Preventive medicine of von Hippel-Lindau disease-associated pancreatic neuroendocrine tumors.

Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel-Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10-75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

The prevalence of thyroid autoimmunity in patients with prolactinoma

Prolactin (PRL) is a hormone characterized by its immunomodulatory properties. The aim of this study was to evaluate the prevalence of thyroid autoimmunity in patients with prolactinoma. Seventy-seven patients and 56 healthy individuals in the control group, sex and age matched, had their serum PRL, free tetraiodothyronine, thyroid-stimulating hormone and anti-thyroid peroxidase (anti-TPO) levels measured. The prevalence of anti-TPO for patients was 13% and 8.9% for control group (p = 0.58). The analysis of subgroups of patients, divided in accordance with tumor size at diagnosis, showed no significant difference in the frequency of anti-TPO. However, when they were divided in accordance with the prolactin levels at the moment of the study, 18.8% with valid hyperprolactinemia and 3.4% without hyperprolactinemia had positive autoantibody (p = 0.07). In conclusion, there was no greater prevalence of thyroid autoimmunity in patients with prolactinoma. Nevertheless, those with valid hyperprolactinemia showed a greater tendency for positive autoantibody anti-TPO

Redução da densidade mineral óssea em mulheres na menacme com prolactinoma / Decreased bone mineral density in pre-menopause women with prolactinoma

A hiperprolactinemia tumoral e conseqüente hipogonadismo têm sido associados à osteoporose. Avaliamos a densidade mineral óssea (DMO) por absortometria com dupla fonte de RX em 24 mulheres entre 18 e 49 anos, com prolactinoma (15 macro e 9 micro). Utilizamos teste t de Student não pareado ou Mann-Whitney para comparar subgrupos, e teste de Spearman para correlações. O maior acometimento foi de coluna lombar, onde 20,83 por cento das pacientes tinham Z-escore < -2 DP. Não detectamos diferenças densitométricas entre macro e microprolactinomas, nem entre pacientes com prolactina normal versus as hiperprolactinêmicas. A DMO e o Z-escore na coluna foram maiores nas pacientes com > 8 ciclos menstruais no ano anterior à densitometria versus as oligoamenorréicas (p = 0,030). O número de ciclos/ano correlacionou-se com a DMO na coluna (r = 0,515, p = 0,017), e o índice de massa corporal, com a DMO em colo femural (r = 0,563, p = 0,006) e fêmur total (r = 0,529, p = 0,011). Conclusões: Em nossa amostra de mulheres jovens com prolactinoma, 20,83 por cento têm densidade óssea abaixo do esperado para a idade. O maior acometimento de regiões ricas em osso trabecular, como as vértebras, sugere a participação do hipogonadismo na gênese da doença óssea. Independentemente dos valores séricos de prolactina, o retorno dos ciclos menstruais parece ser o melhor índice de bom controle dessas pacientes.

Tumoral hyperprolactinemia and consequent hypogonadism have been associated with osteoporosis. Bone mineral density (BMD) was measured by dual-energy RX absorptiometry in 24 patients with prolactinoma (15 macro and 9 micro adenomas; age range = 18 to 49 years). Student unpaired t or Mann-Whitney tests were used to compare groups, and Spearman test studied correlations. Lumbar spine (LS) was the most affected, as LS Z-score was < -2 SD in 20.83 percent of the patients. No difference was found in densitometric parameters for the comparison between macro and microprolactinoma, or those with normal prolactin versus hyperprolactinemia. LS BMD and LS Z-score were higher in the patients with > 8 menstrual cycles in the preceding year then in those with oligoamenorrhea (p = 0.030). The number of cycles was correlated to LS BMD (r = 0.515, p = 0.017) and body mass index to femoral neck BMD (r = 0.563, p = 0.006) and total femur BMD (r = 0.529, p = 0.011). CONCLUSIONS: Decreased bone mineral density was detected in 20.83 percent of our young patients with prolactinoma. The great involvement of trabecular bone skeletal regions, such as vertebrae, suggests the participation of hypogonadism in the pathogenesis of bone disease. Irrespective of prolactin levels, return to normal menses seems the best index of good control.

Body fat in nonobese women with prolactinoma treated with dopamine agonists.

OBJECTIVES: To evaluate body fat in nonobese women with prolactinoma treated with dopamine agonists, using whole body dual energy X-ray absorptiometry (DXA) and to correlate DXA results with biochemical data and clinical aspects of the prolactinoma. DESIGN, PATIENTS AND MEASUREMENTS: A cross-sectional study was performed in two University referral centres. Thirty-one nonobese premenopausal women with prolactinoma were subjected to DXA and blood analysis at clinical evaluation. They were compared with 21 control women of similar age and body mass index (BMI). RESULTS: Women with prolactinoma treated with dopamine agonists and controls had similar body fat percentages in all sites evaluated with DXA (arms, legs, trunk, android, gynoid and total body). Patients with normal PRL levels at study entry had lower body fat percentages in all sites. In the patient group, arm, leg, truncal, android, gynoid and total body fat were positively associated with PRL levels. CONCLUSION: Body fat percentage is similar in nonobese women with prolactinoma and in controls. The lower body fat content in patients with normal PRL levels is likely to be due to the metabolic effects of adequate dopamine receptor type 2 (DR2) activation as a result of regular dopamine agonist treatment. This finding reinforces the importance of the appropriate treatment with dopamine agonists in women with prolactinoma, which, besides normalizing PRL levels, reduces body fat content and the consequent risk of developing Metabolic Syndrome and its complications.

[Decreased bone mineral density in pre-menopause women with prolactinoma]. / Redução da densidade mineral óssea em mulheres na menacme com prolactinoma.

UNLABELLED: Tumoral hyperprolactinemia and consequent hypogonadism have been associated with osteoporosis. Bone mineral density (BMD) was measured by dual-energy RX absorptiometry in 24 patients with prolactinoma (15 macro and 9 micro adenomas; age range = 18 to 49 years). Student unpaired t or Mann-Whitney tests were used to compare groups, and Spearman test studied correlations. Lumbar spine (LS) was the most affected, as LS Z-score was < -2 SD in 20.83% of the patients. No difference was found in densitometric parameters for the comparison between macro and microprolactinoma, or those with normal prolactin versus hyperprolactinemia. LS BMD and LS Z-score were higher in the patients with > 8 menstrual cycles in the preceding year then in those with oligoamenorrhea (p = 0.030). The number of cycles was correlated to LS BMD (r = 0.515, p = 0.017) and body mass index to femoral neck BMD (r = 0.563, p = 0.006) and total femur BMD (r = 0.529, p = 0.011). CONCLUSIONS: Decreased bone mineral density was detected in 20.83% of our young patients with prolactinoma. The great involvement of trabecular bone skeletal regions, such as vertebrae, suggests the participation of hypogonadism in the pathogenesis of bone disease. Irrespective of prolactin levels, return to normal menses seems the best index of good control.

[IGF-1 plasma levels evaluation in prolactinoma]. / Avaliação plasmática de IGF-1 no prolactinoma.

Prolactinomas are the most frequent pituitary tumors and may co-secrete GH (growth hormone). IGF-1 (insulin-like growth factor-1) is the main responsible for GH actions and a parameter for the diagnosis of acromegaly. With the objective of identifying through a IGF-1 levels analysis, in the initial evaluation of prolactinoma patients, the existence of mixed tumors [GH and prolactin (PRL)], we studied 7 men and 27 women, aged between 19 and 72 years, confronting them with the results of basal and glucose stimulated (glucose tolerance test--GTT) GH levels, indicated when GH >0.4 ng/mL or IGF-1 levels were elevated. The prevalence of patients with GH >0.4 ng/mL and elevated IGF-1 was higher than expected; however, after GTT, no patient fulfilled the diagnostic criteria for acromegaly. However, we suggest that, they should be submitted to IGF-1 evaluation, due to the risk of GH co-secretion in prolactinomas. Special attention should be paid to those who present a significant decrease of PRL levels without concomitant tumor size reduction.

Avaliação plasmática de igf-1 no prolactinoma / IGF-1 plasma levels evaluation in prolactinoma

Prolactinomas são os tumores hipofisários mais comuns, podendo co-secretar GH (hormônio do crescimento). IGF-1 (fator de crescimento insulina-símile-1) é o principal responsável pelas ações do GH e parâmetro diagnóstico de acromegalia. Objetivando determinar por uma dosagem de IGF-1, na avaliação inicial de pacientes com prolactinoma, ocorrência de tumores mistos [GH e prolactina (PRL)], estudamos 7 homens e 27 mulheres, entre 19 e 72 anos, confrontando-os aos resultados de GH basal e durante teste oral de tolerância à glicose, quando GH basal >0,4 ng/mL ou níveis de IGF-1 alterados. A proporção de pacientes com GH >0,4 ng/mL e IGF-1 elevada foi alta; mas, após administração de 75g de glicose por via oral, nenhum paciente foi diagnosticado como acromegálico. Sugerimos, porém que a dosagem de IGF-1 seja realizada pelo risco de co-secreção de GH nos prolactinomas. Atenção especial para pacientes que apresentem significativa diminuição dos níveis de PRL, sem correspondente regressão do tamanho do adenoma.

Prolactinomas are the most frequent pituitary tumors and may co-secrete GH (growth hormone). IGF-1 (insulin-like growth factor-1) is the main responsible for GH actions and a parameter for the diagnosis of acromegaly. With the objective of identifying through a IGF-1 levels analysis, in the initial evaluation of prolactinoma patients, the existence of mixed tumors [GH and prolactin (PRL)], we studied 7 men and 27 women, aged between 19 and 72 years, confronting them with the results of basal and glucose stimulated (glucose tolerance test - GTT) GH levels, indicated when GH >0.4 ng/mL or IGF-1 levels were elevated. The prevalence of patients with GH >0.4 ng/mL and elevated IGF-1 was higher than expected; however, after GTT, no patient fulfilled the diagnostic criteria for acromegaly. However, we suggest that, they should be submitted to IGF-1 evaluation, due to the risk of GH co-secretion in prolactinomas. Special attention should be paid to those who present a significant decrease of PRL levels without concomitant tumor size reduction.

[Prolactinomas and bone mineral density in men]. / Prolactinomas e densidade mineral óssea em homens.

Throughout the years evidence has been accumulated on the morbidity of hyperprolactinemia, particularly in terms of bone mineral density decrease. This complication of hyperprolactinemia affects both women and men. In this paper, we analyze aspects related to bone loss in men with hyperprolactinemia due to prolactinomas: prevalence, clinical relevance, physiopathology, diagnosis and the consequences of the treatment of hyperprolactinemia and hypogonadism on bone mineral density.

Prolactinomas e densidade mineral óssea em homens / Prolactinomas and bone mineral density in men

Ao longo dos anos, têm se acumulado evidências acerca da morbidade relativa à hiperprolactinemia, especialmente em relacão à diminuicão da densidade mineral óssea. Esta complicacão da hiperprolactinemia afeta tanto mulheres quanto homens. Neste artigo, analisamos aspectos relativos à perda de massa óssea observada em homens com hiperprolactinemia decorrente de prolactinomas: prevalência, relevância clínica, fisiopatologia, diagnóstico e as conseqüências do tratamento da hiperprolactinemia e do hipogonadismo sobre a densidade mineral óssea.

Criptococose pulmonar pseudotumoral associada à síndrome de Cushing / Pseudotumoral pulmonary cryptococcosis in association with Cushing's syndrome

Em pacientes com síndrome de Cushing, observa-se freqüência aumentada de infecções oportunistas que possuem uma elevada mortalidade e estão associadas à gravidade do hipercortisolismo. Criptococose pulmonar é uma destas infecções oportunistas e pode mimetizar uma neoplasia pulmonar, tornando o seu diagnóstico difícil. Apresentamos um caso de um paciente do sexo masculino, jovem, com síndrome de Cushing ACTH-dependente e grave hipercortisolismo. O paciente obteve a cura após cirurgia transfenoidal, mas desenvolveu quadro febril. Tomografia computadorizada de tórax mostrou um nódulo pulmonar que não se alterava em radiografias seriadas. A investigação para tuberculose, infecção fúngica e bacteriana foi inconclusiva, tornando a hipótese de neoplasia pulmonar mais provável. O paciente faleceu por sepse urinária. A necropsia, no entanto, demonstrou tratar-se de criptococose pseudotumoral. Pacientes com síndrome de Cushing e infiltrado pulmonar devem ser avaliados quanto à infecção fúngica, como Cryptococcus neoformans.

[Pseudotumoral pulmonary cryptococcosis in association with Cushing's syndrome]. / Criptococose pulmonar pseudotumoral associada à síndrome de Cushing.

Opportunistic infections in endogenous Cushing's syndrome are associated with severe cortisol excess and carry a high mortality. Pulmonary cryptococcosis is one of these opportunistic infections and can mimic a lung neoplasm, therefore making its diagnosis difficult. We report a case of a young male with ACTH-dependent Cushing's syndrome and severe hypercortisolism. The patient achieved cure after the transfenoidal surgery, but developed a febrile state. A chest computed tomography showed a pulmonary nodule that did not change in serial chest radiographs. Diagnosis of tuberculosis, fungal and bacterial infections were inconclusive, so the hypothesis of lung neoplasm became more probable. The necropsy, however, disclosed a pseudotumoral cryptococcosis. Opportunistic infections, like Cryptococcus neoformans, should be considered in patients with Cushing's syndrome and a pulmonary infiltrate.

Effect of iodine or iopanoic acid on thyroid Ca2+/NADPH-dependent H2O2-generating activity and thyroperoxidase in toxic diffuse goiters.

OBJECTIVE: The aim of the present study was to compare the effects of iopanoic acid (IOP) or a saturated solution of potassium iodide (SSKI) administration to patients with toxic diffuse goiters (TDG). DESIGN: Patients with TDG are treated with thionamides and high doses of iodine preoperatively. In this study, two types of preoperative drug regimens were used: propylthiouracil or methimazole plus SSKI for 10-15 days (n=8) or IOP for 7 days (n=6). METHODS: Serum thyroid hormones (total and free thyroxine (T(4)), total tri-iodothyronine (T(3)) and reverse T(3) (rT(3)), were evaluated after 7 days of either SSKI or IOP treatment, and after 10-15 days of SSKI administration. During thyroidectomy, samples of thyroid gland were obtained to evaluate thyroperoxidase and thyroid H(2)O(2)-generating activities. RESULTS: Serum total T(3) was significantly decreased after 7 days of either treatment, and serum rT(3) was significantly increased in IOP-treated patients. Serum total and free T(4) were unaffected by 7 days of IOP treatment, but decreased after 7 days of SSKI treatment, although significantly diminished levels were only reached after a further 3-8 days of SSKI administration. During both drug regimens, serum TSH remained low (SSKI: 0.159+/-0.122; IOP: 0.400+/-0.109 microU/ml). Thyroperoxidase activity was significantly lower in thyroid samples from patients treated with SSKI for 10-15 days than in the thyroid glands from IOP-treated patients. However, thyroid H(2)O(2) generation was inhibited in samples from patients treated with either IOP or SSKI. CONCLUSIONS: We show herein that IOP treatment can be effective in the management of hyperthyroidism and that this drug inhibits thyroid NADPH oxidase activity, just as previously described for SSKI, probably due to its iodine content.

Alteraçäo da funçäo hipofisária associada a mucocele gigante / Pituitary function change associated with giant mucocele

Este relato mostra o caso de uma paciente com mucocele gigante do seio esfeinodal, apresentando-se como massa intracraniana,, invadindo a tela túrsica e levando à disfunçäo hipofisária com deficiência córtico e somatotrófica. Revendo a literatura, näo foram encontrados casos semelhantes. Desta forma, seräo discutidos alguns relatos de caso de mucoceles que se apresentaram como massa intracraniana e a reversibilidade da funçäo hipofisária após a cirurgia descompressiva.

Captaçäo diferenciada de meta-iodobenzilguanidina em paciente com feocromocitoma bilateral e neoplasia endócrina múltipla tipo 2A / Differentiated captation of meta-iodobenzylguanidine in patients with bilateral pheochromocytoma and multiple endocrine neoplasm type 2A

O feocromocitoma que ocorre na síndrome de Neoplasia endócrina múltipla tipo 2A (NEM-2A), também conhecida como síndrome de Siple, é muitas vezes bilateral e multicêntrico. O uso da cintilografia com meta-iodobenzilguanidina (M-IBG) é um método seguro e eficaz para o diagnóstico de localização do feocromocitoma, particularmente nos casos de sítio extra adrenal, recorrência pós-operatória ou doença metastática maligna. Apresentamos o caso de uma paciente feminina de 26 anos com NEM-2A e feocromocitoma adrenal bilateral (visualizando na Ressonância Nuclear Magnética e confirmado pelo exame histopatológico), cuja cintilografia com I(131) M-IBG revelou marcada diferença de captação entre as adrenais (mínima à direita e mais intensa à esquerda). Relevante no caso, foi o fato do tumor à direita ser muito maior (5,5 cm de diâmetro) do que à esquerda (3,0 cm de diâmetro), funcionalmente iguais (caracterizado por complicações pré-operatórias quando da manipulação cirúrgico) e histopatologicamente similares. Concluímos que nos casos de NEM-2A, a exploração cirúrgica bilateral das adrenais.

Avaliaçäo psicológica de pacientes com doença de Graves / Psychological investigation in patients with Graves Disease

Já é conhecida na literatura médica a correlaçäo entre distúrbios hormonais, especialmente os da glândula tireóide, e alteraçöes de comportamento. Vários pesquisadores procuraram investigar uma possível associaçäo entre a ocorrência de um evento estressor e o aparecimento da doença de Graves. Com os objetivos de fazer uma revisäo sobre esse tema e uma avaliaçäo psicológica nos pacientes com doença de Graves, os autores submeteram 62 deles a um questionário elaborado pelo Serviço de Psicologia Médica e Saúde Mental em conjunto com o Serviço de Endocrinologia do HUCFF. Os resultados apontam para a dificuldade de considerar o fator psíquico, embora presente em um grande número de casos, como único agente desencadeador da doença de Graves. Também mostram a necessidade de se oferecer a esses pacientes a possibilidade de um tratamento psíquico associado ao endocrinológico

Avaliacao psicologica de pacientes com doenca de Graves

Ja e conhecida na literatura medica a correlacao entre disturbios hormonais, especialmente os da glandula tireoide, e alteracoes de comportamento. Varios pesquisadores procuraram investigar uma possivel associacao entre a ocorrencia de um evento estressor e o aparecimento da doenca de Graves. Com os objetivos de fazer uma revisao sobre esse tema e uma avaliacao psicologica nos pacientes com doenca de Graves, os autores submeteram 62 deles a um questionario elaborado pelo Servico de Psicologia Medica e Saude Mental em conjunto com o Servico de Endocrinologia do HUCFF. Os resultados apontaram para a dificuldade de considerar o factor psiquico, embora presente em um grande numero de caos, como unico agente desencadeador da doenca de Graves. Tambem mostram a necessidade de se oferecer a esses pacientes a possibilidade de um tratamento psiquico associado ao endocrinologico.