Successful parathyroid tissue autograft after 3 years of cryopreservation: a case report / Implante bem-sucedido de paratireoide criopreservada por 3 anos: relato de caso

After a total parathyroidectomy, well-established protocols for the cryopreservation of parathyroid tissue and for the delayed autograft of this tissue exist, especially in cases of secondary hiperparathyroidism (HPT) or familial or sporadic parathyroid hyperplasia. Although delayed autografts are effective, the published success rates vary from 10% to 83%. There are numerous factors that influence the viability, and therefore the success, of an autograft, including cryopreservation time. Certain authors believe that the tissue is only viable for 24 months, but there is no consensus on how long the parathyroid tissue can be preserved. A 63-year-old male who was diagnosed with sporadic multiple endocrine neoplasia type 1 and primary hyperparathyroidism, and was submitted to a total parathyroidectomy and an autograft in the forearm. The implant failed, and the patient developed severe hypoparathyroidism in the months following the surgery. Thirty-six months after the total parathyroidectomy, the cryopreserved autograft was successfully transplanted, and hypoparathyroidism was reversed (most recent systemic parathyroid hormone, PTH, of 36 pg/mL, and total calcium of 9.1 mg/dL; no oral calcium supplementation). The case presented here indicates that cryopreserved parathyroid tissue may remain viable after 24 months in storage, and may retain the capacity to reverse permanent postsurgical hypoparathyroidism. These data provide reasonable evidence that the time limit for cryopreservation remains undetermined and that additional research would be valuable. Arq Bras Endocrinol Metab. 2014;58(3):313-6.

O implante de tecido paratireoideano criopreservado após paratireoidectomia total é um procedimento bem estabelecido e, embora tenha sua eficácia comprovada, as taxas de sucesso variam de 10% a 83% na literatura. O tempo de criopreservação é um dos diversos fatores relacionados ao sucesso do implante. Alguns autores defendem que o tecido permanece viável até 24 meses de criopreservação, no entanto, não há consenso. Homem de 63 anos diagnosticado com neoplasia endócrina múltipla tipo I e hiperparatireoidismo primário foi submetido a paratireoidectomia total e autoimplante em membro superior. O implante falhou e o paciente desenvolveu hipoparatireoidismo. Após 36 meses da paratireoidectomia total, foi realizado o implante de paratireoide criopreservada, com sucesso. O hipoparatireoidismo foi revertido e o paciente permanece sem suplementação de cálcio e PTH sistêmico de 36 pg/mL e cálcio total de 9,1 mg/dL. O caso apresentado mostra que o tecido paratireoideano criopreservado pode permanecer viável após 24 meses e há possibilidade de reverter o hipoparatireoidismo pós-cirúrgico. Isso traz evidência de que o tempo limite de criopreservação permanece incerto e que novas pesquisas seriam de grande valia. Arq Bras Endocrinol Metab. 2014;58(3):313-6.

A differential diagnosis of inherited endocrine tumors and their tumor counterparts

Inherited endocrine tumors have been increasingly recognized in clinical practice, although some difficulties still exist in differentiating these conditions from their sporadic endocrine tumor counterparts. Here, we list the 12 main topics that could add helpful information and clues for performing an early differential diagnosis to distinguish between these conditions. The early diagnosis of patients with inherited endocrine tumors may be performed either clinically or by mutation analysis in at-risk individuals. Early detection usually has a large impact in tumor management, allowing preventive clinical or surgical therapy in most cases. Advice for the clinical and surgical management of inherited endocrine tumors is also discussed. In addition, recent clinical and genetic advances for 17 different forms of inherited endocrine tumors are briefly reviewed.

Narrowing the gap of personalized medicine in emerging countries: the case of multiple endocrine neoplasias in Brazil

The finished version of the human genome sequence was completed in 2003, and this event initiated a revolution in medical practice, which is usually referred to as the age of genomic or personalized medicine. Genomic medicine aims to be predictive, personalized, preventive, and also participative (4Ps). It offers a new approach to several pathological conditions, although its impact so far has been more evident in mendelian diseases. This article briefly reviews the potential advantages of this approach, and also some issues that may arise in the attempt to apply the accumulated knowledge from genomic medicine to clinical practice in emerging countries. The advantages of applying genomic medicine into clinical practice are obvious, enabling prediction, prevention, and early diagnosis and treatment of several genetic disorders. However, there are also some issues, such as those related to: (a) the need for approval of a law equivalent to the Genetic Information Nondiscrimination Act, which was approved in 2008 in the USA; (b) the need for private and public funding for genetics and genomics; (c) the need for development of innovative healthcare systems that may substantially cut costs (e.g. costs of periodic medical followup); (d) the need for new graduate and postgraduate curricula in which genomic medicine is emphasized; and (e) the need to adequately inform the population and possible consumers of genetic testing, with reference to the basic aspects of genomic medicine.

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.

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.

Transitory increase in creatinine levels after parathyroidectomy: evidence of another action of the parathyroid glands? / Alteração transitória da creatinina após paratireoidectomia: evidência de outra ação das glândulas paratireoides?

OBJECTIVE: Little information is available on glomerular function changes after surgical treatment of primary hyperparathyroidism. The acute effects of some head and neck operations on renal function were studied. MATERIAL AND MATHODS: Retrospective analysis of changes in creatinine levels and estimated glomerular filtration rate (eGFR) after surgery. Preoperative values were compared with values available until 72 hours after the operation. RESULTS: In tertiary hyperparathyroidism, mean preoperative and postoperative eGFR values were 57.7 mL/min and 40.8 mL/min (p < 0.0001), respectively. A similar decrease was observed after parathyroidectomy for primary hyperparathyroidism, from 85.4 mL/min to 64.3 mL/min (p < 0.0001). After major head and neck procedures, there was a slight increase in eGFR (from 94.3 mL/min to 105.4 mL/min, p = 0.002). CONCLUSION: Parathyroidectomy may be followed by a transient decrease in eGFR that is not often observed in other head and neck operations.

OBJETIVO: Há pouca informação sobre alterações da função glomerular após o tratamento cirúrgico do hiperparatireoidismo primário. O efeito agudo sobre a função renal foi estudado após algumas operações em cirurgia de cabeça e pescoço. MATERIAIS E MÉTODOS: Análise retrospectiva dos níveis de creatinina e da taxa de filtração glomerular estimada (eGFR). Os valores pré-operatórios foram comparados aos valores disponíveis até 72 horas após a operação. RESULTADOS: No hiperparatireoidismo terciário, os valores médios pré e pós-operatórios da eGFR foram 57,7 mL/min e 40,8 mL/min (p < 0,0001), respectivamente. O decréscimo após paratireoidectomia por hiperparatireoidismo primário foi de 85,4 mL/min para 64,3 mL/min (p < 0,0001). Após operações maiores de cabeça e pescoço, houve leve elevação da eGFR (de 94,3 mL/min para 105,4 mL/min, p = 0,002). CONCLUSÕES: A paratireoidectomia pode ser seguida de uma redução transitória na eGFR que não é frequentemente observada após outras operações em cabeça e pescoço.

Isolated familial somatotropinoma: 11Q13-LOH and gene/protein expression analysis suggests a possible involvement of aip also in non-pituitary tumorigenesis

OBJECTIVE: Non-pituitary tumors have been reported in a subset of patients harboring germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene. However, no detailed investigations of non-pituitary tumors of AIP-mutated patients have been reported so far. PATIENTS: We examined a MEN1- and p53-negative mother-daughter pair with acromegaly due to somatotropinoma. Subsequently, the mother developed a large virilizing adrenocortical carcinoma and a grade II B-cell non-Hodgkin's lymphoma. DESIGN: Mutational analysis was performed by automated sequencing. Loss-of-heterozygosity (LOH) analysis was carried out by sequencing and microsatellite analysis. AIP expression was assessed through quantitative PCR (qPCR) and immunohistochemistry. RESULTS: The functional inactivating mutation c.241C>T (R81X), which blocks the AIP protein from interacting with phosphodiesterase 4A (PDE4A), was identified in the heterozygous state in the leukocyte DNA of both patients. Analyzing the tumoral DNA revealed that the AIP wild-type allele was lost in the daughter's somatotropinoma and the mother's adrenocortical carcinoma. Both tumors displayed low AIP protein expression levels. Low AIP gene expression was confirmed by qPCR in the adrenocortical carcinoma. No evidence of LOH was observed in the DNA sample from the mother's B-cell lymphoma, and this tumor displayed normal AIP immunostaining. CONCLUSIONS: Our study presents the first molecular analysis of non-pituitary tumors in AIP-mutated patients. The finding of AIP inactivation in the adrenocortical tumor suggests that further investigation of the potential role of this recently identified tumor suppressor gene in non-pituitary tumors, mainly in those tumors in which the cAMP and the 11q13 locus are implicated, is likely to be worthwhile.

Hypercalcitoninemia is not pathognomonic of medullary thyroid carcinoma: [revision]

Hypercalcitoninemia has frequently been reported as a marker for medullary thyroid carcinoma. Currently, calcitonin measurements are mostly useful in the evaluation of tumor size and progression, and as an index of biochemical improvement of medullary thyroid carcinomas. Although measurement of calcitonin is a highly sensitive method for the detection of medullary thyroid carcinoma, it presents a low specificity for this tumor. Several physiologic and pathologic conditions other than medullary thyroid carcinoma have been associated with increased levels of calcitonin. Several cases of thyroid nodules associated with increased values of calcitonin are not medullary thyroid carcinomas, but rather are related to other conditions, such as hypercalcemias, hypergastrinemias, neuroendocrine tumors, renal insufficiency, papillary and follicular thyroid carcinomas, and goiter. Furthermore, prolonged treatment with omeprazole (> 2-4 months), beta-blockers, glucocorticoids and potential secretagogues, have been associated with hypercalcitoninemia. An association between calcitonin levels and chronic auto-immune thyroiditis remains controversial. Patients with calcitonin levels >100 pg/mL have a high risk for medullary thyroid carcinoma (~90%-100%), whereas patients with values from 10 to 100 pg/mL (normal values: <8.5 pg/mL for men, < 5.0 pg/mL for women; immunochemiluminometric assay) have a <25% risk for medullary thyroid carcinoma. In multiple endocrine neoplasia type 2 (MEN2), RET mutation analysis is the gold-standard for the recommendation of total preventivethyroidectomy to relatives at risk of harboring a germline RET mutation (50%). False-positive calcitonin results within MEN2 families have led to incorrect indications of preventive total thyroidectomy to RET mutation negative relatives. In this review, we focus on the differential diagnosis of hypercalcitoninemia, underlining its importance for the avoidance of misdiagnosis...

Sporadic medullary thyroid carcinoma: clinical data from a university hospital

INTRODUCTION: Medullary thyroid carcinoma may occur in a sporadic (s-medullary thyroid carcinoma, 75 percent) or in a multiple endocrine neoplasia type 2 form (MEN2, 25 percent). These clinical forms differ in many ways, as s-medullary thyroid carcinoma cases are RET-negative in the germline and are typically diagnosed later than medullary thyroid carcinoma in MEN2 patients. In this study, a set of cases with s-medullary thyroid carcinoma are documented and explored. PURPOSE: To document the phenotypes observed in s-medullary thyroid carcinoma cases from a university group and to attempt to improve earlier diagnosis of s-medullary thyroid carcinoma. Some procedures for diagnostics are also recommended. METHOD: Patients (n=26) with apparent s-medullary thyroid carcinoma were studied. Their clinical data were reviewed and peripheral blood was collected and screened for RET germline mutations. RESULTS: The average age at diagnosis was 43.9 years (± 10.82 SD) and did not differ between males and females. Calcitonin levels were increased in all cases. Three patients presented values that were 100-fold greater than the normal upper limit. Most (61.54 percent) had values that were 20-fold below this limit. Carcinoembryonic antigen levels were high in 70.6 percent of cases. There was no significant association between age at diagnosis, basal calcitonin levels or time of disease onset with thyroid tumor size (0.6-15 cm). Routine thyroid cytology yielded disappointing diagnostic accuracy (46.7 percent) in this set of cases. After total thyroidectomy associated with extensive cervical lymph node resection, calcitonin values remained lower than 5 pg/mL for at least 12 months in eight of the cases (30.8 percent). Immunocyto- and histochemistry for calcitonin were positive in all analyzed cases. None of the 26 cases presented germline mutations in the classical hotspots of the RET proto-oncogene. CONCLUSION: Our cases were identified late. The basal ...

Screening of RET gene mutations in multiple endocrine neoplasia type-2 using Conformation Sensitive Gel Electrophoresis (CSGE)

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant inherited tumor syndrome caused by RET proto-oncogene germline mutations (RET). Here we tested the Conformation Sensitive Gel Electrophoresis (CSGE) as a screening method for RET hot-spot mutations. Seven MEN2 families were studied by direct sequencing analysis, CSGE and Single Strand Conformational Polymorphism (SSCP). Using CSGE/SSCP, we were able to detect four out of five types of RET mutations verified by sequencing analysis: Cys620Arg, Cys634Arg, Cys634Tyr, and Met918Thr, furthermore a missense substitution at codon 648 (Val648Ile). RET polymorphisms 691 and 769 were also verified. Data obtained using CSGE/SSCP were fully concordant. We conclude that CSGE showed to be a sensitive, fast, low-cost, and simple procedure to detect RET mutations in codons which are reported as the most prevalent RET variants (~ 95 percent) in large MEN2 series. As to the Val804Met mutation, this method still needs to be optimized.

A neoplasia endócrina múltipla tipo 2 (NEM2) é uma síndrome tumoral herdada por mutações germinativas no proto-oncogene RET (RET). Analisamos a aplicação do método Eletroforese em Gel Sensível à Conformação (CSGE) no rastreamento de mutações hot spots do RET. Sete famílias com NEM2 foram rastreadas pelo seqüenciamento gênico, CSGE e análise do Polimorfismo Conformacional de Cadeia Simples (SSCP). Usando ambas as metodologias de rastreamento, identificamos quatro dos cinco tipos de mutações verificadas pelo seqüenciamento: Cys620Arg, Cys634Arg, Cys634Tyr e Met918Thr, além da variação gênica Val648Ile. Das análises englobando mutações hot spots do RET, 90,6 por cento concordaram com o seqüenciamento genético (incluindo a variação gênica Val648Ile). Polimorfismos nos códons 691 e 769 foram documentados. Os dados obtidos por CSGE/SSCP foram totalmente concordantes. Concluímos que o CSGE revelou ser metodologia sensível, rápida, de fácil execução e baixo custo no rastreamento de mutações nos códons associados à grande maioria (~ 95 por cento) dos pacientes com NEM2.