Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 9 de 9
Filtrar
Mais filtros










Base de dados
Tipo de estudo
Intervalo de ano de publicação
1.
Endocr Connect ; 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31557724

RESUMO

Primary hyperparathyroidism is the most frequent manifestation of Multiple Endocrine Neoplasia type 1 (MEN1) syndrome. Bone and renal complications are common. Surgery is the treatment of choice, but the best timing for surgery is controversial and predictors of persistence and recurrence are not well known. Our study describes the clinical characteristics and the surgical outcomes, after surgery and in the long-term, of the patients with MEN1 and primary hyperparathyroidism included in the Spanish Registry of Multiple Endocrine Neoplasia, Pheochromocytomas and Paragangliomas (REGMEN). 89 patients (49 men and 40 women, 34.2 + 13 years old) were included. 64 out of the 89 underwent surgery: a total parathyroidectomy was done in 13 patients, a subtotal parathyroidectomy in 34 and a less than subtotal parathyroidectomy in 15. Remission rates were higher after a total or a subtotal parathyroidectomy than after a less than subtotal (3/4 and 20/22 vs. 7/12, p<0.05), without significant differences in permanent hypoparathyroidism (1/5, 9/23 and 0/11, N.S.). After a median follow-up of 111 months, 20 of the 41 operated patients with long-term follow-up had persistent or recurrent hyperparathyroidism. We did not find differences in disease-free survival rates between different techniques, patients with or without permanent hypoparathyroidism and patients with different mutated exons, but a second surgery was more frequent after a less than subtotal parathyroidectomy.

2.
J Autoimmun ; 103: 102285, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31182340

RESUMO

Autoimmune thyroid diseases (AITDs), i.e., Graves' disease (GD) and Hashimoto thyroiditis (HT), are the most prevalent organ-specific autoimmune diseases, but their pathogenesis is still incompletely understood. The PD-1/PD-L1 pathway is an important mechanism of peripheral tolerance that has not been investigated in AITDs. Here, we report the analysis of the expression of PD-1, PD-L1 and PD-L2 in PBMCs, infiltrating thyroid lymphocytes (ITLs) and in thyroid follicular cells (TFCs) in GD, HT and multinodular goiter (MNG) patients and healthy controls PBMCs (HC). By combining flow cytometry, tissue immunofluorescence and induction experiments on primary and thyroid cell line cultures, we show that: 1) while PD-1+ T cells are moderately expanded in PBMCs from GD vs HC, approximately half of T cells in the infiltrate are PD-1+ including some PD-1hi; 2) PD-L1, but not PD-L2, is expressed by 81% of GD glands and in 25% of non-autoimmune glands; 3) PD-L1, was expressed by TFCs in areas that also contain abundant PD-1 positive T cells but; 4) co-localization in TFCs indicated only partial overlap between the smaller areas of the PD-L1+ and the larger areas of HLA class II+ expression; 5) IFNγ is capable of inducing PD-L1 in >90% of TFCs in primary cultures and cell lines. Collectively these results indicate that the PD-1/PD-L1 axis is operative in AITD glands and may restrain the autoimmune response. Yet the discrepancy between easy induction in vitro and the limited expression in vivo (compared to HLA) suggests that PD-L1 expression in vivo is partially inhibited in GD and HT glands. In conclusions 1) the PD-1/PD-L1 pathway is activated in AITD glands but probably not to the extent to inhibit disease progression and 2) Thyroid autoimmunity arising after PD-1/PD-L1 blocking therapies in cancer patients may result from interfering PD-1/PD-L1 tolerance mechanism in thyroid with minimal (focal) thyroiditis. Finally acting on the PD-1/PD-L1 pathway could be a new approach to treat AITD and other organ-specific autoimmunity in the future.

3.
Artigo em Inglês | MEDLINE | ID: mdl-27933172

RESUMO

Skeletal manifestations of primary hyperparathyroidism (pHPT) include brown tumors (BT), which are osteoclastic focal lesions often localized in the jaws. Brown tumors are a rare manifestation of pHTP in Europe and USA; however, they are frequent in developing countries, probably related to vitamin D deficiency and longer duration and severity of disease. In the majority of cases, the removal of the parathyroid adenoma is enough for the bone to remineralize, but other cases require surgery. Hyperparathyroidism in MEN1 develops early, and is multiglandular and the timing of surgery remains questionable. To our knowledge, there are no reports of BT in MEN 1 patients. We present a 29-year-old woman with MEN 1 who developed a brown tumor of the jaw 24 months after getting pregnant, while breastfeeding. Serum corrected calcium remained under 2.7 during gestation, and at that point reached a maximum of 2.82 mmol/L. Concomitant PTH was 196 pg/mL, vitamin D 13.7 ng/mL and alkaline phosphatase 150 IU/L. Bone mineral density showed osteopenia on spine and femoral neck (both T-scores = -1.6). Total parathyroidectomy was performed within two weeks, with a failed glandular graft autotransplantation, leading to permanent hypoparathyroidism. Two months after removal of parathyroid glands, the jaw tumor did not shrink; thus, finally it was successfully excised. We hypothesize that higher vitamin D and mineral requirements during maternity may have triggered an accelerated bone resorption followed by appearance of the jaw BT. We suggest to treat pHPT before planning a pregnancy in MEN1 women or otherwise supplement with vitamin D, although this approach may precipitate severe hypercalcemia. LEARNING POINTS: Brown tumors of the jaw can develop in MEN 1 patients with primary hyperparathyroidism at a young age (less than 30 years).Pregnancy and lactation might trigger brown tumors by increasing mineral and vitamin D requirements.Early parathyroidectomy is advisable in MEN 1 patients with primary hyperparathyroidism, at least before planning a pregnancy.Standard bone mineral density does not correlate with the risk of appearance of a brown tumor.Removal of parathyroid glands does not always lead to the shrinkage of the brown tumor, and surgical excision may be necessary.

4.
J Immunol ; 194(9): 4199-206, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25801430

RESUMO

Graves' disease (GD) is an autoimmune thyroid disease defined by the production of stimulating autoantibodies to the thyroid-stimulating hormone receptor (TSHR) (TSAbs) that induce a sustained state of hyperthyroidism in patients. We previously demonstrated that TSHR, the target of this autoimmune response, is also a key susceptibility gene for GD, probably acting through thymic-dependent central tolerance. We also showed that TSHR is, unexpectedly, expressed in thymocytes. In this report, we confirm the expression of TSHR in thymocytes by protein immunoblotting and quantitative PCR, and show that expression is confined to maturing thymocytes. Using functional assays, we show that thymic TSHR is functional and that TSAbs can stimulate thymocytes through this receptor. This new activity of TSAbs on thymocytes may: 1) explain GD-associated thymic enlargement (hyperplasia), and 2) suggest the provocative hypothesis that the continuous stimulation of thymocytes by TSAbs could lead to a vicious cycle of iterative improvement of the affinity and stimulating capability of initially low-affinity antibacterial (e.g., Yersinia) Abs cross-reactive with TSHR, eventually leading to TSAbs. This may help to fill one of the gaps in our present understanding of unusual characteristics of TSAbs.


Assuntos
Autoanticorpos/imunologia , Doença de Graves/imunologia , Ativação Linfocitária/imunologia , Receptores da Tireotropina/imunologia , Timócitos/imunologia , Adolescente , Criança , Pré-Escolar , Humanos , Lactente , Receptores da Tireotropina/genética , Timócitos/citologia
5.
Eur J Endocrinol ; 172(3): 301-7, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25515555

RESUMO

OBJECTIVE: Specific germline mutations in the RET proto-oncogene are correlated with clinical features in multiple endocrine neoplasia type 2A (MEN2A); however, data are scarce regarding differences in clinical profiles dependent on the type of nucleotide and amino acid substitution at the same codon. We aimed to analyse differences in clinical risk profiles and outcomes among different amino acids encoded by codon 634. DESIGN: The study was retrospective and multicentric. METHODS: We collected data included in the Spanish Online National Database from patients with MEN2A carrying a RET proto-oncogene mutation on codon 634. The mean follow-up time was 7.6±6.9 years (1-32). RESULTS: Patients (n=173) from 49 unrelated families were C634Y carriers, and 26 patients from eight different families had C634R mutation. We found higher penetrance of medullary thyroid carcinoma, phaeochromocytoma and hyperparathyroidism (P<0.001, P=0.007 and P<0.001 respectively) in C634R carriers than in C634Y carriers. The Kaplan-Meier estimate of cumulative lymph node and distant metastases rates showed that these events occurred earlier in patients harbouring the C634R mutation (P<0.001). A multivariate adjusted Cox regression analysis indicated that the C634R mutation was an independent factor for persistent/recurrent disease (hazard ratio, 3.17; 95% CI: 1.66-6.03; P<0.001). CONCLUSIONS: Our results suggest that there could be clinical differences caused by different amino acid substitutions at codon 634; specifically, the C634R mutation was associated with a more aggressive MEN2A phenotype than the C634Y mutation.


Assuntos
Neoplasia Endócrina Múltipla Tipo 2a/genética , Mutação/genética , Proteínas Proto-Oncogênicas c-ret/genética , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Humanos , Lactente , Masculino , Estudos Retrospectivos , Adulto Jovem
6.
J Immunol ; 193(8): 3872-9, 2014 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-25217160

RESUMO

Down syndrome (DS), or trisomy of chromosome 21, is the most common genetic disorder associated with autoimmune diseases. Autoimmune regulator protein (AIRE), a transcription factor located on chromosome 21, plays a crucial role in autoimmunity by regulating promiscuous gene expression (pGE). To investigate if autoimmunity in DS is promoted by the reduction of pGE owing to dysregulation of AIRE, we assessed the expression of AIRE and of several peripheral tissue-restricted Ag genes by quantitative PCR in thymus samples from 19 DS subjects and 21 euploid controls. Strikingly, despite the 21 trisomy, AIRE expression was significantly reduced by 2-fold in DS thymuses compared with controls, which was also confirmed by fluorescent microscopy. Allele-specific quantification of intrathymic AIRE showed that despite its lower expression, the three copies are expressed. More importantly, decreased expression of AIRE was accompanied by a reduction of pGE because expression of tissue-restricted Ags, CHRNA1, GAD1, PLP1, KLK3, SAG, TG, and TSHR, was reduced. Of interest, thyroid dysfunction (10 cases of hypothyroidism and 1 of Graves disease) developed in 11 of 19 (57.9%) of the DS individuals and in none of the 21 controls. The thymuses of these DS individuals contained significantly lower levels of AIRE and thyroglobulin, to which tolerance is typically lost in autoimmune thyroiditis leading to hypothyroidism. Our findings provide strong evidence for the fundamental role of AIRE and pGE, namely, central tolerance, in the predisposition to autoimmunity of DS individuals.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade/imunologia , Síndrome de Down/imunologia , Fatores de Transcrição/biossíntese , Adolescente , Adulto , Doenças Autoimunes/complicações , Doenças Autoimunes/genética , Autoimunidade/genética , Tolerância Central , Criança , Pré-Escolar , Síndrome de Down/complicações , Síndrome de Down/genética , Feminino , Expressão Gênica , Humanos , Hipotireoidismo/complicações , Lactente , Masculino , Timo/metabolismo , Tireoglobulina/biossíntese , Tireoglobulina/imunologia , Fatores de Transcrição/imunologia , Adulto Jovem
7.
Artigo em Inglês | MEDLINE | ID: mdl-24683479

RESUMO

UNLABELLED: Isolated GH deficiency type IA (IGHDIA) is an infrequent cause of severe congenital GHD, often managed by pediatric endocrinologists, and hence few cases in adulthood have been reported. Herein, we describe the clinical status of a 56-year-old male with IGHDIA due to a 6.7 kb deletion in GH1 gene that encodes GH, located on chromosome 17. We also describe phenotypic and biochemical parameters, as well as characterization of anti-GH antibodies after a new attempt made to treat with GH. The height of the adult patient was 123 cm. He presented with type 2 diabetes mellitus, dyslipidemia, osteoporosis, and low physical and psychological performance, compatible with GHD symptomatology. Anti-GH antibodies in high titers and with binding activity (>101 IU/ml) were found 50 years after exposure to exogenous GH, and their levels increased significantly (>200 U/ml) after a 3-month course of 0.2 mg/day recombinant human GH (rhGH) treatment. Higher doses of rhGH (1 mg daily) did not overcome the blockade, and no change in undetectable IGF1 levels was observed (<25 ng/ml). IGHDIA patients need lifelong medical surveillance, focusing mainly on metabolic disturbances, bone status, cardiovascular disease, and psychological support. Multifactorial conventional therapy focusing on each issue is recommended, as anti-GH antibodies may inactivate specific treatment with exogenous GH. After consideration of potential adverse effects, rhIGF1 treatment, even theoretically indicated, has not been considered in our patient yet. LEARNING POINTS: Severe isolated GHD may be caused by mutations in GH1 gene, mainly a 6.7 kb deletion.Appearance of neutralizing anti-GH antibodies upon recombinant GH treatment is a characteristic feature of IGHDIA.Recombinant human IGF1 treatment has been tested in children with IGHDIA with variable results in height and secondary adverse effects, but any occurrence in adult patients has not been reported yet.Metabolic disturbances (diabetes and hyperlipidemia) and osteoporosis should be monitored and properly treated to minimize cardiovascular disease and fracture risk.Cerebral magnetic resonance imaging should be repeated in adulthood to detect morphological abnormalities that may have developed with time, as well as pituitary hormones periodically assessed.

8.
Thyroid ; 23(12): 1510-3, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23758637

RESUMO

BACKGROUND: Recent studies have suggested that metformin (MF) may lower thyrotropin concentration. This suggests a possible need for a dose reduction of levothyroxine in hypothyroid patients taking MF. However, contradictory results from heterogeneous study populations indicate that the underlying causes have not been completely elucidated. Patients with postoperative hypothyroidism-a condition not influenced by endogenous thyroid hormone production-have not been evaluated in order to evaluate the impact of MF. AIM: To determine the impact of MF in total thyroidectomized patients receiving levothyroxine replacement. PATIENTS AND METHODS: One hundred ninety-two patients underwent total thyroidectomy during three years and were receiving levothyroxine substitution. Patients were divided into two groups depending on MF use: the non-MF group included 159 patients, of whom 134 were women [mean (SD) age, 52 (15.7) years; mean (SD) body weight, 70.2 (13.5) kg; 56 with differentiated thyroid cancer]; the MF group comprised 33 patients, of whom 24 were women [mean (SD) age, 63 (9.8) years; mean (SD) body weight, 79.3 (13.9) kg; 9 with differentiated thyroid cancer]. Levothyroxine requirements were compared between the groups, and the differentiated thyroid cancer cases were also analyzed separately. RESULTS: Thyrotropin levels did not differ significantly between the MF and the non-MF groups. No differences in total levothyroxine dosage were found: 114 (100-150) [median (Q1-Q3)] µg in the non-MF group versus 125 (100-142) µg in the MF group (p=0.9). When calculating the weight-adjusted levothyroxine dose, significant differences were evident: 1.66 (1.38-2.08) µg/kg in the non-MF group versus 1.53 (1.26-1.70) µg/kg in the MF group (p=0.010). However, in a multivariate regression model with thyrotropin levels, age, body mass index, sex, and type of thyroid disease, MF treatment lost its significance. CONCLUSIONS: Thyroidectomized patients receiving MF treatment need a lower thyroxine dose than patients who do not receive the drug, possibly due to different characteristics (greater weight, age) of the patients with diabetes mellitus type 2.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipotireoidismo/tratamento farmacológico , Metformina/uso terapêutico , Tiroxina/uso terapêutico , Adulto , Idoso , Diabetes Mellitus Tipo 2/complicações , Feminino , Terapia de Reposição Hormonal , Humanos , Hipotireoidismo/complicações , Masculino , Pessoa de Meia-Idade , Tireoidectomia , Tiroxina/administração & dosagem , Resultado do Tratamento
9.
Clin Endocrinol (Oxf) ; 70(6): 833-7, 2009 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-19250265

RESUMO

OBJECTIVE: Fertility in women with classical congenital adrenal hyperplasia (CAH) has been reported low; however, the true pregnancy rate for women trying to conceive with this condition is unknown. Our aim was to calculate pregnancy rate for women with CAH calculated as a proportion of those who had attempted conception. Fertility expressed as live birth rate is also calculated. PATIENTS: One hundred and six women with classical CAH followed in a multidisciplinary service [81 salt-losing (SL) and 25 nonsalt-losing (NSL) form]. RESULTS: Twenty-five (23.6%) women with CAH women considered motherhood, 23 had actively tried conception of whom 21 (91.3%) achieved 34 pregnancies. Pregnancy rate is no different from that in the normal population (95%). Pregnancy rates were similar in the SL (88.9%) and NSL (92.9%) subgroups but those with NSL-CAH were more likely to seek motherhood than those with SL-CAH (16/25 vs. 9/81). Optimized glucocorticoid and mineralocorticoid regimes during fertility monitoring resulted spontaneous conception in nearly all recent cases. Fertility rate was 0.25 live births per woman compared with 1.8 in the UK population (P < 0.001). CONCLUSION: We report a normal pregnancy rate (91.3%) for women with classical CAH, similar in SL and NSL subgroups. Fertility rate, however, remains much lower than in general population.


Assuntos
Hiperplasia Suprarrenal Congênita/fisiopatologia , Coeficiente de Natalidade , Fertilidade , Adolescente , Hiperplasia Suprarrenal Congênita/epidemiologia , Adulto , Estudos de Coortes , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Gravidez , Taxa de Gravidez , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA