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ABSTRACT Osteoporosis is a systemic skeletal disease characterized by reduced bone mass and deterioration of bone tissue microarchitecture leading to an increased risk of fractures. Fragility fractures, especially hip fractures, are associated with a significant reduction in the physical function and quality of life of affected patients, as well as increased mortality, leading to a major financial impact on health care. Many drugs have been registered for the treatment of osteoporosis and very recently, a new anabolic agent, romosozumab, has been approved in some countries. Despite the expansion of efficacious antiresorptive and anabolic therapies in recent years, a concomitant increase in concerns have been raised by physicians, patients and the lay press about the potential for adverse events, especially atypical femoral fractures (AFF) following prolonged use of bisphosphonates. Whatever the mechanism(s) may be, direct or indirect, linking prolonged bisphosphonate use to atypical femoral fractures, this adverse event is very rare in comparison to the magnitude of risk reduction of typical osteoporotic fractures. An estimated 162 osteoporosis-related fractures are prevented for each atypical femoral fracture associated with an anti-resorptive medication. Until a risk calculator for predicting risk of atypical fractures, becomes available in clinical practice, and we view this as an unlikely scenario, it is up to the physician to consider continuing or discontinuing bisphosphonate use after the critical 3-5 year period of treatment with zoledronic acid or alendronate, but close monitoring for the residual bone effects overtime should be planned. For other bisphosphonates, in which no residual effects are expected, drug holiday is usually not applied.

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ABSTRACT A literature review on the clinical, laboratory, and treatment features of type B insulin resistance syndrome (TBIRS). Data from PubMed, the Virtual Health Library and Cochrane database were selected and analyzed using the REDCap application and R statistical program. From 182 papers, 65 were selected, which assessed 119 clinical cases, 76.5% in females and 42.9% in African-Americans, with an average age of 44 years. A common feature of TBIRS is co-occurrence of autoimmune diseases, such as systemic lupus erythematosus (most frequently reported). Hyperglycemia of difficult control was the mostly reported condition. Tests for anti-insulin receptor antibodies were positive in 44.2% of the cases. Disease management comprised fractional diet, insulin therapy (maximum dose given was 57 600 IU/day), plasmapheresis and immunosuppression with several classes of drugs, mainly glucocorticoids. Remission occurred in 69.7% of cases, in 30.3% of these spontaneously. The mortality rate was 15.38%. There was an inverse relationship between anti-insulin antibodies and remission (p = 0.033); and a positive correlation between combined immunosuppressive therapy and remission (p = 0.002). Relapse occurred in 7.6% of the cases. This rare syndrome has difficult-to-control diabetes, even with high doses of insulin, and it is usually associated with autoimmune diseases. Therapeutic advances using immunomodulatory therapy have led to significant improvements in the rate of remission.

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ABSTRACT Objective The purpose of the study is to quantitatively assess shear-wave elastography (SWE) value in American College of Radiology Thyroid Imaging Reporting and Data Systems (ACR TI-RADS) 4. Materials and methods One hundred and fifty-two ACR TI-RADS 4 thyroid nodules undergoing SWE were included in the study. The mean (EMean), minimum (EMin) and maximum (EMax) of SWE elasticity were measured. Results The areas under the receiver operating characteristic (ROC) curves for SWE EMean, EMin and EMax in detecting benign and malignant nodules were 0.95, 0.83 and 0.84, respectively. Cut-off value of EMean ≤ 23.30 kPa is able to downgrade the lesion category to ACR TI-RADS 3 and cut-off value of EMean ≥ 52.14 kPa is able to upgrade the lesion category to ACR TI-RADS 5. Conclusions The EMean of SWE will probably identify nodules that have a high potential for benignity in ACR TI-RADS 4. It may help identify and select benign nodules while reducing unnecessary biopsy of benign thyroid nodules.

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ABSTRACT Objective This study aims to determine the cost effectiveness of rapid frozen section (RFS) for indeterminate thyroid nodules. Materials and methods A retrospective chart review was conducted between January 2009 and June 2013 at a tertiary care institution. Main outcomes were number needed to treat, RFS efficacy, and cost-savings of avoiding second completion thyroidectomy. Cost-effectiveness was estimated using 2015 Medicare reimbursement rate. Results Out of 1,114 patients undergoing thyroid surgery, 314 had preoperative AUS/FLUS cytopathology and subsequent thyroid lobectomy with RFS. RFS identified 13 of the 32 patients with malignancy resulting in a total thyroidectomy. 19 of the 29 malignancies not detected by RFS were papillary microcarcinomas. Conclusions Completion thyroidectomy was avoided in 1 out of every 24 patients resulting in cost-savings of $ 80.04 per patient. In the era of outpatient thyroid surgery, intraoperative RFS for indeterminate thyroid nodules is cost-effective.

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ABSTRACT Objective This study aimed to determine the thyroid-stimulating hormone (TSH) reference interval (RI) and to assess the influence of the use of thyroid ultrasonography (TUS) on reference individual selection from a healthy adult population in Fortaleza, Brazil. Subjects and methods This cross-sectional study recruited patients (N = 272; age = 18-50 years) with normal thyroid function (NTF) and placed them in three groups according to their test results: NTF (n = 272; all participants), TUS (n = 170; participants who underwent thyroid US), RI (n = 124; reference individuals with normal TSH levels). TSH, FT4, TT3, TgAb, and TPOAb concentrations were determined by electrochemiluminescence assay. TUS was performed using a 7-12 MHz multifrequency linear transducer by two radiologists. The 2.5th and 97.5th percentiles of the distribution curve corresponded to lower and upper TSH RI levels, respectively. Results The mean TSH level was 1.74 ± 0.96 mIU/L, and TSH range was 0.56-4.45 mIU/L. There was no difference in the TSH concentrations between men and women nor between the groups. TUS did not appear to be an essential tool for the reference group selection. Conclusion The upper limit of TSH was comparable to the reference interval provided by the assay manufacturer (4.45 vs. 4.20 mIU/L) but the lower limit was not (0.56 vs. 0.27 mIU/L). This finding may have a clinical impact since these values may lead to the misdiagnosis of euthyroid patients with subclinical hyperthyroidism.

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ABSTRACT Objective Discrimination and bullying are common conditions among LGBT people. During schooling, these practices compromising education. The aim of this study is to evaluate educational attainment among Brazilian transgender women (TW) and how their education level affects the risk of HIV infection. Study design a cross-sectional population-based study. Subjects and methods 95 adult TW were selected. Information concerning verbal and physical aggression, school dropout, school years (SY), and educational level were assessed. HIV status was screened using a fourth-generation immunoassay followed by western blot testing. Results The mean of SY was 9.1 ± 3.8 ys. The mean age at school dropout was 16.3 ± 3.4 ys old. Verbal aggression was reported by 83%, physical by 48%, and 18% of the TW dropped out school immediately after being physically assaulted. Participants who suffered physical aggression attended school for almost 4 years less than those participants who did not suffer this abuse (OR = -3.96, p < 0.0001). A similar result was found for verbal aggression (OR = -4.35; p < 0.0001). HIV/AIDS prevalence was 18% (n = 17). The mean of SY among HIV/AIDS positive and negative individuals were 6.8 ± 43 versus 9.7 ± 3, respectively (p = 0.004). Lower education was associated with higher frequency of HIV/AIDS among TW and this relationship was sustained after adjustment for injectable drug use and sex work (OR = 0.79, p = 0.04). Conclusion Among Brazilian TW, lower education level was a risk factor associated with HIV. The reasons for low schooling among TW are multifactorial, but verbal and physical harassment strongly contribute for it.

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ABSTRACT Objective The aim of the present study was to evaluate whether arterial stiffness is affected in the patients with hypoparathyroidism through pulse wave analysis (PWA). Subjects and methods Sixty-three patients diagnosed with hypoparathyroidism and sixty volunteers were evaluated for the study. When 21 patients were excluded in the hypoparathyroidism group due to exclusion criteria, the research continued with 42 patients and 60 volunteers who are similar to the patients in terms of age, gender and body mass index (BMI). Fasting plasma glucose after 10 hours of fasting, creatinine, thyroid stimulating hormone (TSH), free thyroxine (fT4), albumin, calcium, phosphorus, magnesium, 25-OH vitamin D, parathormone (PTH) and urine calcium results in 24-hour urine for the patients in the hypoparathyroidism group were recorded. Evaluation of arterial stiffness was performed by Mobil-O-Graph 24h PWA device. Results Systolic blood pressure (SBP) (p = 0.01), diastolic blood pressure (DBP) (p = 0.005), mean blood pressure (p = 0.009), central SBP (p = 0.004), central DBP (p = 0.01) and pulse wave velocity (PWV) (p = 0.02) were found higher in the hypoparathyroidism group. A positive correlation was detected between phosphorus level and SBP [(p = 0.03. r = 0.327)], central SBP [(p = 0.04, r = 0.324)] and PWV [(p = 0.003, r = 0.449)]. We detected that age and serum phosphorus levels were independent predictor variables for PWV (B = 0.014, p < 0.001 and B = 0.035, p < 0.001, respectively). Conclusion We detected that hypoparathyroidism causes an increase in blood pressure and arterial stiffness. The most significant determinant factors were detected as advanced age and hyperphosphatemia. The patients diagnosed with hypoparathyroidism should be closely monitored and treatment planning should include to prevent the patients from hyperphosphatemia.

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ABSTRACT Objective Type 2 diabetes mellitus (T2DM) is a worldwide health problem, and medical nutrition therapy is essential for improving the quality of life of patients with type 2 diabetes. Salt restriction may lead to iodine deficiency in these patients. Moreover, type 2 diabetes can be an indirect reason for thyroid disorders. This study was conducted to determine the relationship between dietary iodine intake, urinary iodine excretion and thyroid functions in people with T2DM. Materials and methods Iodine nutritional status was determined by a one day 24-h dietary recall and food-frequency questionnaire. Iodine status was detemined by urinary iodine excretion with morning urine sample. Results Iodine intake according to one day 24-h dietary recall was lower in T2DM patients [94.8 (76.0-112.0) μg] than people in control group [137.1 (123.1-165.4) μg] (p < 0.05). Iodine intake determined by food-frequency questionnaire rich in iodine was lower in T2DM patients [93.1 (84.4-113.9) μg] than people in control group [140.2 (125.1-166.1) μg] (p < 0.05). Mild iodine deficiency was found in %38.8 of diabetic and %55.1 of healthy individuals (p < 0.05). No significant relationship was found between urinary iodine excretion and thyroid function tests in groups (p > 0.05). However, the relationship between dietary iodine excretion and urinary iodine intake in the diabetic group was lower than in the control group (p < 0.05). Conclusion With this respect, the results showed that while planning medical nutrition therapy for diabetic individuals, the risk of iodine deficiency should be considered.

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ABSTRACT Objective To analyze the morphological and functional characteristics of primary macronodular adrenal hyperplasia (PMAH) nodules carrying or not carrying ARMC5 mutations and the consequences of the presence of mutations in terms of the pattern of macronodule composition and functional state. Subjects and methods The analyses were performed by hematoxylin-eosin staining, immunohistochemistry, microdissection of spongiocyte tissue and RT-qPCR of histological sections from 16 patients diagnosed with PMAH with germline (5) or germline/somatic mutations (5) and without mutations (6) in the ARMC5 gene. Results Hyperplastic nodules were predominantly composed of spongiocytes in mutated and nonmutated sections. ARMC5 mRNA expression in spongiocytes was higher in ARMC5-mutated nodules than in ARMC5-nonmutated nodules, and homogenous ARMC5 protein distribution was observed. The presence of arginine-vasopressin receptor (AVP1AR) and ectopic ACTH production were observed in both cell populations regardless of ARMC5 mutations; the numbers of serotonin receptor (5HT4R)- and proliferating cell nuclear antigen (PCNA)-positive cells were higher in macronodules carrying ARMC5 mutations than in those without mutations. Conclusions Our results suggest that the presence of ARMC5 mutations does not interfere with the pattern of distribution of spongiocytes and compact cells or with the presence of AVP1AR, gastric-inhibitory polypeptide receptor (GIPR) and ectopic ACTH. Nevertheless, the higher numbers of PCNA-positive cells in mutated nodules than in nonmutated nodules suggest that mutated ARMC5 can be related to higher proliferation rates in these cells. In conclusion, our results provide more information about the crosstalk among abnormal GPCRs, ectopic ACTH in steroidogenesis and the ARMC5 gene, which may be relevant in understanding the pathogenesis and diagnosis of patients with PMAH.

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ABSTRACT Objectives Indirect calorimetry is established as a gold standard to determine the resting metabolic rate (RMR), however, its clinical use is limited, especially in low-income settings. Thus, the use of predictive equations appear as an alternative to estimate the RMR, but its precision is debatable, especially in obese individuals and in populations without specifically developed equations. To evaluate the agreement between the RMR estimated by equations and by indirect calorimetry in low-income obese women. Subjects and methods A cross-sectional study with adult and obese women, which estimated the RMR by indirect calorimetry and compared with 13 predictive equations using the concordance correlation coefficient, root mean square error (RMSE) and Bland-Altman methods. The maximum allowed differences were predefined as 10%. Results No equation presented its confidence intervals for the Bland-Altman limits of agreement inside the predefined acceptable range. The Harris-Benedict equation achieved better agreement (bias of 2.9% and RMSE of 274.3kcal) whereas the Henry-Rees equation achieved better precision (42.3% of the sample within the 10% maximum allowed difference). Conclusion None of the studied equations satisfactorily estimated the RMR estimated by indirect calorimetry. In the absence of specific equations for this population, the use of the Harris-Benedict and Henry-Rees equations could be considered.

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ABSTRACT Objective The consequences of sleep deprivation in type 1 diabetes (T1D) patients are poorly understood. Our aim was to determine how sleep disorders influence lipid profile and insulin sensitivity in T1D patients. Materials and methods This was a cross-sectional study at a public university hospital. Demographic information and medical histories were obtained during regular scheduled visit of T1D patients to the outpatient clinic. Insulin sensitivity was obtained using the estimated glucose disposal rate (eGDR) formula. Sleep quality was assessed using the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale and Berlin Questionnaire. Results The adult participants (n = 66, 62% women) had a median age of 28.0 years (interquartile range 21.8-33.0). Six patients (9%) had metabolic syndrome according to the International Diabetes Federation criteria. Thirty patients (46%) were considered poor sleepers according to the Pittsburgh Sleep Quality Index. The LDL-c and total cholesterol levels of poor sleepers were higher than those of good sleepers (103 v. 81; p = 0.003 and 178.0 v. 159.5 mg/dL; p = 0.009, respectively). Three patients (4%) were at high risk of obstructive sleep apnea syndrome (OSAS) according to the Berlin Questionnaire. The eGDR was lower in the group of patients with high probability of having OSAS (6.0 v. 9.1 mg.kg-1.min-1;p = .03). Conclusions Poor subjective quality of sleep and higher risk of OSAS were correlated with a worsened lipid profile and decreased insulin sensitivity, respectively. Therefore, T1D patients with sleep disturbances might have an increased cardiovascular risk in the future.

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ABSTRACT Objective The aim of this randomized comparative study was to assess renal and metabolic effects of vildagliptin in insulin-treated type 2 diabetes (T2DM) patients without overt chronic kidney disease. Subjects and methods We randomized 47 insulin-treated non-proteinuric patients with satisfactory controlled T2DM and estimated glomerular filtration rate (eGFR) ≥ 60 mL/min/1.73m 2 either to continue insulin therapy (control) or to receive combined insulin-vildagliptin treatment (VIG group). We assessed eGFR using serum creatinine (eGFRcreat), cystatin C (eGFRcys), and both (eGFRcreat-cys), and urinary creatinine-adjusted excretion of albumin (UACR), type IV collagen (uCol IV/Cr), and neutrophil gelatinase-associated lipocalin (uNGAL/Cr) at baseline and after 6 months of treatment. Results Study groups were comparable in terms of age and sex (60.1 ± 6.1 years and 42.9% men in control group vs. 60.8 ± 5.2 years and 39.1% in VIG group). After 6 months of treatment, there were no significant changes in main assessed parameters in control group. VIG group demonstrated significant decrease in HbA1c, diastolic blood pressure, frequency of hypoglycemia, and high-sensitivity C-reactive protein level as compared to the changes in control group. While eGFRcreat, UACR, and uNGAL/Cr showed no significant changes after vildagliptin addition, eGFRcys, eGFRcreat-cys, and uCol IV/Cr changed significantly in comparison with control group (+7.0% [3.7;13.3]; +5.1% [1.4;8.5]; -32,8% [-55.8;-24.4], respectively, p < 0.01 each). Correlation and regression analysis revealed glucose-independent pattern of these changes. Conclusion Addition of vildagliptin to ongoing insulin therapy in patients with T2DM was associated with a reduction in uCol IV/Cr and an increase in eGFRcys and eGFRcreat-cys, independent of T2DM control parameters.

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ABSTRACT Objective The most vital complications of thyroidectomy are recurrent nerve damage and hypocalcaemia. We aimed to compare the tissue perfusion scores (PS) of IG fluorescence angiography (IGFA) and visual examination by the surgeon after total thyroidectomy. Subjects and methods Forty-three patients were accepted into the study. Localisation of the parathyroid gland (PG) was determined by the naked eye and scored in terms of tissue perfusion. The averages of fluorescent light intensities for each IGFA were calculated, the perfusions were scored and compared with the PS given by the surgeon. Biochemical parameters were noted. Results 37.2% of patients had autotransplanted PGs, according to their visual scores. The means of IGFA-PS for PGs scored as 0, 1 or 2 on visual inspection were 48.58 ± 4.49 [30-70], 89.65 ± 8.93 [36-144] and 158.76 ± 8.93 [70-253], respectively, which correlated with the visual PSs in a statistically significant manner (P < 0.0001). The predictive cut-off value for IGFA-PS was determined to be 70, given a visual PS of 0 (95% CI [0.72-0.85]), and this was interpreted to be a candidate cut-off point for the autotransplantation of PGs. Conclusion IGFA scoring may be considered as an operative predictor, providing objective criteria to evaluate the tissue and blood perfusion of PGs after thyroidectomy. IGFA scoring may be considered to have value in minimising postoperative permanent hypoparathyroidism in patients.

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ABSTRACT Objective Recent research has investigated the possible inverse relationship between vitamin K intake and body fat. In addition, an increasing number of studies are supporting a key role for this vitamin in improving lipid profile and insulin sensitivity and reducing the risk of type 2 diabetes mellitus, but little is known about what mechanisms would be involved. Thus, the objective of this study was to investigate the relationship between vitamin K intake (in the form of phylloquinone – PK), body fat, lipid profile and markers of glucose homeostasis in adults and the elderly. Subjects and methods A cross-sectional study with 298 participants (46% men) in the São Paulo Health Survey 2014-2015. Spearman correlations were performed to evaluate the associations between vitamin K intake and the biochemical and body composition measures. Results Among normal-weight male adults (n = 15), PK intake presented a positive correlation with the quantitative insulin sensitivity check index (QUICKI) (r = 0.525; p = 0.045). Among men with high fat mass index (FMI) (n = 101), PK intake had a negative correlation with homeostasis model assessment estimate for β-cell function (HOMA-β) (r = −0.227; p = 0.022). In women with high FMI (n = 122), PK intake had a negative correlation with HOMA-β (r = −0.199, p = 0.032) and insulin (r = −0.207, p = 0.026). No correlations were found between PK intake and lipid profile. Conclusions Our findings support a potential relationship among PK intake, body fat and markers of glucose homeostasis in adults and the elderly.

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ABSTRACT Objective We investigated the association between demographic, socio-economic, perinatal, parental and lifestyle-related factors with general and abdominal obesity among prepubertal children aged 6 to 8 years in a Southeastern city of Brazil. Subjects and methods A total of 486 children were randomly selected from public schools in the city of Patos de Minas, and examined to determine body mass index (BMI) and waist circumference (WC). Demographic, socio-economic, perinatal, parental and lifestyle-related data were obtained and assessed as independent risk factors for overweight/obesity and abdominal obesity, using multiple regression analysis. Results Obesity/overweight (BMI percentile ≥ 85), seen in 19% of the children, was positively associated with low maternal education, being born small for gestational age, maternal BMI and screen time, whereas abdominal obesity (WC percentile > 90), seen in 9.9% of the children, was positively associated with maternal age and maternal BMI. When BMI and WC percentile were analyzed as continuous variables, birth by cesarean section, parental BMI, and lower sleep time were positively associated with BMI percentile, and birth by cesarean section, being born small for gestational age, and parental BMI were positively associated with WC percentile. Conclusion Our findings suggest that the frequency of overweight and obesity in a city in the Southeastern region of Brazil is similar to the global frequency reported by the World Health Organization. We also found that many modifiable risk factors were associated with general and abdominal obesity, and these may possibly substantiate future strategies to prevent childhood obesity and its consequences in adult life.

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ABSTRACT Objective Compare the concordance degree between plasma glucose and glucose measurements on Dried Blood Spots (DBS) during pregnancy. Subjects and methods Glucose measurement was performed in pregnant women after a fast of 8-12 hours. Venous blood was collected with sodium fluoride, the plasma was separated, and glucose measured by the enzymatic oxidase glucose method. Capillary blood samples were collected and analyzed by DBS. For statistics, the paired Student’s t test, interclass correlation coefficient (ICC), graphic approach of Altman and Bland, and survival – concordance plot were used. Results 307 pregnant women were evaluated, 88.6% without diabetes and 11.4% with previous diabetes. The glucose ranged from 66 to 190 mg/dL [3.66 to 10.55 mmol/L] in plasma and from 53 to 166 mg/dL [2.94 to 9.21 mmol/L] in DBS. The glucose average values were 88.1 ± 12 mg/dL [4.98 ± 0.67 mmol/L] in plasma and 89.2 ±11,5 mg/dL, [4.95 ± 0.64 mmol/L] in DBS – p-value = 0.084. The ICC value was moderate (0.510), and Pearson’s correlation coefficient was r = 0.507 p < 0.001. Altman and Bland’s graph showed that difference between the values obtained by both methods is -24.62 to 22.3 mg/dL [-1.37 to 1.24 mmol/L]. Significant fixed bias (-1,16 average difference) and proportional bias (r = 0.056; p = 0.33) were not observed. Anemia was associated with differences between plasma glucose and DBS measurements (p = 0.031). Conclusion Capillary glucose in DBS correlates with plasma glucose; however, the methods do not present good concordance. The presence of anemia worsens this result.

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ABSTRACT Hypovitaminosis D is a common condition with a negative impact on health. This statement, prepared by experts from the Brazilian Society of Endocrinology and Metabolism and the Brazilian Society of Clinical Pathology/Laboratory Medicine, includes methodological aspects and limitations of the measurement of 25-hydroxyvitamin D [25(OH)D] for identification of vitamin D status, and identifies individuals at increased risk for deficiency of this vitamin in whom 25(OH)D measurement is recommended. For the general population, 25(OH)D levels between 20 and 60 ng/mL are considered normal, while individuals with levels below 20 ng/mL are considered to be vitamin D deficient. This statement identifies potential benefits of maintaining 25(OH)D levels > 30 ng/mL in specific conditions, including patients aged > 65 years or pregnant, those with recurrent falls, fragility fractures, osteoporosis, secondary hyperparathyroidism, chronic kidney disease, or cancer, and individuals using drugs with the potential to affect the vitamin D metabolism. This statement also calls attention to the risk of vitamin D intoxication, a life-threatening condition that occurs at 25(OH)D levels above 100 ng/mL

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ABSTRACT Objective Fibroblast growth factor 21 (FGF21) is among the activators that can stimulate thermogenesis in the white adipose tissue and brown adipose tissue. People with obesity have elevated blood levels of FGF21, but also develop resistance to its action, impairing its beneficial role. Inversely, clinical treatments to weight loss has been pointed out as an important therapy for increasing and recovering sensitivity to FGF21. The aim was to analyse the effect of long-term weight loss interdisciplinary intervention on FGF21 and body composition. Subjects and methods Eighty-six post-pubertal obese adolescents (14-19 years-old), were submitted to 20 weeks of weight loss therapy (clinical, nutritional, psychological and physical exercise support). Anthropometric measures, body composition and rest metabolic rate (RMR) by bioelectrical impedance, and serum FGF21 sample by ELISA were evaluated. The adolescents were grouped according to FGF21 individual delta variations after therapy: Higher Increase (HI); lower increase (LI); lower decrease (LD); higher decrease (HD). Results All groups present weight loss. Only in FGF21 ≥ 76,5 pg/mL variation the free-fat-mass and rest metabolic rate were preserved and to others group these variables were significantly reduced. Conclusion High increase in FGF21 can contribute to preservation of FFM and RMR after weight loss therapy, could have important implications for energy balance regulation. Future studies are necessary to continue determining the role of magnitude effects of FGF21 levels in obesity to improve clinical practice, especially in paediatrics population.

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SUMMARY Checkpoint inhibitors have substantially improved the prognosis for patients with advanced malignancy. Treatment with immunomodulants has the ability to reactivate the immune system against tumor cells, but can also trigger the development of immune-related adverse events that reflects a loss of tolerance of the immune system for self-antigens. Regarding the endocrine system, thyroid and pituitary are the most frequent glands involved; in particular hypophysitis is commonly observed with anti-CTLA4 with a variable impaired anterior pituitary dysfunction (mainly ACTH and TSH dysregulation) while a posterior pituitary dysfunction has been rarely described. A 68-year-old man with a diagnosis of metastatic mesothelioma started in September 2016 first-line treatment with tremelimumab and durvalumab. After 3 cycles he presented sudden onset of polydipsia and polyuria without other symptoms. Diagnostic work-up, including a water deprivation test, established a diagnosis of central diabetes insipidus. Patient started sublingual desmopressin 60 mcg three times a day, that was subsequently increased up to 480 mcg/die. At magnetic resonance imaging the posterior lobe of pituitary gland did not show high signal intensity on T1-weighted images. After regression of diabetes insipidus symptoms under desmopressin, patient restarted cancer treatment and received additional 10 doses without worsening of endocrinological toxicity or further treatment-related toxicities, maintaining the same desmopressin dosage. Posterior pituitary dysfunction has been rarely observed in patients treated with immunomodulants. To our knowledge, this is the first observation of permanent central diabetes insipidus in patients treated with combined immune checkpoint inhibitors (tremelimumab and durvalumab).

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SUMMARY CHARGE syndrome is a complex disorder involving multiple congenital anomalies and is caused by heterozygous mutations in the CHD7 gene. Growth retardation is a characteristic finding and about 10% of cases present growth hormone (GH) deficiency. GH treatment of short stature in CHARGE syndrome has shown some benefit, but normal height is rarely attained. We report a girl with CHARGE syndrome due to a de novo frameshift mutation in the CHD7 gene (c.2509_2512delCATT), in whom recurrent hypoglycaemia led to the diagnosis of GH deficiency in the second month of life. Early initiation of treatment with recombinant GH resulted in normal growth over ten years of follow-up. This case is the youngest reported CHARGE patient to be diagnosed and treated for GH deficiency and demonstrates that GH deficiency in CHARGE syndrome may manifest early in life through hypoglycaemia, before growth retardation is noted, and can be successfully treated with recombinant GH.