Outcome and long-term follow-up of adrenal lesions in multiple endocrine neoplasia type 1

ABSTRACT Objective To describe the prevalence, clinical characteristics and outcome of adrenal lesions in long-term follow-up of Multiple endocrine neoplasia type 1 (MEN1) patients. Subjects and methods We retrospectively studied sixteen patients from six families of individuals with MEN1. Adrenal involvement was evaluated using clinical, biochemical and imaging data. Results Adrenal lesions were identified in nine of sixteen (56.3%) patients: seven women and two men (mean age: 52.2 years). Adrenal involvement was detected at MEN1 diagnosis in more than half of the patients. Eighteen adrenal nodules were founded (median of two nodules per patient) with mean adrenal lesion diameter of 17.4 mm. Three patients had unilateral adrenal involvement. Hormonal hypersecretion (autonomous cortisol secretion) was found in two patients. None of the patients was submitted to adrenalectomy, presented an aldosterone-secreting lesion, a pheochromocytoma, an adrenal carcinoma or metastatic disease during the follow-up. A predominance of stable adrenal disease, in terms of size and hormonal secretion, was observed. Adrenal lesions were evenly distributed between the germline mutations. Conclusion Adrenal tumours are a common feature of MEN1 that can affect more than half of the patients. Most of the tumours are bilateral non-functional lesions, but hormonal secretion may occur and should be promptly identified to reduce the morbidity/mortality of the syndrome. Periodic surveillance of these patients should be performed.

Outcome and long-term follow-up of adrenal lesions in multiple endocrine neoplasia type 1.

OBJECTIVE: To describe the prevalence, clinical characteristics and outcome of adrenal lesions in long-term follow-up of Multiple endocrine neoplasia type 1 (MEN1) patients. SUBJECTS AND METHODS: We retrospectively studied sixteen patients from six families of individuals with MEN1. Adrenal involvement was evaluated using clinical, biochemical and imaging data. RESULTS: Adrenal lesions were identified in nine of sixteen (56.3%) patients: seven women and two men (mean age: 52.2 years). Adrenal involvement was detected at MEN1 diagnosis in more than half of the patients. Eighteen adrenal nodules were founded (median of two nodules per patient) with mean adrenal lesion diameter of 17.4 mm. Three patients had unilateral adrenal involvement. Hormonal hypersecretion (autonomous cortisol secretion) was found in two patients. None of the patients was submitted to adrenalectomy, presented an aldosterone-secreting lesion, a pheochromocytoma, an adrenal carcinoma or metastatic disease during the follow-up. A predominance of stable adrenal disease, in terms of size and hormonal secretion, was observed. Adrenal lesions were evenly distributed between the germline mutations. CONCLUSION: Adrenal tumours are a common feature of MEN1 that can affect more than half of the patients. Most of the tumours are bilateral non-functional lesions, but hormonal secretion may occur and should be promptly identified to reduce the morbidity/mortality of the syndrome. Periodic surveillance of these patients should be performed.

Thoracic spine metastasis presenting 18 years after complete resection of a phaeochromocytoma.

Phaeochromocytomas are rare neuroendocrine tumours (NET) with malignant behaviour in about 10% of cases. The median time from the diagnosis of primary tumour and bone metastasis is 3.4 years. We report a case of a 66-year-old woman presenting with a hypertensive crisis and back pain. She has a history of a phaeochromocytoma completely resected 18 years before. MRI showed a neoplastic mass on the 10th thoracic vertebra (T10), with fracture and spinal cord compression. The CT-guided biopsy was consistent with metastasis of a NET. Therefore, she was treated with phenoxybenzamine and external beam radiotherapy. However, clinical (dorsal pain) and biochemical (ie, elevated chromogranin A) signs suggested persistent disease and the patient was treated with iodine-131 metaiodobenzylguanidine and T10 kyphoplasty. After 8 years, she remains clinically stable. This case demonstrates that phaeochromocytomas may reveal malignant behaviour several years after diagnosis, and therefore patients should be maintained under long term surveillance.

Late-Night Salivary Cortisol: Cut-Off Definition and Diagnostic Accuracy for Cushing's Syndrome in a Portuguese Population.

INTRODUCTION: Diagnosis of Cushing's syndrome remains a challenge in clinical endocrinology. Even though late-night salivary cortisol is used as screening tool, individualized cut-off levels for each population must be defined. MATERIAL AND METHODS: Three groups of subjects were studied: normal subjects, suspected and proven Cushing's syndrome. Salivary cortisol was measured using an automated electrochemiluminescence assay. The functional sensitivity of the assay is 0.018 µg/dL. The diagnostic cut-off level was defined by Receiver Operating Characteristic curve and Youden's J index. RESULTS: We studied 127 subjects: 57 healthy volunteers, 39 patients with suspected and 31 with proven Cushing's syndrome. 2.5th - 97.5th percentile of the late-night salivary cortisol concentrations in normal subjects was 0.054 to 0.1827 µg/dL. Receiver Operating Characteristic curve analysis showed an area under the curve of 0.9881 (p < 0.0001). A cut-off point of 0.1 µg/dL provided a sensitivity of 96.77% (95% CI 83.3 - 99.92%) and specificity of 91.23% (95% CI 80.7 - 97.09%). There was a significant correlation between latenight salivary cortisol and late-night serum cortisol (R = 0.6977; p < 0.0001) and urinary free cortisol (R = 0.5404; p = 0.0025) in proven Cushing's syndrome group. DISCUSSION: The mean ± SD late-night salivary cortisol concentration in patients with proven Cushing's syndrome (0.6798 ± 0.52 µg/ dL) was significantly higher (p < 0.0001). In our population, the late-night salivary cortisol cut-off was 0.1 µg/dL with high sensitivity and specificity. CONCLUSION: Late-night salivary cortisol has excellent diagnostic accuracy, making it a highly reliable, noninvasive, screening tool for outpatient assessment. Given its convenience and diagnostic accuracy, late-night salivary cortisol may be added to other traditional screening tests on hypercortisolism.

Introdução: O diagnóstico de síndrome de Cushing continua a ser um desafio complexo. Apesar do cortisol salivar noturno ser utilizado como teste de rastreio, a definição de um valor diagnóstico deverá ser individualizada. Material e Métodos: Foram estudados 3 grupos: voluntários saudáveis, com suspeita clínica e com diagnóstico estabelecido de Síndrome de Cushing. O doseamento de cortisol salivar foi realizado por eletroquimioluminescência automatizado. A definição do ponto-de-corte foi obtida pela curva Receiver Operating Characteristic e índice J de Youden. Resultados: Entre os 127 indivíduos, 57 pertenciam ao grupo de voluntários saudáveis, 39 com suspeita clínica e 31 com diagnóstico estabelecido. O percentil 2,5 ­ 97,5 de cortisol salivar noturno no grupo de voluntários saudáveis foi 0,054 ­ 0,1827 µg/dL. A análise da curva Receiver Operating Characteristic revelou uma área abaixo da curva de 0,9881 (p < 0,0001) e o ponto-de-corte de 0,1 µg/dL com sensibilidade de 96,77% e especificidade de 91,23%. Verificou-se uma correlação significativa entre cortisol salivar noturno e o cortisol sérico noturno (R = 0,6977; p < 0,0001), bem como, com cortisol livre urinário (R = 0,5404; p = 0,0025) no grupo com diagnóstico estabelecido. Discussão: A concentração média ± DP cortisol salivar noturno no grupo com diagnóstico estabelecido (0,6798 ± 0,52 µg/dL) foi significativamente superior aos restantes grupos. Na nossa população, o valor de ponto-de-corte foi de 0,1 µg/dL com elevada sensibilidade e especificidade. Conclusão: Os resultados demonstram uma excelente acurácia do cortisol salivar noturno. Dada a sua conveniência e elevada exatidão, o doseamento de cortisol salivar noturno poderá ser adicionado aos testes de rastreio tradicionais para estudo de hipercortisolismo.

The spectrum of pediatric adrenal insufficiency: insights from 34 years of experience.

Background Adrenal insufficiency (AI) is a life-threatening disease characterized by deficient production of glucocorticoids and/or mineralocorticoids. It is caused by primary or secondary/tertiary adrenal failure. Prompt diagnosis and management are essential and may even be life-saving. Methods We retrospectively collected clinical, laboratory and radiological data from AI patients observed over 34 years (1984-2017) in a pediatric endocrinology department of a tertiary care hospital. Results Seventy AI patients were identified: 59% with primary adrenal insufficiency (PAI) and 41% with central adrenal insufficiency (CAI). PAI patients were diagnosed at 1.5 ± 4.4 years and followed for 11.6 ± 6.2 years; 85% had classical congenital adrenal hyperplasia (CAH) and 7% had autoimmune PAI. At presentation, 73% had hyponatremia and more than half had mucocutaneous hyperpigmentation, asthenia, anorexia, weight loss, nausea and vomiting. All the patients were treated with hydrocortisone and 90% were also on fludrocortisone. Regarding CAI patients, they were diagnosed at 5.4 ± 5.0 years and they were followed for 9.6 ± 6.4 years; craniopharyngioma was present in 31% of the cases and 14% had pituitary hypoplasia. Besides corticotropin, thyrotropin (93%), growth hormone (63%) and antidiuretic hormone (52%) were the most common hormone insufficiencies. The most frequent manifestations were hypoglycemia (34.5%), nausea/vomiting (27.6%) and infectious diseases (27.6%); all the patients were treated with hydrocortisone. Conclusions Despite medical advances, the diagnosis and management of AI remains a challenge, particularly in the pediatric population. Raising awareness and knowledge in medical teams and population about the disease is of crucial importance to improve clinical outcomes and to reduce disease morbidity/mortality.

RISK OF MALIGNANCY IN THYROID CYTOLOGY: THE IMPACT OF THE RECLASSIFICATION OF NONINVASIVE FOLLICULAR THYROID NEOPLASM WITH PAPILLARY-LIKE NUCLEAR FEATURES (NIFTP).

Objective: Noninvasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC) was recently reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP). We aimed to compare the risk of malignancy (ROM) of the Bethesda System for Reporting Thyroid Cytopathology (BSRTC) on fine-needle aspiration cytology (FNAC), before and after the reclassification, in a large cohort of patients. Methods: We analyzed 5,625 consecutive FNAC samples performed in 2012-2014 and selected category III (atypia of undetermined significance [AUS]/follicular lesion of undetermined significance [FLUS]), IV (follicular neoplasm [FN]/suspicious for a follicular neoplasm [SFN]), V (suspicious for malignancy [SFM]), and VI (malignant) of the BSRTC. We reviewed the histology of operated patients and compared ROM before and after the introduction of the NIFTP category. Results: A total of 772 patients were identified and 45% underwent surgery (n = 348). There were 180 cases of AUS/FLUS (10 NIFTP), 114 cases of FN/SFN (2 NIFTP), 29 cases of SFM (3 NIFTP), and 25 cases of BSRTC VI (no NIFTP). Exclusion of NIFTP from malignant lesions resulted in a relative and absolute decrease in the ROM in AUS/FLUS (15.2% and 5.5%, respectively), FN/SFN (7.6% and 1.8%, respectively) and SFM (14.2% and 10.3%, respectively) categories. Among the NIFTP patients, 93% underwent total thyroidectomy and 20% received radioiodine. Conclusion: Reclassification of noninvasive EFVPTC as NIFTP resulted in a decrease in overall ROM, and the BSRTC categories most affected were III and V. Abbreviations: AUS = atypia of undetermined significance; BSRTC = Bethesda System for Reporting Thyroid Cytopathology; EFVPTC = encapsulated follicular variant of papillary thyroid carcinoma; FLUS = follicular lesion of undetermined significance; FN = follicular neoplasm; FNAC = fine-needle aspiration cytology; FVPTC = follicular variant of papillary thyroid carcinoma; NIFTP = noninvasive follicular thyroid neoplasm with papillary-like nuclear features; PTC = papillary thyroid carcinoma; ROM = risk of malignancy; SFM = suspicious for malignancy; SFN = suspicious for a follicular neoplasm.

Congenital hyperreninemic hypoaldosteronism due to aldosterone synthase deficiency type I in a Portuguese patient - Case report and review of literature.

Hyperreninemic hypoaldosteronism due to aldosterone synthase (AS) deficiency is a rare condition typically presenting as salt-wasting syndrome in the neonatal period. A one-month-old Portuguese boy born to non-consanguineous parents was examined for feeding difficulties and poor weight gain. A laboratory workup revealed severe hyponatremia, hyperkaliaemia and high plasma renin with unappropriated normal plasma aldosterone levels, raising the suspicion of AS deficiency. Genetic analysis showed double homozygous of two different mutations in the CYP11B2 gene: p.Glu198Asp in exon 3 and p.Val386Ala in exon 7. The patient maintains regular follow-up visits in endocrinology clinics and has demonstrated a favourable clinical and laboratory response to mineralocorticoid therapy. To our knowledge, this is the first Portuguese case of AS deficiency reported with confirmed genetic analysis.

[The Impact of Prolonged Use of Continuous Subcutaneous Insulin Infusion in the Control of Type-1 Diabetes]. / Impacto do Uso Prolongado da Terapêutica Subcutânea Contínua com Insulina no Controlo da Diabetes Mellitus Tipo 1.

INTRODUCTION: The use of continuous subcutaneous insulin infusion therapy in type 1 diabetes mellitus has increased due to its benefits on glycemic control and on the lifestyle flexibility. The aim of this study was to assess the impact of continuous subcutaneous insulin infusion therapy on glycemic control, body mass index, total daily dose of insulin and complications associated with this therapy, during 20 years of experience in Centro Hospitalar e Universitário de Coimbra. MATERIAL AND METHODS: This retrospective study included patients with type 1 diabetes mellitus who started continuous subcutaneous insulin infusion therapy up until 2005, followed at Centro Hospitalar e Universitário de Coimbra. Glycated hemoglobin A1c, body mass index, total daily dose of insulin and acute complications associated with continuous subcutaneous insulin infusion therapy were evaluated immediately prior to initiation of continuous subcutaneous insulin infusion therapy with follow-up at six months, one year, five, 10, 15 and 20 years. The frequency of acute complications associated with this type of therapy was also evaluated. RESULTS: This study included 20 patients (seven males, 13 females) with mean disease duration up to the start of continuous subcutaneous insulin infusion therapy of 16.1 ± 7.9 years, mean age of onset of continuous subcutaneous insulin infusion therapy of 31.1 ± 8.4 years and follow-up during 13.2 ± 2.3 years. The reasons for initiating pump therapy were: inadequate metabolic control in 15 patients, history of asymptomatic or severe hypoglycemia in four patients, and pregnancy/pregnancy planning in one patient. The previous median of glycated hemoglobin A1c was 9.3% (6.5 - 16.0) and, at six months, decreased to the minimum value of 7.2% (5.3 - 9.8); p < 0.0125. The reduction of glycated hemoglobin A1c remained statistically significant in the first 10 years of follow-up. There was a statistically significant difference in the body mass index variation at 10 years with continuous subcutaneous insulin infusion therapy compared to previous body mass index; 24.7 kg/m2 (18.9 - 31.8) vs 25,5 kg/m2 (18.9 - 38.9), p <0.0125. Daily insulin requirements were reduced from 56.5 U (32.0 - 94.0) to 43.8 U (33.0 - 64.0) (p < 0.0125) at six months and no statistical differences were found in the remaining follow-up. There were two severe episodes of hypoglycemia (incidence 0.0095/patient/year), five episodes of diabetic ketoacidosis (0.0238/patient/year) and no infections at the site of catheter insertion. DISCUSSION: This study shows that continuous subcutaneous insulin infusion therapy improved glycemic control, especially during the first 10 years of follow-up and allowed a significant decrease in total daily dose of insulin in the first six months. The rate of acute complications was low. CONCLUSION: Treatment with continuous subcutaneous insulin infusion therapy seems effective in achieving metabolic control in selected patients with type 1 diabetes mellitus.

Introdução: O uso da terapêutica com perfusão subcutânea contínua de insulina na diabetes mellitus tipo 1 é cada vez mais frequente devido aos seus efeitos benéficos no controlo glicémico e na flexibilidade do estilo de vida. Constituiu objetivo deste estudo avaliar o impacto da terapêutica com perfusão subcutânea contínua de insulina no controlo glicémico, índice de massa corporal, dose diária total de insulina e complicações desta modalidade terapêutica durante vinte anos de experiência no Centro Hospitalar e Universitário de Coimbra. Material e Métodos: Estudo retrospetivo que inclui doentes com diabetes mellitus tipo 1 seguidos no Centro Hospitalar e Universitário de Coimbra, que iniciaram terapêutica com perfusão subcutânea contínua de insulina até 2005 e com pelo menos 10 anos de tratamento com terapêutica com perfusão subcutânea contínua de insulina. Avaliou-se a hemoglobina glicada A1c, o índice de massa corporal e a dose diária total de insulina imediatamente antes e seis meses, um ano, cinco, 10, 15 e 20 anos após terapêutica com perfusão subcutânea contínua de insulina a partir dos registos médicos. Avaliou-se ainda a frequência de complicações agudas associadas a este tipo de terapêutica. Resultados: Obtiveram-se dados de 20 doentes (sete homens; 13 mulheres) com duração média de doença até início da terapêutica com perfusão subcutânea contínua de insulina de 16,1 ± 7,9 anos, idade média de início de terapêutica com perfusão subcutânea contínua de insulina de 31,1 ± 8,4 anos e seguimento durante 13,2 ± 2,3 anos. As indicações para colocação de bomba foram: inadequado controlo metabólico em 15 doentes, história de hipoglicemias assintomáticas ou severas em quatro doentes, e gravidez/planeamento de gravidez em um doente. A mediana de hemoglobina glicada A1c prévia foi 9,3% (6,5 - 16,0) tendo diminuído aos seis meses para o valor mínimo de 7,2% (5,3 - 9,8); p < 0,0125. A redução da hemoglobina glicada A1c manteve-se estatisticamente significativa nos primeiros 10 anos de seguimento. Verificou-se uma diferença estatisticamente significativa na variação do índice de massa corporal após 10 anos de seguimento comparativamente com o valor prévio à terapêutica com perfusão subcutânea contínua de insulina; 24,7kg/m2 (18,9 - 31,8) vs 25,5 kg/m2 (18,9 - 38,9), p < 0,0125. As necessidades diárias de insulina foram reduzidas de 56,5 U (32,0 - 94,0) para 43,8 U (33,0 - 64,0) (p < 0,0125) nos primeiros seis meses e não se encontraram diferenças estatísticas no restante seguimento relativamente às necessidades prévias à terapêutica com perfusão subcutânea contínua de insulina. Verificaram-se duas hipoglicemias severas (incidência 0,0095/doente/ano), cinco cetoacidoses diabéticas (0,0238/doente/ano) e nenhuma infeção no local de inserção do cateter. Discussão: Este estudo demonstrou a eficácia da terapêutica com perfusão subcutânea contínua de insulina, que está associada a uma diminuição significativa da hemoglobina glicada A1c sustentada durante 10 anos e a uma redução da dose diária total de insulina, significativa nos primeiros seis meses. A taxa de complicações agudas foi baixa. Conclusão: A evidência sugere que a terapêutica com perfusão subcutânea contínua de insulina é efetivamente vantajosa no controlo metabólico em doentes com diabetes mellitus tipo 1 selecionados.

Bifocal germinoma in a patient with 16p11.2 microdeletion syndrome.

Intracranial germinomas are rare tumors affecting mostly patients at young age. Therefore, molecular data on its etiopathogenesis are scarce. We present a clinical case of a male patient of 25 years with an intracranial germinoma and a 16p11.2 microdeletion. His initial complaints were related to obesity, loss of facial hair and polydipsia. He also had a history of social-interaction difficulties during childhood. His blood tests were consistent with hypogonadotropic hypogonadism and secondary adrenal insufficiency, and he had been previously diagnosed with hypothyroidism. He also presented with polyuria and polydipsia and the water deprivation test confirmed the diagnosis of diabetes insipidus. His sellar magnetic resonance imaging (MRI) showed two lesions: one located in the pineal gland and other in the suprasellar region, both with characteristics suggestive of germinoma. Chromosomal microarray analysis was performed due to the association of obesity with social disability, and the result identified a 604 kb 16p11.2 microdeletion. The surgical biopsy confirmed the histological diagnosis of a germinoma. Pharmacological treatment with testosterone, hydrocortisone and desmopressin was started, and the patient underwent radiotherapy (40 Gy divided in 25 fractions). Three months after radiotherapy, a significant decrease in suprasellar and pineal lesions without improvement in pituitary hormonal deficiencies was observed. The patient is currently under follow-up. To the best of our knowledge, we describe the first germinoma in a patient with a 16p11.2 deletion syndrome, raising the question about the impact of this genetic alteration on tumorigenesis and highlighting the need of molecular analysis of germ cell tumors as only little is known about their genetic background. Learning points: Central nervous system germ cell tumors (CNSGTs) are rare intracranial tumors that affect mainly young male patients. They are typically located in the pineal and suprasellar regions and patients frequently present with symptoms of hypopituitarism. The molecular pathology of CNSGTs is unknown, but it has been associated with gain of function of the KIT gene, isochromosome 12p amplification and a low DNA methylation. Germinoma is a radiosensitive tumor whose diagnosis depends on imaging, tumor marker detection, surgical biopsy and cerebrospinal fluid cytology. 16p11.2 microdeletion syndrome is phenotypically characterized by developmental delay, intellectual disability and autism spectrum disorders. Seminoma, cholesteatoma, desmoid tumor, leiomyoma and Wilms tumor have been described in a few patients with 16p11.2 deletion. Bifocal germinoma was identified in this patient with a 16p11.2 microdeletion syndrome, which represents a putative new association not previously reported in the literature.

Congenital hyperreninemic hypoaldosteronism due to aldosterone synthase deficiency type I in a Portuguese patient - Case report and review of literature

SUMMARY Hyperreninemic hypoaldosteronism due to aldosterone synthase (AS) deficiency is a rare condition typically presenting as salt-wasting syndrome in the neonatal period. A one-month-old Portuguese boy born to non-consanguineous parents was examined for feeding difficulties and poor weight gain. A laboratory workup revealed severe hyponatremia, hyperkaliaemia and high plasma renin with unappropriated normal plasma aldosterone levels, raising the suspicion of AS deficiency. Genetic analysis showed double homozygous of two different mutations in the CYP11B2 gene: p.Glu198Asp in exon 3 and p.Val386Ala in exon 7. The patient maintains regular follow-up visits in endocrinology clinics and has demonstrated a favourable clinical and laboratory response to mineralocorticoid therapy. To our knowledge, this is the first Portuguese case of AS deficiency reported with confirmed genetic analysis.

Addison's disease in antiphospholipid syndrome: a rare complication.

Addison's disease (AD) is the most common endocrine manifestation of antiphospholipid syndrome (APS), but it remains a very rare complication of the syndrome. It is caused by adrenal venous thrombosis and consequent hemorrhagic infarction or by spontaneous (without thrombosis) adrenal hemorrhage, usually occurring after surgery or anticoagulant therapy. We present a clinical case of a 36-year-old female patient with a previous diagnosis of APS. She presented with multiple thrombotic events, including spontaneous abortions. During evaluation by the third episode of abortion, a CT imaging revealed an adrenal hematoma, but the patient was discharged without further investigation. A few weeks later, she presented in the emergency department with manifestations suggestive of adrenal insufficiency. Based on that assumption, she started therapy with glucocorticoids, with significant clinical improvement. After stabilization, additional investigation confirmed AD and excluded other etiologies; she also started mineralocorticoid replacement. This case illustrates a rare complication of APS that, if misdiagnosed, may be life threatening. A high index of suspicion is necessary for its diagnosis, and prompt treatment is crucial to reduce the morbidity and mortality potentially associated. Learning points: AD is a rare but life-threatening complication of APS. It is important to look for AD in patients with APS and a suggestive clinical scenario. APS must be excluded in patients with primary adrenal insufficiency and adrenal imaging revealing thrombosis/hemorrhage. Glucocorticoid therapy should be promptly initiated when AD is suspected. Mineralocorticoid replacement must be started when there is confirmed aldosterone deficiency. Hypertension is a common feature of APS; in patients with APS and AD, replacement therapy with glucocorticoids and mineralocorticoids may jeopardize hypertension management.

Dental caries and bacterial load in saliva and dental biofilm of type 1 diabetics on continuous subcutaneous insulin infusion.

OBJECTIVES: Since most of the studies evaluates diabetics on multiple daily injections therapy and continuous subcutaneous insulin infusion may help gain better metabolic control and prevent complications, the objective of this study was to evaluate the prevalence of dental caries, the unstimulated salivary flow rate and the total bacteria load, Streptococcus spp. levels and Lactobacillus spp. levels in saliva and supragingival dental biofilm of type 1 diabetics on insulin pump. MATERIAL AND METHODS: Sixty patients with type 1 diabetes on insulin pump and 60 nondiabetic individuals were included. The dental caries evaluation was performed using ICDAS and the oral hygiene was assessed according to Greene and Vermillion Simplified Oral Hygiene Index. Unstimulated saliva and supragingival dental biofilm were collected. Total bacteria, Streptococcus spp. and Lactobacillus spp. was quantified by qPCR. RESULTS: Patients with type 1 diabetes had a higher prevalence of dental caries and filled and missing teeth when compared with the control group. These patients were associated with more risk factors for the development of dental caries, namely a lower unstimulated salivary flow rate and a higher bacterial load in saliva and dental biofilm. CONCLUSION: Some risk factors related to dental caries were associated with type 1 diabetics. An early diagnosis combined with the evaluation of the risk profile of the diabetic patient is imperative, allowing the dental caries to be analyzed through a perspective of prevention and the patient to be integrated into an individualized oral health program.

Aging Hallmarks: The Benefits of Physical Exercise.

World population has been continuously increasing and progressively aging. Aging is characterized by a complex and intraindividual process associated with nine major cellular and molecular hallmarks, namely, genomic instability, telomere attrition, epigenetic alterations, a loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. This review exposes the positive antiaging impact of physical exercise at the cellular level, highlighting its specific role in attenuating the aging effects of each hallmark. Exercise should be seen as a polypill, which improves the health-related quality of life and functional capabilities while mitigating physiological changes and comorbidities associated with aging. To achieve a framework of effective physical exercise interventions on aging, further research on its benefits and the most effective strategies is encouraged.

Treatment of Addison's disease during pregnancy.

Addison's disease, or primary adrenocortical insufficiency, is a long-term, potentially severe, rare endocrine disorder. In pregnancy, it is even rarer. We report the case of a 30-year-old pregnant patient with Addison's disease, referred to Obstetrics-Endocrinology specialty consult at 14 weeks gestation. She had been to the emergency department of her local hospital various times during the first trimester presenting with a clinical scenario suggestive of glucocorticoid under-replacement (nausea, persistent vomiting and hypotension), but this was interpreted as normal pregnancy symptoms. Hydrocortisone dose was adjusted, and the patient maintained regular follow-up. No complications were reported for the remainder of gestation and delivery. Pregnant patients with Addison's disease should be monitored during gestation and in the peripartum period by multidisciplinary teams. Adjustments in glucocorticoid and mineralocorticoid replacement therapy are often necessary, and monitoring should be based mainly on clinical findings, which becomes increasingly difficult during pregnancy. Patient education and specialized monitoring are key to avoiding complications from under- or over-replacement therapy in this period. LEARNING POINTS: An increase in glucocorticoid replacement dose is expected to be necessary during pregnancy in a woman with Addison's disease.Patient education regarding steroid cover and symptoms of acute adrenal crisis are fundamental.Monitoring in this period is challenging and remains mainly clinical.The increase in hydrocortisone dose often obviates the need to increase fludrocortisone dose.

Dental caries and bacterial load in saliva and dental biofilm of type 1 diabetics on continuous subcutaneous insulin infusion

Abstract Objectives Since most of the studies evaluates diabetics on multiple daily injections therapy and continuous subcutaneous insulin infusion may help gain better metabolic control and prevent complications, the objective of this study was to evaluate the prevalence of dental caries, the unstimulated salivary flow rate and the total bacteria load, Streptococcus spp. levels and Lactobacillus spp. levels in saliva and supragingival dental biofilm of type 1 diabetics on insulin pump. Material and Methods Sixty patients with type 1 diabetes on insulin pump and 60 nondiabetic individuals were included. The dental caries evaluation was performed using ICDAS and the oral hygiene was assessed according to Greene and Vermillion Simplified Oral Hygiene Index. Unstimulated saliva and supragingival dental biofilm were collected. Total bacteria, Streptococcus spp. and Lactobacillus spp. was quantified by qPCR. Results Patients with type 1 diabetes had a higher prevalence of dental caries and filled and missing teeth when compared with the control group. These patients were associated with more risk factors for the development of dental caries, namely a lower unstimulated salivary flow rate and a higher bacterial load in saliva and dental biofilm. Conclusion Some risk factors related to dental caries were associated with type 1 diabetics. An early diagnosis combined with the evaluation of the risk profile of the diabetic patient is imperative, allowing the dental caries to be analyzed through a perspective of prevention and the patient to be integrated into an individualized oral health program.

Laparoscopic adrenalectomy as an effective approach to massive bilateral pheochromocytomas.

Pheochromocytomas are catecholamine-secreting neoplasms, arising from adrenomedullary chromaffin cells. In type 2 multiple endocrine neoplasia (MEN2) syndrome, pheochromocytomas are usually benign but with predisposition to be bilateral (50%-80% of cases).The authors present the case of a young patient diagnosed with uncommonly large bilateral cystic pheochromocytomas and simultaneous detection of medullary thyroid carcinoma. Molecular testing confirmed germline RET codon C634 mutation, consistent with MEN2A syndrome. The patient underwent bilateral laparoscopic adrenalectomy plus total thyroidectomy with central lymph node dissection without associated complications. The histopathological study of the surgical specimens revealed bilateral benign pheochromocytomas (Ki67 of 2%) and a medullary carcinoma of the thyroid T1bN0M0; R0, respectively. One year after surgery, the patient was considered free of disease.This case demonstrates that bilateral laparoscopic adrenalectomy can be a safe and feasible approach for phechromocytomas in MEN2 syndrome, even in lesions with large diameter. However, due to elevated possibility of recurrence, patients should maintain lifelong follow-up.

[Prevalence of Dental Caries in Patients with Type 1 Diabetes Mellitus Treated with Multiple Insulin Injections and that of Individuals without Diabetes]. / Prevalência de Lesões de Cárie de Doentes com Diabetes Mellitus Tipo 1 Tratados com Múltiplas Administrações de Insulina e de Indivíduos sem Diabetes.

INTRODUCTION: In addition to macro and microvascular complications that are associated with the disease, hyperglycaemia is also a risk factor for several oral complications. The aim of this study is to establish a relationship between dental caries in patients with type 1 diabetes mellitus treated with multiple insulin injections and that of individuals without diabetes. It is also an aim to characterize the oral hygiene habits of this population. MATERIAL AND METHODS: An observational clinical study of analytical and cross-sectional nature was conducted. Thirty patients with type 1 diabetes mellitus and 30 individuals without diabetes were observed and questioned about information regarding their medical history. Oral examination was conducted according to the standards of the World Health Organization and ICDAS was used for caries detection. Statistical analysis was performed and the significance level was set at 5%. RESULTS: Patients with diabetes mellitus showed similar caries levels to that of individuals without diabetes. Patients with diabetes mellitus had a higher dental plaque index. Only 10% of the patients having episodes of nocturnal hypoglycaemia brush their teeth after glucose intake. DISCUSSION: Although there's some controversy in the literature regarding the prevalence of caries in patients with diabetes mellitus, the results are in agreement with a great number of studies. However, patients with diabetes mellitus have a higher plaque index which can be associated with a higher risk for developing certain oral pathologies. CONCLUSION: No statistically significant association was found between type 1 diabetes mellitus and dental caries.

Introdução: A diabetes mellitus apresenta diferentes complicações micro e macrovasculares, sendo também um fator de risco para diversas complicações orais. O objetivo do presente estudo é estabelecer uma relação entre a cárie dentária em doentes com diabetes mellitus do tipo 1 tratados com múltiplas injeções de insulina e em indivíduos sem diabetes. É ainda objetivo caracterizar os hábitos de higiene oral desta população. Material e Métodos: Um estudo clínico e observacional de caráter analítico e transversal foi realizado. Trinta doentes com diabetes mellitus do tipo 1 e 30 indivíduos sem diabetes foram observados e questionados sobre informações referentes à sua histórica médica. O exame oral foi realizado de acordo com as normas da Organização Mundial de Saúde, tendo-se utilizado o índice de cárie ICDAS. A análise estatística foi realizada e foi estabelecido um nível de significância de 5%. Resultados: Os doentes com diabetes mellitus apresentaram um índice de cárie semelhante ao dos indivíduos sem diabetes. Verificou-se, ainda, um índice de placa bacteriana superior nos doentes com diabetes mellitus. Apenas 10% dos doentes que referiam episódios de hipoglicemia noturna escovam os dentes após a ingestão de glicose. Discussão: Apesar de existir alguma controvérsia na literatura quanto à prevalência de cárie em doentes com diabetes mellitus, os resultados obtidos estão de acordo com a maioria dos estudos realizados até à data. No entanto, os doentes apresentam um maior índice de placa bacteriana, o que lhes pode conferir um maior risco para o desenvolvimento de determinadas patologias orais.Conclusão: Não foi encontrada nenhuma associação estatisticamente significativa entre a diabetes mellitus do tipo 1 e o desenvolvimento de cárie dentária.

Endoscopic ultrasound-guided ethanol ablation therapy for pancreatic insulinoma: an unusual strategy.

SUMMARY: Insulinomas are the most frequent cause of hyperinsulinaemic hypoglycaemia. Although surgical enucleation is the standard treatment, a few other options are available to high-risk patients who are elderly or present with co-morbidities. We present a case report of an 89-year-old female patient who was admitted to the emergency department due to recurrent hypoglycaemia, especially during fasting. Laboratory work-up raised the suspicion of hyperinsulinaemic hypoglycaemia, and abdominal CT scan revealed a 12 mm nodular hypervascular lesion of the pancreatic body suggestive of neuroendocrine tumour. The patient was not considered a suitable candidate for surgery, and medical therapy with diazoxide was poorly tolerated. Endoscopic ultrasound-guided ethanol ablation therapy was performed and a total of 0.6 mL of 95% ethanol was injected into the lesion by a transgastric approach; no complications were reported after the procedure. At 5 months of follow-up, no episodes of hypoglycaemia were reported, no diazoxide therapy was necessary, and revaluation abdominal CT scan revealed a pancreatic nodular lesion with a size involution of about half of its original volume. The patient is regularly followed-up at the endocrinology clinic and shows a significant improvement in her wellbeing and quality of life. LEARNING POINTS: Insulinomas are the most frequent cause of hyperinsulinaemic hypoglycaemia.Surgical enucleation is the standard treatment with a few other options available to high-risk patients.Endoscopic ultrasound-guided ethanol ablation therapy is one feasible option in high-risk patients with satisfactory clinical outcomes, significant positive impact on quality of life and low complication rates related to the procedure.

TERT, BRAF, and NRAS in Primary Thyroid Cancer and Metastatic Disease.

Context: Little is known about the frequency of key mutations in thyroid cancer metastases and its relationship with the primary tumor genotype. Objectives: To evaluate the frequency of TERT promoter (TERTp), BRAF, and NRAS mutations in metastatic thyroid carcinomas, analyzing primary thyroid tumors, lymph node metastases (LNMs), and distant metastases. Design and Patients: Mutation analysis was performed in 437 tissue samples from 204 patients, mainly with papillary thyroid carcinomas (PTCs; n = 180), including 196 LNMs and 56 distant metastases. All the distant metastases included corresponded to radioiodine-refractory metastatic tissue. Results: We found the following mutation frequency in primary PTCs, LNMs, and distant metastases, respectively: TERTp: 12.9%, 10.5%, and 52.4%; BRAF: 44.6%, 41.7%, and 23.8%; and NRAS: 1.2%, 1.3%, and 14.3%. There was a significant concordance between the primary tumor genotype and the corresponding LNM for all the genes, in particular BRAF-mutated PTC. The overall concordance between primary tumors and respective distant metastases was low. In the group of patients with PTCs, we found a high frequency of TERTp mutations and a low frequency of BRAF mutations in distant metastases, in comparison with the paired primary tumors. When present in distant metastases, BRAF mutations frequently coexisted with TERTp mutations. Conclusions: When the genotype of primary tumors is compared with the genotype of LNMs, the concordance is high for all the genes studied. On the other hand, distant metastases show an enrichment in TERTp mutations and a decrease in BRAF mutations. TERTp mutations may play a role in distant metastases.

Selenium and Thyroid Disease: From Pathophysiology to Treatment.

Introduction. Selenium is a micronutrient embedded in several proteins. In adults, the thyroid is the organ with the highest amount of selenium per gram of tissue. Selenium levels in the body depend on the characteristics of the population and its diet, geographic area, and soil composition. In the thyroid, selenium is required for the antioxidant function and for the metabolism of thyroid hormones. Methods. We performed a review of the literature on selenium's role in thyroid function using PubMed/MEDLINE. Results. Regarding thyroid pathology, selenium intake has been particularly associated with autoimmune disorders. The literature suggests that selenium supplementation of patients with autoimmune thyroiditis is associated with a reduction in antithyroperoxidase antibody levels, improved thyroid ultrasound features, and improved quality of life. Selenium supplementation in Graves' orbitopathy is associated with an improvement of quality of life and eye involvement, as well as delayed progression of ocular disorders. The organic form of selenium seems to be the preferable formulation for supplementation or treatment. Conclusion. Maintaining a physiological concentration of selenium is a prerequisite to prevent thyroid disease and preserve overall health. Supplementation with the organic form is more effective, and patients with autoimmune thyroiditis seem to have benefits in immunological mechanisms. Selenium supplementation proved to be clinically beneficial in patients with mild to moderate Graves' orbitopathy.