The impact of genetic, molecular and histological changes on the surgical treatment and clinical outcomes of patients with multiple endocrine neoplasia type 1-related primary hyperparathyroidism

• Grant number: 16/25594-9
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2018
• End date: January 31, 2020
• Field of knowledge: Health Sciences - Medicine - Surgery
• Principal Investigator: Fábio Luiz de Menezes Montenegro
• Grantee: Fábio Luiz de Menezes Montenegro
• Host Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil
• Associated researchers: Delmar Muniz Lourenço Jr ; Luiz Fernando Ferraz da Silva ; Marília D Elboux Guimarães Brescia ; Sergio Pereira de Almeida Toledo

Abstract

Hyperparathyroidism (HPT) is the most prevalent clinical manifestation of type 1 multiple endocrine neoplasia (MEN1). HPT may be detected by clinical complications attributed to parathyroid tissue hyperfunction or by abnormal levels of calcium or parathormone (PTH). The pathology of the parathyroid is benign, but renal and osseous complications can be severe.In MEN1, there is a significant prevalence of young patients and multiglandular parathyroid disease is common. In MEN 1 it is assumed that the patient inherits one mutated allele and that the development of parathyroid disease ensues after the event of the second mutation. The second hit may occur at different moments in each parathyroid. Thus, morphological asymmetries of the parathyroids are found during parathyroidectomy. Parathyroidectomy is still the only definitive treatment of HPT in MEN1. It may reduce the risk of osseous and renal complications. Besides the individual benefit, there is an economic advantage to the society. The multiglandular nature of HPT in MEN1 makes difficult to tailor the extent of the operation in these patients. There are different proposals: less than subtotal, subtotal parathyroidectomy, total parathyroidectomy and immediate autograft and total parathyroidectomy alone. A limited parathyroidectomy harbors a reduced risk of hypoparathyroidism, but an increased recurrence rate. Hypoparathyroidism is a complication with many problems including the quality of life. Imaging studies may not identify all hyperfunctioning tissue. Intraoperative surgeon macroscopic judgement may be equivocal. Conventional histopathology can also fail to predict the functional fate of parathyroid remnant tissue. There is doubt regarding the functional behavior of the remnant parathyroid tissue in the long run (the parathyroid stump in subtotal resection or autografted parathyroid). We hypothesize that the detection of second hit (somatic mutation)in the remnant parathyroid tissue might be predictive of the tissue function and this is hypothesis is still untested. The present study aims test the correlation of the structural, molecular and genetic findings in the parathyroid tissue with metabolic profiles, calcium or calcitriol supplements and clinical course after parathyroidectomy. If these correlations really exist, the present study may provide evidence for clinical decision regarding the type of parathyroidectomy and the prognosis in patients with HPT in MEN1. The methodology establishes the prospective analysis of samples of the grafted parathyroids or the parathyroid stump in 45 patients with HPT in MEN1 submitted to parathyroidectomy. The evaluation includes:a)loss of tissue heterozygosity; b) menin protein presence and its expression;c) serum profile of PTH, calcium, phosphorus, magnesium, alkaline phosphatase, urea, creatinine, albumin, P1NP, CTx and Osteocalcin 3-10 postoperative days, 1,2,4,6,9,12,18 and 24 months after the operation. d) calcium and/or calcitriol requirements;e) bone densitometry course;f) Quality of life (SF36 questionnaire) before, 6, 12, 18 and 24 months after the operation During the operation, samples of the parathyroids will be obtained (including autografted tissue or parathyroid stump, depending on the case). Part of this tissue will be submitted to conventional histology and immunohistochemistry with antimenin antibodies. The other part will be stored in liquid nitrogen for future DNA extraction, PCR, sequencing of the MEN1 gene and loss of heterozygosity analysis. (AU)

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

BRESCIA, MARILIA D'ELBOUX GUIMARAES; RODRIGUES, KARINE CANDIDO; D'ALESSANDRO, ANDRE FERNANDES; ALVES FILHO, WELLINGTON; VAN DER PLAS, WILLEMIJN Y.; KRUIJFF, SCHELTO; ARAP, SERGIO SAMIR; TOLEDO, SERGIO PEREIRA DE ALMEIDA; MONTENEGRO, FABIO LUIZ DE MENEZES; LOURENCO, DELMAR MUNIZ. Impact of parathyroidectomy on quality of life in multiple endocrine neoplasia type 1. ENDOCRINE CONNECTIONS, v. 11, n. 6, p. 13-pg., 2022-06-01. (16/25594-9, 15/25444-4, 13/19810-2, 16/07504-2)

DE MENEZES MONTENEGRO, FABIO LUIZ; GUIMARAES BRESCIA, MANILLA D'ELBOUX; LOURENCO JR, DELMAR MUNIZ; ARAP, SERGIO SAMIR; D'ALESSANDRO, ANDRE FERNANDES; E SILVA FILHO, GILBERTO DE BRITTO; DE ALMEIDA TOLEDO, SERGIO PEREIRA. Could the Less-Than Subtotal Parathyroidectomy Be an Option for Treating Young Patients With Multiple Endocrine Neoplasia Type 1-Related Hyperparathyroidism?. FRONTIERS IN ENDOCRINOLOGY, v. 10, MAR 7 2019. (16/07504-2, 16/25594-9, 15/25444-4)