmento de uma das glândulas no antebraço. A patologia confirmou AP e as outras três glândulas normais, sem hiperplasia, apesar do diagnóstico de MEN 1. Esse caso ilustra a importância do teste genético para definir a abordagem terapêutica em um caso esporádico de MEN 1.

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.

Neoplasia endocrina múltiple tipo 1: caso clínico / Multiple endocrine neoplasia type 1: clinical case

Las neoplasias endocrinas múltiples se caracterizan por la presencia de tumores en dos o más glándulas endocrinas en un mismo paciente. Actualmente se conocen tres tipos fundamentales que son: neoplasia endocrina múltiple tipo 1, tipo 2 y tipo 3. La neoplasia endocrina múltiple tipo 1 se caracteriza por presentar tumores en la paratiroides, la hipófisis y el páncreas, en forma secuencial o simultánea, cuya histología puede ir desde hiperplasias hasta adenomas y carcinomas, productores o no de hormonas. La clínica varía según los órganos afectados y su grado de compromiso, así como de las distintas sustancias secretadas por las neoplasias. Su morbimortalidad se relaciona principalmente con los tumores productores de gastrina. Se presenta un caso clínico y una revisión del tema

Insulinoma pancreático / Pancreatic insulinoma

El insulinoma es un tumor de escasa incidencia, de origen endocrino que puede formar parte de los síndromes de neoplasia endocrina múltiple de tipo I. Se presentan casos diagnosticados y operados en el período de 1995 a 1999. Los casos fueron sometidos a resección quirúrgica. Los síntomas y signos de hipoglicemia más frecuentes fueron sudoración, taquicardia y compromiso de conciencia. El valor promedio de la glicemia de ayuno fue de 39 mg/dl y de 76 UI para la insulinemia. La sencibilidad del TAC y de la angiografía fue de 40 por ciento y 50 por ciento, respectivamente. Según localización, en 2 casos el tumor estabaen la cabeza, dos en el cuerpo y uno en la cola. Se realizaron tres enucleaciones, una pancreatectomía distal y una pancreatoduodenectomía. La evolución fue sin complicaciones en 3 de los 5 casos, uno desarrolló una fístula biliar manejada en forma conservadora y otro una fístula pancreática y colecciones intraabdominales que requirió reoperación con evolución posterior satisfactoria. Todos los pacientes analizados han sido seguidos por 19 meses de promedio, comprobándose su estado asistomático y normoglicémico. La cirugía parece ser curativa para la mayoría de los casos pero está exenta de morbilidad

Macroprolactinoma como componente da síndrome de neoplasia endócrina múltipla tipo I / Macroprolactinoma how component of multiple endocrine neoplasm type I syndrome

Com o objetivo de discutir peculiaridades clínicas da neoplasia endócrina múltipla (NEM) do tipo 1 säo apresentados oito casos de uma família afetada, dos quais quatro se submetem a investigaçäo médica. Alguns aspectos clínicos se sobressaem nessa série, tais como: o macroprolactinoma em três casos foi o principal responsável pelas manifestaçöes da síndrome e em dois casos mostrou caráter invasivo; incidência maior no sexo masculino; a precocidade do surgimento dos sintomas (21 a 32 anos de idade) e possível ausência de comprometimento pancreático. A falta de comprometimento pancreático sugere que pode se tratar de uma variante incompleta da síndrome de NEM tipo 1, embora o acompanhamento pancreático seja necessário para se confirmar esta hipótese. A adenomectomia hipofisária foi realizada em dois casos, um dos quais faleceu em consequencia de recidiva tumoral e o controle dos níveis de prolactina foi obtido com bromocriptina no outro caso; bromocriptina foi a única terapeutica utilizada no terceiro paciente. Três pacientes realizaram paratiroidectomia total seguido de implante autólogo das paratireóides em dois deles. O implante manteve calcemia normal em ambos os casos. Recomenda-se repetidas determinaçöes de calcemia em todos os portadores de tumor hipofisário, como meio de identificar portadores de NEM do tipo 1