Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study.

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.

Seventy two-hour glucose monitoring profiles in mild gestational diabetes mellitus: differences from healthy pregnancies and influence of diet counseling.

OBJECTIVE: To study glucose profiles of gestational diabetes (GDM) patients with 72 h of continuous glucose monitoring (CGM) either before (GDM1) or after (GDM2) dietary counseling, comparing them with nondiabetic (NDM) controls. DESIGN AND METHODS: We performed CGM on 22 GDM patients; 11 before and 11 after dietary counseling and compared them to 11 healthy controls. Several physiological and clinical characteristics of the glucose profiles were compared across the groups, including comparisons for pooled 24-h measures and hourly median values, summary measures representing glucose exposure (area under the median curves) and variability (amplitude, standard deviation, interquartile range), and time points related to meals. RESULTS: Most women (81.8%) in the GDM groups had fasting glucose <95mg/dL, suggesting mild GDM. Variability, glucose levels 1 and 2h after breakfast and dinner, peak values after dinner and glucose levels between breakfast and lunch, were all significantly higher in GDM1 than NDM (P<0.05 for all comparisons). The GDM2 results were similar to NDM in all aforementioned comparisons (P>0.05). Both GDM groups spent more time with glucose levels above 140mg/dL when compared with the NDM group. No differences among the groups were found for: pooled measurements and hourly comparisons, exposure, nocturnal, fasting, between lunch and dinner and before meals, as well as after lunch (P>0.05 for all). CONCLUSION: The main differences between the mild GDM1 group and healthy controls were related to glucose variability and excursions above 140mg/dL, while glucose exposure was similar. Glucose levels after breakfast and dinner also discerned the GDM1 group. Dietary counseling was able to keep glucose levels to those of healthy patients.

Diabetes and other endocrine-metabolic abnormalities in the long-term follow-up of pancreas transplantation.

Pancreas transplantation (PTX) has been demonstrated to restore long-term glucose homeostasis beyond what can be achieved by intensive insulin therapy or islet transplants. Moreover, PTX has been shown to decrease the progression of the chronic complications of diabetes. However, PTX patients require chronic use of immunosuppressive drugs with potential side effects. The long-term follow-up of PTX patients demands special care regarding metabolic deviations, infectious complications, and chronic rejection. Diabetes and other endocrine metabolic abnormalities following transplantation are common and can increase morbidity and mortality. Previous recipient-related and donor-related factors, as well as other aspects inherent to the transplant, act together in the pathogenesis of those abnormalities. Early recognition of these disturbances is the key to timely treatment; however, adequate tools to achieve this goal are often lacking. In a way, the type of PTX procedure, whether simultaneous pancreas kidney or not, seems to differentially influence the evolution of endocrine and metabolic abnormalities. Further studies are needed to define the best approach for PTX patients. This review will focus on the most common endocrine metabolic disorders seen in the long-term management of PTX: diabetes mellitus, hyperlipidemia, and bone loss. The authors here cover each one of these endocrine topics by showing the evaluation as well as proper management in the follow-up after PTX.

Metabolic long-term follow-up of functioning simultaneous pancreas-kidney transplantation versus pancreas transplantation alone: insights and limitations.

BACKGROUND: Pancreas transplantation involves a set of procedures that, in some cases, lead to different complications and outcomes. The aim of this study was to analyze the long-term effects of pancreas transplantation regarding carbohydrate and lipid metabolism parameters to determine differences between simultaneous pancreas-kidney (SPK) transplantation and pancreas transplantation alone (PTA). METHODS: Sixty-four patients (46 SPK and 18 PTA), with an immunosuppression protocol based on tacrolimus plus mycophenolate mofetil and prednisone, were evaluated for at least 1 year after transplantation. No patient made use of any hypoglycemic or hypolipidemic drugs. Comparisons were performed between SPK and PTA patients using the chi-square test, Fischer's exact test, and unpaired Student's t test, as appropriate. RESULTS: Patients were 39.8+/-9.3 years old, predominantly male (60.9%), with a mean follow-up of 25.4+/-10.4 months after transplantation. The PTA group exhibited worse renal function and higher tacrolimus levels than the SPK group. Fasting glucose, 2 hr plasma glucose after overload, C-peptide, and HbA1C were within the normal range, with no statistically significant differences between the PTA and SPK groups. Insulin (INS) and the homeostasis model assessment of INS resistance index were above the normal range in both the groups. Lipids were also similar between groups. CONCLUSIONS: The majority of patients with long-term functioning pancreas transplant achieved good glucose control without use of exogenous INS or oral antidiabetic drugs, although they were hyperinsulinemic. There were no significant differences concerning glucose and lipid parameters between the SPK and PTA groups, even though the PTA patients exhibited higher tacrolimus levels and worse renal function.

The impact of functioning pancreas-kidney transplantation and pancreas alone transplantation on the lipid metabolism of statin-naïve diabetic patients.

OBJECTIVE: To compare the lipid profile (total cholesterol - TC, triglycerides - TG, high density lipoprotein cholesterol - HDL-c, low density lipoprotein cholesterol - LDL-c and non-HDL cholesterol - NHDL-c) of patients with functioning pancreas-kidney transplantation (PKT) or pancreas transplantation alone (PTA) after one (T1) and two yr (T2) following their pre-transplantation data (T0). METHODS: Fifty-three type 1 diabetic patients underwent pancreas transplantation (42 PKT and 11 PTA) remaining euglycemic after transplantation were evaluated before and one and two yr after the procedures. They were using predominantly tacrolimus-mycophenolate mofetil-based immunosuppression and low glucocorticoid dose with systemic venous drainage of the pancreatic graft. None of them used hypolipidemic agents for economical reasons. Lipids were reported as means +/- standard error of the mean. Data obtained in T0 were compared with T1 and T2 using ANOVA followed by Student's t-test. RESULTS: TC, LDL-c, NHDL-c and TG were lower in T1 and T2 when compared with T0 (p < 0.05) in PKT, while no change was observed for HDL-c (p > 0.05). PTA group showed no significant changes in lipids. CONCLUSION: In spite of the known side effects of tacrolimus-based immunosuppression to lipids, our study with a statin-naïve sample showed improvements (PKT) or stabilization (PTA) in the serum lipid profile after pancreas transplantation.

[Cutaneous non-Langerhans cells histiocytoses as cause of central diabetes insipidus]. / Histiocitose cutânea não-Langerhans como causa de diabetes insípido central.

The histiocytoses are rare diseases caused by alterations in the monocyte-histiocytic series with several clinical findings. Among the cutaneous syndromes of non-Langerhans cells, xanthoma disseminatum is the only disease of this group that has been classically associated to the central diabetes insipidus (CDI). The case reported describes a 30-year-old man that two years after presenting with CDI developed non confluent disseminated cutaneous brown papular lesions throughout the body. The histopathology, immunohistochemistry, and electronic microscopy were compatible with the diagnosis of non-Langerhans histiocytoses, suggesting the diagnosis of juvenile xanthogranuloma. The endocrine-metabolic evaluation did not show other alterations besides CDI in a 10-year follow up. The magnetic resonance of hypophysis showed absence of the pituitary hyperintense sign (bright spot). The radiologic and scinthigraphic evaluation of the bones did not show the presence of osteolytic lesions. This case prints out the importance of skin examination in cases of CDI and its association with cutaneous non-Langerhans histiocytoses in a broader spectrum, rather then restricted to the cases of xanthoma disseminatum.

Histiocitose cutânea não-Langerhans como causa de diabetes insípido central / Cutaneous non-Langerhans cells histiocytoses as cause of central diabetes inspidus

As histiocitoses são doenças raras, resultantes de alterações na linhagem monocítica-histiocítica, com manifestações clínicas diversas. Entre as síndromes cutâneas de células não-Langerhans, o xantoma disseminado é a única entidade desse grupo classicamente associada ao diabetes insípido central (DIC). O caso clínico relatado refere-se a um paciente de 30 anos de idade que, dois anos após o diagnóstico de DIC, evoluiu com lesões cutâneas papulosas, eritêmato-acastanhadas, difusas, discretas e não confluentes. Os achados histológicos, imuno-histoquímicos e a microscopia eletrônica mostraram resultados compatíveis com a histiocitose de células não-Langerhans e sugestivos do xantogranuloma juvenil. A avaliação endócrino-metabólica não mostrou alterações durante o seguimento por 10 anos, com exceção do DIC. A ressonância magnética da hipófise demonstrou ausência do sinal hiperintenso (mancha brilhante) correspondente à neuro-hipófise. As radiografias e a cintilografia dos ossos não mostraram lesões osteolíticas. Este caso desperta a atenção para a importância do exame da pele nos casos de DIC e de sua associação com a histiocitose de células não-Langerhans de maneira mais ampla, e não restrita aos casos de xantoma disseminado.

The histiocytoses are rare diseases caused by alterations in the monocyte-histiocytic series with several clinical findings. Among the cutaneous syndromes of non-Langerhans cells, xanthoma disseminatum is the only disease of this group that has been classically associated to the central diabetes insipidus (CDI). The case reported describes a 30-year-old man that two years after presenting with CDI developed non confluent disseminated cutaneous brown papular lesions throughout the body. The histopathology, immunohistochemistry, and electronic microscopy were compatible with the diagnosis of non-Langerhans histiocytoses, suggesting the diagnosis of juvenile xanthogranuloma. The endocrine-metabolic evaluation did not show other alterations besides CDI in a 10-year follow up. The magnetic resonance of hypophysis showed absence of the pituitary hyperintense sign (bright spot). The radiologic and scinthigraphic evaluation of the bones did not show the presence of osteolytic lesions. This case prints out the importance of skin examination in cases of CDI and its association with cutaneous non-Langerhans histiocytoses in a broader spectrum, rather then restricted to the cases of xanthoma disseminatum.

[Beriberi after bariatric surgery: not an unusual complication. Report of two cases and literature review]. / Beribéri pós bypass gástrico: uma complicação não tão rara. Relato de dois casos e revisão da literatura.

The number of patients submitted to bariatric surgery to treat morbid obesity is increasing, therefore, some nutritional deficiencies, with which many physicians are no longer familiarized, are reappearing. Postoperatively, many nutritional disorders may occur, one of them is thiamine deficiency (beriberi). The thiamine and/or vitamin B12 deficiency can correspond to 40% of the neuropathy cases after bariatric surgery. Two patients with the clinic of peripheral neuropathy and Wernicke-Korsakoff syndrome will be reported. Some months after the surgery, they presented prostration, depression, mental confusion and nystagmus, associated with pain and paresthesia in limbs (especially lower limbs). With the diagnostic hypothesis of beriberi, the treatment with thiamine started. One of the patients presented complete improvement of the neurological symptoms, however the other one remained with motor deficiency, exactly the one who spent a longer period of time between the symptoms appearance and the treatment beginning. These cases serve to alert us about the importance of nutritional vigilance after bariatric surgery.

Beribéri pós bypass gástrico: uma complicação não tão rara. Relato de dois casos e revisão da literatura / Beriberi after bariatric surgery: not an unusual complication. Report of two cases and literature review

É crescente o número de pacientes submetidos à cirurgia bariátrica para tratamento da obesidade mórbida; devido a isso, estão reaparecendo deficiências nutricionais com as quais muitos médicos já não estão familiarizados. No pós-operatório, podem ocorrer vários distúrbios nutricionais, sendo um deles a deficiência de tiamina (beribéri). A deficiência de tiamina e/ou vitamina B12 pode corresponder a 40 por cento dos casos de neuropatia após a cirurgia bariátrica. Serão descritos dois pacientes com a clínica de neuropatia periférica e síndrome de Wernicke-Korsakoff. Alguns meses após a cirurgia, eles apresentaram prostração, depressão, confusão mental e nistagmo, associados a dor e parestesia dos membros (principalmente inferiores). Com a hipótese diagnóstica de beribéri, foi iniciado o tratamento com tiamina. Um dos pacientes apresentou melhora completa do quadro neurológico, porém o outro permaneceu com déficit motor, sendo aquele em que decorreu o maior tempo entre o aparecimento dos sintomas e o início do tratamento. Estes casos servem para nos alertar sobre a importância da vigilância nutricional após a cirurgia bariátrica.

Managing thyroid cancer without thyroxine withdrawal.

Thyroxine (T4) withdrawal or recombinant TSH is used for the stimulation of thyroglobulin (Tg), whole-body scanning (WBS) and iodine-131 treatment in patients with thyroid carcinoma. This study evaluated the T4 dose reduction protocol as an alternative for patients' preparation. Fifty-one patients were submitted to total T4 withdrawal for WBS and Tg measurement. T4 treatment was then resumed and maintained until TSH reached levels < 0.3 mIU/l. The T4 dose was then decreased to 0.8 microg/kg/day and TSH was measured weekly. Tg was assayed when TSH was > 30 mIU/l. Patients diagnosed with the disease upon initial evaluation were treated. We also evaluated the clinical and laboratory changes observed for both preparations. Using the reduced dose protocol, TSH levels > 30 mIU/l were reached within 6 and 8 weeks in 84.6 and 100% of the patients, respectively. T4 withdrawal was associated with more common symptoms of hypothyroidism and elevation of creatine kinase (CK) and LDL cholesterol. The T4 dose reduction protocol proved to be useful for Tg stimulation and ablative therapy, without the complication of severe hypothyroidism or the cost of recombinant TSH.

Managing thyroid cancer without thyroxine withdrawal

A suspensão da tiroxina (T4) ou o TSH recombinante são usados para a estimulação da tireoglobulina (Tg), para o mapeamento de corpo inteiro (MCI) e para o tratamento com 131Iodo em pacientes com carcinoma tireoideano. Esse estudo avaliou um protocolo de redução de dose do T4 como alternativa para o preparo desses pacientes. Cinquenta e um pacientes submeteram-se à suspensão total de T4 para o MCI e a medida de Tg. Tratamento com T4 foi então reinstituído e mantido até que o TSH atingisse níveis < 0.3 mUI/l. A dose de T4 foi então dominuída para 0,8 µg/kg/dia e o TSH medido semanalmente. A Tg foi analisada quando o TSH estava > 30 mUI/l. Pacientes diagnosticados com a doença na fase inicial da avaliação foram tratados. Nós também avaliamos as alterações clínicas e laboratoriais observadas para ambos os preparos. Usando o protocolo de redução de dose, níveis de TSH > 30 mUI/l foram atingidos em 6 e 8 semanas em 84,6 and 100% dos pacientes, respectivamente. A suspensão do T4 esteve associada com sintomas mais comuns de hipotireoidismo e com elevação da creatino- quinase (CK) e LDL-colesterol. O protocolo de redução da dose de T4 mostrou-se útil para a estimulação da Tg e terapia ablativa, sem apresentar as complicações do hipotireoidismo severo ou chegar ao custo do TSH recombinante.