Plasma signatures of Congenital Generalized Lipodystrophy patients identified by untargeted lipidomic profiling are not changed after a fat-containing breakfast meal.

BACKGROUND: The incapacity to store lipids in adipose tissue in Congenital Generalized Lipodystrophy (CGL) causes hypoleptinemia, increased appetite, ectopic fat deposition and lipotoxicity. CGL patients experience shortened life expectancy. The plasma lipidomic profile has not been characterized fully in CGL, nor has the extent of dietary intake in its modulation. The present work investigated the plasma lipidomic profile of CGL patients in comparison to eutrophic individuals at the fasted state and after a breakfast meal. METHOD: Blood samples from 11 CGL patients and 10 eutrophic controls were collected after 12 h fasting (T0) and 90 min after an ad libitum fat-containing breakfast (T90). The lipidomic profile of extracted plasma lipids was characterized by non-target liquid chromatography mass spectrometry. RESULTS: Important differences between groups were observed at T0 and at T90. Several molecular species of fatty acyls, glycerolipids, sphingolipids and glycerophospholipids were altered in CGL. All the detected fatty acyl molecular species, several diacylglycerols and one triacylglycerol species were upregulated in CGL. Among sphingolipids, one sphingomyelin and one glycosphingolipid species showed downregulation in CGL. Alterations in the glycerophospholipids glycerophosphoethanolamines, glycerophosphoserines and cardiolipins were more complex. Interestingly, when comparing T90 versus T0, the lipidomic profile in CGL did not change as intensely as it did for control participants. CONCLUSIONS: The present study found profound alterations in the plasma lipidomic profile of complex lipids in CGL patients as compared to control subjects. A fat-containing breakfast meal did not appear to significantly influence the CGL profile observed in the fasted state. Our study may have implications for clinical practice, also aiding to a deeper comprehension of the role of complex lipids in CGL in view of novel therapeutic strategies.

Altered acylated ghrelin response to food intake in congenital generalized lipodystrophy.

BACKGROUND: Patients with congenital generalized lipodystrophy (CGL) have very low levels of leptin and are described as having a voracious appetite. However, a direct comparison between CGL and eutrophic individuals is lacking, regarding both appetite parameters and acylated ghrelin, the hormone form that is active in acute food intake stimulation. The objective of the present study was to address whether and in what extent the subjective appetite parameters and acylated ghrelin response to a meal are affected in CGL individuals, in comparison to eutrophic individuals. Additionally, an obese group was included in the study, to allow the comparison between a leptin-resistant and a leptin-deficient condition on these aspects. METHODS: Eutrophic controls (EUT, n = 10), obese subjects (OB, n = 10) and CGL (n = 11) were fasted overnight and then received an ad libitum meal. Blood was collected and the visual analogue scale was applied before and 90 minutes after the meal. An additional blood sample was collected at 60 minutes for ghrelin determination. RESULTS: The CGL patients showed low fasting levels of leptin and adiponectin, dyslipidemia, and insulin resistance. The caloric intake was similar among the 3 groups. However, both CGL (p = 0.02) and OB (p = 0.04) had shorter satiation times than EUT. The CGL patients also had lower satiety time (p = 0.01) and their sensation of hunger was less attenuated by the meal (p = 0.03). Fasting acylated ghrelin levels were lower in CGL than in EUT (p = 0.003). After the meal, the levels tended to decrease in EUT but not in CGL and OB individuals. CONCLUSION: The data indicate that, although not hyperphagic, the CGL patients present appetite disturbances in relation to eutrophic individuals. Their low fasting levels of acylated ghrelin and the absence of the physiological drop after meal intake suggest a role of these disturbances in hunger attenuation and satiety but not in acute satiation.

Controversial issues in the management of hyperprolactinemia and prolactinomas - An overview by the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism.

Prolactinomas are the most common pituitary adenomas (approximately 40% of cases), and they represent an important cause of hypogonadism and infertility in both sexes. The magnitude of prolactin (PRL) elevation can be useful in determining the etiology of hyperprolactinemia. Indeed, PRL levels > 250 ng/mL are highly suggestive of the presence of a prolactinoma. In contrast, most patients with stalk dysfunction, drug-induced hyperprolactinemia or systemic diseases present with PRL levels < 100 ng/mL. However, exceptions to these rules are not rare. On the other hand, among patients with macroprolactinomas (MACs), artificially low PRL levels may result from the so-called "hook effect". Patients harboring cystic MACs may also present with a mild PRL elevation. The screening for macroprolactin is mostly indicated for asymptomatic patients and those with apparent idiopathic hyperprolactinemia. Dopamine agonists (DAs) are the treatment of choice for prolactinomas, particularly cabergoline, which is more effective and better tolerated than bromocriptine. After 2 years of successful treatment, DA withdrawal should be considered in all cases of microprolactinomas and in selected cases of MACs. In this publication, the goal of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism (SBEM) is to provide a review of the diagnosis and treatment of hyperprolactinemia and prolactinomas, emphasizing controversial issues regarding these topics. This review is based on data published in the literature and the authors' experience.

Controversial issues in the management of hyperprolactinemia and prolactinomas - An overview by the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism

ABSTRACT Prolactinomas are the most common pituitary adenomas (approximately 40% of cases), and they represent an important cause of hypogonadism and infertility in both sexes. The magnitude of prolactin (PRL) elevation can be useful in determining the etiology of hyperprolactinemia. Indeed, PRL levels > 250 ng/mL are highly suggestive of the presence of a prolactinoma. In contrast, most patients with stalk dysfunction, drug-induced hyperprolactinemia or systemic diseases present with PRL levels < 100 ng/mL. However, exceptions to these rules are not rare. On the other hand, among patients with macroprolactinomas (MACs), artificially low PRL levels may result from the so-called "hook effect". Patients harboring cystic MACs may also present with a mild PRL elevation. The screening for macroprolactin is mostly indicated for asymptomatic patients and those with apparent idiopathic hyperprolactinemia. Dopamine agonists (DAs) are the treatment of choice for prolactinomas, particularly cabergoline, which is more effective and better tolerated than bromocriptine. After 2 years of successful treatment, DA withdrawal should be considered in all cases of microprolactinomas and in selected cases of MACs. In this publication, the goal of the Neuroendocrinology Department of the Brazilian Society of Endocrinology and Metabolism (SBEM) is to provide a review of the diagnosis and treatment of hyperprolactinemia and prolactinomas, emphasizing controversial issues regarding these topics. This review is based on data published in the literature and the authors' experience.

Microvascular Complications in Type 1 Diabetes: A Comparative Analysis of Patients Treated with Autologous Nonmyeloablative Hematopoietic Stem-Cell Transplantation and Conventional Medical Therapy.

OBJECTIVE: To explore the impact on microvascular complications, long-term preservation of residual B-cell function and glycemic control of patients with type 1 diabetes treated with autologous nonmyeloablative hematopoietic stem-cell transplantation (AHST) compared with conventional medical therapy (CT). RESEARCH DESIGN AND METHODS: Cross-sectional data of patients treated with AHST were compared with patients who received conventional therapy from the Brazilian Type 1 Diabetes Study Group, the largest multicenter observational study in type 1 diabetes mellitus in Brazil. Both groups of patients had diabetes for 8 years on average. An assessment comparison was made on the presence of microvascular complications, residual function of B cell, A1c, and insulin dose of the patients. RESULTS: After a median of 8 years of diagnosis, none of the AHST-treated patients (n = 24) developed microvascular complications, while 21.5% (31/144) had at least one (p < 0.005) complication in the CT group (n = 144). Furthermore, no case of nephropathy was reported in the AHST group, while 13.8% of CT group (p < 0.005) developed nephropathy during the same period. With regard of residual B-cell function, the percentage of individuals with predicted higher C-peptide levels (IDAA1C ≤ 9) was about 10-fold higher in the AHST group compared with CT (75 vs. 8.3%) (p < 0.001) group. Among AHST patients, 54.1% (13/24) had the HbA1c < 7.0 compared with 13.1% in the CT (p < 0.001) group. CONCLUSION: Patients with newly diagnosed type 1 diabetes treated with AHST presented lower prevalence of microvascular complications, higher residual B-cell function, and better glycemic control compared with the CT group.

Evaluation of clinical and laboratory parameters used in the identification of index cases for genetic screening of familial hypercholesterolemia in Brazil.

BACKGROUND AND AIMS: There is controversy on the accuracy of different diagnostic criteria for familial hypercholesterolemia (FH). The aim of this study is to assess the performance of different clinical criteria used to identify individuals for FH genetic cascade screening in Brazil. METHODS: All index cases (IC) registered in the Hipercol Brasil program between 2011 and 2016 were analyzed. Inclusion criteria were age ≥18 years and elevated LDL-cholesterol (LDL-C) levels, with a conclusive result in the genetic test, whether positive or negative. Initially, we tested the multivariable association between clinical and laboratory markers and the presence of an FH causing mutation. Then, we analyzed sensitivity, specificity, positive and negative predictive values for the LDL-C quartile distribution, LDL-C as a continuous variable, as well as the performance measures for the Dutch Lipid Clinic Network (DLCN) score to identify a mutation. RESULTS: Overall, 753 ICs were included and an FH causing mutation was found in 34% (n = 257) of the subjects. After multivariable analysis, LDL-C as a continuous variable, tendon xanthomas and corneal arcus were independently associated with the presence of FH mutations. LDL-C values ≥ 230 mg/dL (5.9 mmol/L) had the best tradeoff between sensitivity and specificity to diagnose a mutation. The DLCN score presented a better performance than LDL-C to identify a mutation, area under the ROC curve were 0.744 (95% CI: 0.704-0.784) and 0.730 (95% CI: 0.687-0.774), respectively, p=0.014. CONCLUSIONS: In our population, LDL ≥230 mg/dL is a feasible criterion to indicate ICs to genetic testing.

Role of the addition of cabergoline to the management of acromegalic patients resistant to longterm treatment with octreotide LAR.

The aim of this prospective open trial was to evaluate the efficacy in normalizing IGF-I levels of the addition of cabergoline to the treatment of acromegalic patients partially responsive to Octreotide-LAR (OCT-LAR), a long acting somatotastin analog (SSA). Fifty-two patients who did not achieve hormonal control after longterm therapy (at least, 12 months) with OCT-LAR (30 mg every 28 days intramuscularly) were given cabergoline in addition to the SSA treatment. Normalization of IGF-I levels was achieved in 40.4% of patients by 6 months after the addition of cabergoline (1.0-3.0 mg/week; mean, 2.19 ± 0.64), and these patients were considered responsive. Compared to non-responsive subjects, responsive patients had significantly lower mean %ULNR-IGF-I and GH levels. However, the rate of hyperprolactinemia and positive immunohistochemical staining for PRL was similar in both groups, before the addition of cabergoline. Responsive patients were followed for at least 12 months on combination treatment and persisted with normal IGF-I levels. Patients with baseline %ULNR IGF-I up to 220% and/or GH up to 5 ng/ml were those who benefited the most from combination treatment. No patients with %ULNR-IGF-I>250% reached normalization of IGF-I levels. Our findings demonstrated that the addition of cabergoline, even at relatively low doses, is effective in both short- and long-term control of IGF-I levels in acromegalic patients partially responsive to octreotide LAR, particularly in those with mild/moderately elevated GH/IGF-levels, irrespective of prolactin status.

Influência dos níveis séricos de IGF-I e de testosterona sobre o perfil lipídico e glicêmico em homens acromegálicos / Influence of serum IGF-I and testosterone on lipid and glycemic profile in acromegalic men

OBJETIVOS: Investigar a influência do IGF-I e testosterona sobre o perfil lipídico e glicêmico em homens acromegálicos. MÉTODOS: Foram avaliados 15 homens acromegálicos. RESULTADOS: Os pacientes hipogonádicos apresentaram HDL-c mais baixo e triglicérides, LDL-c, glicemia, GH e IGF-I mais elevados. Os valores de IGF-I correlacionaram-se inversamente com HDL-c (r = - 0,57, p = 0,04) e diretamente com triglicerídeos (r = 0,62, p = 0,01) e glicemia (r = 0,66, p = 0,008), enquanto a testosterona correlacionou-se diretamente com HDL-c (r = 0,52, p = 0,05) e inversamente com triglicerídeos (r = - 0,57, p = 0,02); LDL (r = - 0,53, p = 0,04) e glicemia (r = - 0,54, p = 0,03). O IGF-I e a testosterona correlacionaram-se inversamente (r = - 0,585, p = 0,028). CONCLUSÃO: Estes resultados sugerem que a intervenção mais importante na redução do risco cardiovascular nesses pacientes é o controle da atividade da doença.

OBJECTIVES: To evaluate the influence of IGF-I and testosterone on the lipid profile and glycemia in acromegalic men. METHODS: Fifteen acromegalic men were studied. RESULTS: The hypogonadic patients presented lower HDL-c and higher tryglicerides, LDL-c, glycemia, GH and IGF-I. Serum IGF-I was inversely correlated with HDL-c (r = - 0.57, p = 0.04) and directly with TG (r = 0.62, p = 0.01) and glycemia (r = 0.66, p = 0.008), whereas serum testosterone correlated directly with HDL-c (r = 0.52, p = 0.05) and inversely with TG (r = - 0.57, p = 0.02), LDL-c (r = - 0.53, p = 0.04) and fasting blood glucose (r = - 0.54, p = 0.03). IGF-I and testosterone were inversely correlated (r = - 0.585, p = 0.028). CONCLUSION: These results suggest that the most important intervention in reducing cardiovascular risk in these patients is to control the activity of the disease.

Picnodisostose: relato de dois casos / Pycnodysostosis: report of two cases

Picnodisostose (PYCD) é uma rara displasia esquelética autossômica recessiva, decorrente de defeito no gene codificador da enzima catepsina K, caracterizada por baixa estatura (BE), osteoesclerose, acroosteólise, deformidades crânio-faciais e fragilidade óssea. Embora a BE seja característica, deficiência de GH tem sido relatada apenas em parte dos casos de PYCD. Apresentamos dois casos isolados, com quadros clínico-radiológicos característicos. Caso 1: 9 anos, masculino, pais consangüíneos, apresentando BE, osteoesclerose, fragilidade óssea, exoftalmia bilateral, fronte ampla, braquicefalia, alargamento das suturas cranianas, fontanelas abertas, micrognatia, implantação anormal dos dentes, braquidactilia, unhas distróficas e acrosteólise das falanges distais. Caso 2: 17 anos, masculino, com BE, nariz proeminente, braquicefalia, plastibasia, falha de fechamento de suturas e fontanelas, hipoplasia mandibular, dentição anormal, osteoesclerose difusa, braquidactilia, acrosteólise das falanges distais e aumento das pregas cutâneas nas mãos. Ambos apresentaram níveis basais normais de TSH, T4 livre, gonadotrofinas e testosterona, e da resposta do GH e do cortisol, durante teste farmacológico. Em conclusão, a PYCD parece ser uma condição heterogénea com apresentação clínica variável. Assim, embora não tenha sido observado nestes casos, mas tendo em vista as descrições prévias, consideramos importante que pacientes com PYCD sejam rotineiramente submetidos à avaliação hormonal.

Carcinoma papilifero oculto da tireoide com metastases ganglionares a distancia relato de um caso / Occult papillary thyroid carcinoma with distant ganglionary metastasis; a case report

Os autores relatam um caso de carcinoma papilifero oculto da tireoide com comprometimento linfatico extenso e a distancia, ressaltando a raridade desta apresentaçao. Tecem comentarios sobre a incidencia e prognostico do carcinoma papolifero oculto da tireoide. Finalizam fazendo uma breve revisao dos casos existentes na literatura medica