The role of TSH for 18F-FDG-PET in the diagnosis of recurrence and metastases of differentiated thyroid carcinoma with elevated thyroglobulin and negative scan: a meta-analysis

Purpose: To establish the effects of TSH stimulation on the uptake of fluorine-18-labeled 2-fluoro-2-deoxy-D-glucose for differentiated thyroid carcinoma (DTC) with thyroglobulin-positive and scan negative metastases.

Materials and methods: We searched the MEDLINE, EMBASE and the Cochrane Library for prospective controlled trials using TSH stimulation as an intervention. The outcomes of positron emission tomography (PET)-positive lesions, tumor-to-background ratio, maximum standard uptake value of the detected lesions were extracted and synthesized, and patients with the altered clinical management were studied. A meta-analysis was carried out using the Review Manager software.

Results: Seven prospective controlled clinical trials with 168 patients were found. All studies had a low risk of bias. PET scans under TSH stimulation versus thyroid hormone suppression showed statistically significant differences in the number of patients with PET true-positive lesions (odds ratio (OR) 2.45, 95% confidence interval (CI) 1.23–4.90) and in the number of the PET-detected lesions (OR 4.92, 95% CI 2.70–8.95) and tumor-to-background ratios. PET scans taken under TSH stimulation altered clinical management in altogether 12/130 (9%) patients in five paired studies (OR 2.40, 95% CI 1.11–5.22).

Conclusion: The data indicate that TSH stimulation should be recommended for DTC patients undergoing PET scanning in these circumstances. However, further well-designed studies emphasizing on the clinical significance of altered management by PET under TSH stimulation are needed.

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Factors predicting relapse of nonfunctioning pituitary macroadenomas after neurosurgery: a study of 142 patients

Sophie Brochier, Françoise Galland, Michèle Kujas, Fabrice Parker, Stephan Gaillard, Christian Raftopoulos, Jacques Young, Orsalia Alexopoulou, Dominique Maiter and Philippe Chanson.

Context: Adequate postoperative management of nonfunctioning pituitary macroadenomas (NFMAs) remains a challenge for the clinician.

Objective: To identify predictive factors of NFMA relapse after initial surgery.

Patients and methods: This retrospective study included 142 patients operated for an NFMA in two academic centers (CHU Bicêtre in France and UCL St Luc in Belgium). The rate of tumor relapse, defined as recurrence after total surgical resection or regrowth of a surgical remnant, as well as predictive factors was analyzed.

Results: During a mean follow-up of 6.9 years, 10 out of 42 patients (24%) who had complete macroscopic resection of their tumor had recurrence, and 47 out of 100 patients (47%) with a surgical remnant experienced regrowth. The overall relapse rates were 25, 43, and 61% at 5, 10, and 15 years respectively. Invasion of the cavernous sinus, absence of immediate radiotherapy after the first neurosurgery, and immunohistochemical features of the tumor (mainly positive immunostaining for several hormones or for hormones other than gonadotropins) were independent risk factors for tumor relapse. Incomplete excision was only associated with relapse when invasion was withdrawn from the analysis, suggesting that these two factors are closely linked.

Conclusion: NFMAs frequently recur/regrow after initial surgery, particularly when tumor is invasive, precluding complete removal. Immunohistochemical features such as positive immunostaining for several hormones or for hormones other than gonadotropins could help to predict undesirable outcomes.

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TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects

Jose de Jesus Garduño-Garcia, Ulices Alvirde-Garcia, Guadalupe López-Carrasco, Ma Elena Padilla Mendoza, Roopa Mehta, Olimpia Arellano-Campos, Ricardo Choza, Leobardo Sauque, Maria Eugenia Garay-Sevilla, Juan Manuel Malacara, Francisco J Gomez-Perez and Carlos A Aguilar-Salinas.

Objective: To examine the association between thyroid function and the components of the metabolic syndrome and insulin resistance in an Hispanic population.

Design: Cross-sectional study.

Methods: Subjects with no history of thyroid disease or diabetes were included. Thyroid function was stratified as euthyroid or subclinical hypothyroidism (SCH) status and subsequently by free thyroxine (FT4) and TSH tertiles. The association of the metabolic syndrome components (defined by 2004 Adult Treatment Panel III criteria) and insulin resistance with thyroid status, TSH, and FT4 were examined.

Results: A total of 3148 subjects were analyzed. The prevalence of SCH was 8.3%. The prevalence of the metabolic syndrome was similar in euthyroid and SCH patients (31.6 vs 32.06%, P=0.89). Total cholesterol was higher in patients with SCH (5.51±1.19 vs 5.34±1.05 mmol/l, P<0.032). Serum TSH values showed a positive correlation (adjusted for age and sex) with total cholesterol, triglycerides, and waist circumference. In contrast, FT4 showed a positive correlation with high-density lipoprotein cholesterol, and an inverse correlation with waist circumference, insulin, and HOMA-IR.

Conclusion: SCH is not associated with an increased risk for the metabolic syndrome (as conceived as a diagnostic category defined by the National Cholesterol, Education Program, Adult Treatment Panel III criteria). Despite this, low thyroid function (even in the euthyroid state) predisposes to higher cholesterol, glucose, insulin, and HOMA-IR levels. The combined use of TSH and FT4, compared with the assessment based on only FT4, is a more convenient approach to evaluate the association between thyroid function and metabolic variables.

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Aberrant expression of multiple hormone receptors in ACTH-independent macronodular adrenal hyperplasia causing Cushing's syndrome

J W B de Groot, T P Links, A P N Themmen, L H Looijenga, R R de Krijger, P M van Koetsveld, J Hofland, G van den Berg, L J Hofland and R A Feelders.

Objective: Aberrant adrenal expression of various hormone receptors has been identified in ACTH-independent macronodular adrenal hyperplasia (AIMAH) causing cortisol hypersecretion regulated by hormones other than ACTH. We aimed to determine aberrant expression of multiple hormone receptors in vivo and in vitro in adrenal tissue of a patient with AIMAH.

Design: The design of the study includes clinical case description, and biochemical and immunohistochemical analysis to demonstrate aberrant expression of multiple hormone receptors in AIMAH.

Methods: The subject of the study is a male diagnosed with Cushing's syndrome because of AIMAH. Directly after laparoscopic removal of the adrenals, adrenal tissue was incubated with and without test substances (ACTH, forskolin, arginine vasopressin (AVP), desmopressin, epinephrine, norepinephrine, purified human chorionic gonadotropin (hCG), metoclopramide and the combinations of AVP with ACTH, epinephrine and metoclopramide). LH/hCG-receptor (hCG-R) immunohistochemistry and RT-PCR analyses were performed to demonstrate aberrant expression of LH/hCG-R and V1–3-AVPR.

Results: AIMAH was characterized by in vivo cortisol responsiveness to AVP and in vitro cortisol responses to AVP, hCG, epinephrine, and norepinephrine suggesting aberrant adrenal expression of the receptors for AVP (the V1–3-AVPRs), catecholamines (the β-AR), and LH (the LH/hCG-R). Incubation with combinations of AVP and ACTH and of AVP with epinephrine induced a stronger cortisol response compared with incubation with the individual agents. Moreover, we demonstrated adrenal V1–3-AVPR and LH/hCG-R expression.

Conclusion: AIMAH tissue may simultaneously express multiple aberrant hormone receptors, and individual ligands may potentiate each other regarding cell proliferation and cortisol production.

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Multiple endocrine neoplasia type 2 syndromes (MEN 2): results from the ItaMEN network analysis on the prevalence of different genotypes and phenotypes

Cristina Romei, Stefano Mariotti, Laura Fugazzola, Augusto Taccaliti, Furio Pacini, Giuseppe Opocher, Caterina Mian, Maurizio Castellano, Ettore degli Uberti, Isabella Ceccherini, Nadia Cremonini, Ettore Seregni, Fabio Orlandi, Piero Ferolla, Efisio Puxeddu, Francesco Giorgino, Annamaria Colao, Paola Loli, Fabio Bondi, Barbara Cosci, Valeria Bottici, Antonello Cappai, Giovanni Pinna, Luca Persani, Verga Uberta, Marco Boscaro, Maria Grazia Castagna, Carlo Cappelli, Maria Chiara Zatelli, Antongiulio Faggiano, Giuseppe Francia, Maria Luisa Brandi, Alberto Falchetti, Aldo Pinchera, Rossella Elisei and The ItaMEN network.

Objective: Multiple endocrine neoplasia type 2 (MEN 2) is a genetic disease characterized by medullary thyroid carcinoma (MTC) associated (MEN 2A and 2B) or not familial MTC (FMTC) with other endocrine neoplasia due to germline RET gene mutations. The prevalence of these rare genetic diseases and their corresponding RET mutations are unknown due to the small size of the study population.

Methods: We collected data on germline RET mutations of 250 families with hereditary MTC followed in 20 different Italian centres.

Results and conclusions: The most frequent RET amino acid substitution was Val804Met (19.6%) followed by Cys634Arg (13.6%). A total of 40 different germline RET mutations were present. Six families (2.4%) were negative for germline RET mutations. The comparison of the prevalence of RET germline mutations in the present study with those published by other European studies showed a higher prevalence of Val804Met and Ser891Ala mutations and a lower prevalence of Leu790Phe and Tyr791Phe (P<0.0001). A statistically significant higher prevalence of mutations affecting non-cysteine codons was also found (P<0.0001).

Furthermore, the phenotype data collection showed an unexpected higher prevalence of FMTC (57.6%) with respect to other MEN 2 syndromes (34% MEN 2A and 6.8% of MEN 2B). In conclusion, we observed a statistically significant different pattern of RET mutations in Italian MEN 2 families with respect to other European studies and a higher prevalence of FMTC phenotype. The different ethnic origins of the patients and the particular attention given to analysing apparently sporadic MTC for RET germline mutations may explain these findings.

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Cabergoline monotherapy in the long-term treatment of Cushing's disease

Ariane Godbout, Marcos Manavela, Karina Danilowicz, Hugues Beauregard, Oscar Domingo Bruno1 and André Lacroix

Background: Cabergoline is a long-acting dopamine receptor agonist used to treat prolactinomas. Identification of D2 receptors in corticotroph tumors led to clinical trials of cabergoline therapy in limited cases of Nelson's syndrome, ectopic ACTH-secreting tumors, and recently Cushing's disease (CD).

Objetive: To evaluate the long-term efficacy of cabergoline monotherapy in patients with CD.

Methods: Retrospective analysis of non-randomized clinical therapy with cabergoline in 30 patients with CD treated in academic centers of Buenos Aires and Montreal. Cabergoline was initiated at 0.5–1.0 mg/week and adjusted up to a maximal dose of 6 mg/week based on urinary free cortisol (UFC) levels. Complete response to cabergoline was defined as a sustained normalization of UFC with at least two normal values measured at 1–3 months interval; partial response was defined as a decrease of UFC to <125% of the upper limit of normal, and treatment failure as UFC >125% of it.

Results: Within 3–6 months, complete response was achieved in 11 patients (36.6%) and partial response in 4 patients (13.3%). After long-term therapy, nine patients (30%) remain with a complete response after a mean of 37 months (range from 12 to 60 months) with a mean dose of 2.1 mg/week of cabergoline. Two patients escaped after 2 and 5 years of complete response, but one patient transiently renormalized UFC after an increase in cabergoline dosage. No long-term response was maintained in four initial partial responders.

Conclusions: Cabergoline monotherapy can provide an effective long-term medical therapy for selected patients with CD, but requires close follow-up for dose adjustments.

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Conventional and novel biomarkers of treatment outcome in patients with acromegaly: discordant results after somatostatin analog treatment compared with surgery

Kristine Z Rubeck, Michael Madsen, Caroline Marie Andreasen, Sanne Fisker, Jan Frystyk and Jens Otto L Jørgensen

Context: Control of disease activity in acromegaly is critical, but the biochemical definitions remain controversial.

Objetive: To compare traditional and novel biomarkers and health status in patients with acromegaly treated with either surgery alone or somatostatin analog (SA).

Design and Methods: Sixty-three patients in long-term remission based on normalized total IGF1 levels after surgery alone (n=36) or SA (n=27) were studied in a cross-sectional manner. The groups were comparable at diagnosis regarding demographic and biochemical variables. Each subject underwent 3 h of serum sampling including a 2-h oral glucose tolerance test (OGTT). Health status was measured by two questionnaires: EuroQoL and Acrostudy (Patient-assessed-Acromegaly symptom questionnaire (PASQ)).

Results: Total and bioactive IGF1 (µg/l) levels were similar (total: 185±10 (SA) versus 171±8 (surgery) (P=0.28); bioactive: 1.9±0.2 vs 1.9±0.1 (P=0.70)). Suppression of total and free GH (µg/l) during OGTT was blunted in the SA group (total GHnadir: 0.59±0.08 (SA) versus 0.34±0.06 (surgery) (P=0.01); free GHnadir: 0.43±0.06 vs 0.19±0.04 (P<0.01)). The insulin response to OGTT was delayed, and the 2-h glucose level was elevated during SA treatment (P=0.02). Disease-specific health status was better in patients after surgery (P=0.02).

Conclusions: Despite similar and normalized IGF1 levels, SA treatment compared with surgery alone was associated with less suppressed GH levels and less symptom relief; ii) this discordance may be due to specific suppression of hepatic IGF1 production by SA; iii) we suggest that biochemical assessment during SA treatment should include both GH and IGF1.

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Thyroid hormone receptors are down-regulated in skeletal muscle of patients with non-thyroidal illness syndrome secondary to non-septic shock

J Lado-Abeal, A Romer3, I Castro-Piedras, A Rodriguez-Perez and J Alvarez-Escudero

Aim: Non-thyroidal illness syndrome (NTIS) is related to changes in thyroid hormone (TH) physiology. Skeletal muscle (SM) plays a major role in metabolism, and TH regulates SM phenotype and metabolism. We aimed to characterize the SM of non-septic shock NTIS patients in terms of: i) expression of genes and proteins involved in TH metabolism and actions; and ii) NFKB's pathway activation, a responsible factor for some of the phenotypic changes in NTIS. We also investigated whether the patient's serum can induce in vitro the effects observed in vivo.

Methods: Serum samples and SM biopsies from 14 patients with non-septic shock NTIS and 11 controls. Gene and protein expression and NFKB1 activation were analyzed by quantitative PCR and immunoblotting. Human SM cell (HSkMC) cultures to investigate the effects of patient's serum on TH action mediators.

Results: Patients with non-septic shock NTIS showed higher levels of pro-inflammatory cytokines than controls. Expression of TRβ (THRB), TR{alpha}1 (THRA), and retinoid X receptor {gamma} (RXRG) was decreased in NTIS patients. RXRA gene expression was higher, but its protein was lower in NTIS than controls, suggesting the existence of a post-transcriptional mechanism that down-regulates protein levels. NFKB1 pathway activation was not different between NTIS and control patients. HSkMC incubated with patient's serum increased TH receptor and RXRG gene expression after 48 h.

Conclusions: Patients with non-septic shock NTIS showed decreased expression of TH receptors and RXRs, which were not related to increased activation of the NFKB1 pathway. These findings could not be replicated in cultures of HSkMCs incubated in the patient's serum.

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Changes in coagulation indexes and occurrence of venous thromboembolism in patients with Cushing's syndrome: results from a prospective study before and after surgery

Luca Manetti, Fausto Bogazzi, Clara Giovannetti, Valentina Raffaelli, Maura Genovesi, Giovanni Pellegrini, Lucia Ruocco, Aldo Iannelli and Enio Martino

Objetives: To evaluate whether patients with Cushing's syndrome (CS) had i) changes in coagulative and fibrinolytic parameters associated with CS activity and ii) higher prevalence of venous thromboembolic events (VTE).

Design: Prospective study conducted on patients with CS evaluated at diagnosis and 12 months after surgery.

Patients and methods: Forty patients with active CS (36 with Cushing's disease (CD) and 4 with an adrenal adenoma) were evaluated. Forty normal subjects and 70 patients with non-ACTH-secreting pituitary adenomas served as controls. All patients and controls underwent an assessment of coagulation and fibrinolysis indexes before and after surgery.

Results: CS patients at baseline had a hypercoagulative phenotype when compared with normal subjects (activated partial thromboplastin time (aPTT), fibrinogen, D-Dimer, von Willebrand factor (VWF), plasminogen activator inhibitor 1 (PAI-1 or SERPINE1), antithrombin III (ATIII or SERPINC1), P<0.0001, {alpha}2 antiplasmin, P=0.0004, thrombin–antithrombin complex (TAT), P=0.01, factor IX (F9), P=0.03). Patients with still active disease after surgery had higher coagulative parameters than those in remission (VWF (P<0.0001), PAI-1 (P=0.004), TAT (P=0.0001), ATIII (P=0.0002) and {alpha}2 antiplasmin (or SERPINF2; P=0.006)), whereas aPTT levels (P=0.007) were significantly reduced. VTE occurred in three patients with CD (7.5%): one had a pulmonary embolism and two patients had a deep venous thrombosis; no patients submitted to transsphenoidal surgery for non-Cushing's pituitary adenoma had VTE (P=0.04).

Conclusions: Patients with CS have a procoagulative phenotype due to cortisol-associated changes in haemostatic and fibrinolytic markers, leading to increased incidence of VTE. Thromboprophylaxis seems to be appropriated in patients with active disease, particularly in the postoperative period.

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Post-ablative serum thyroglobulin is an independent predictor of recurrence in low-risk differentiated thyroid carcinoma: a 16-year follow-up study

Hanna Pelttari, Matti J Välimäki, Eliisa Löyttyniemi and Camilla Schalin-Jäntti

Objetive: To study whether post-surgical and/or post-ablative thyroglobulin (Tg) concentrations may serve as independent predictors of disease recurrence in patients treated for TNM stage I or II well-differentiated thyroid carcinoma (WDTC).

Design: : An observational retrospective study with a median follow-up of 16 years (range 10–24).

Patients and measurements: Post-operative and post-ablative Tg concentrations, age, tumour size, local infiltration and nodal metastasis at primary surgery as well as disease recurrences and cancer-specific deaths were evaluated in 495 low-risk (TNM stages I and II) patients, the majority of whom had total thyroidectomy and radioactive iodine remnant ablation as initial treatment.

Results: Fifty-one patients (10.3%) experienced disease recurrence during follow-up. In multiple logistic regression analysis, post-ablative Tg concentrations (odds ratio (OR) 3.72, confidence interval (CI) 1.71–8.05, P=0.0009) and local infiltration on primary surgery (OR 2.66, CI 1.03–6.90, P=0.04) were the only independent predictors of recurrence.

Conclusions: Post-ablative Tg concentration is a strong predictor of disease recurrence in WDTC.

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Obesity-related cardiovascular risk factors after weight loss: a clinical trial comparing gastric bypass surgery and intensive lifestyle intervention

D Hofsø, N Nordstrand, L K Johnson, T I Karlsen, H Hager, T Jenssen, J Bollerslev, K Godang, R Sandbu, J Røislien and J Hjelmesæth

Objetive: Weight reduction improves several obesity-related health conditions. We aimed to compare the effect of bariatric surgery and comprehensive lifestyle intervention on type 2 diabetes and obesity-related cardiovascular risk factors.

Design: One-year controlled clinical trial (ClinicalTrials.gov identifier NCT00273104 [ClinicalTrials.gov] ).

Methods: Morbidly obese subjects (19–66 years, mean (S.D.) body mass index 45.1 kg/m2 (5.6), 103 women) were treated with either Roux-en-Y gastric bypass surgery (n=80) or intensive lifestyle intervention at a rehabilitation centre (n=66). The dropout rate within both groups was 5%.

Results: Among the 76 completers in the surgery group and the 63 completers in the lifestyle group, mean (S.D.) 1-year weight loss was 30% (8) and 8% (9) respectively. Beneficial effects on glucose metabolism, blood pressure, lipids and low-grade inflammation were observed in both groups. Remission rates of type 2 diabetes and hypertension were significantly higher in the surgery group than the lifestyle intervention group; 70 vs 33%, P=0.027, and 49 vs 23%, P=0.016. The improvements in glycaemic control and blood pressure were mediated by weight reduction. The surgery group experienced a significantly greater reduction in the prevalence of metabolic syndrome, albuminuria and electrocardiographic left ventricular hypertrophy than the lifestyle group. Gastrointestinal symptoms and symptomatic postprandial hypoglycaemia developed more frequently after gastric bypass surgery than after lifestyle intervention. There were no deaths.

Conclusions: Type 2 diabetes and obesity-related cardiovascular risk factors were improved after both treatment strategies. However, the improvements were greatest in those patients treated with gastric bypass surgery.

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Thyroid hormone receptors are down-regulated in skeletal muscle of patients with non-thyroidal illness syndrome secondary to non-septic shock

J Lado-Abeal, A Romero, I Castro-Piedras, A Rodriguez-Perez and J Alvarez-Escudero

Aim: Non-thyroidal illness syndrome (NTIS) is related to changes in thyroid hormone (TH) physiology. Skeletal muscle (SM) plays a major role in metabolism, and TH regulates SM phenotype and metabolism. We aimed to characterize the SM of non-septic shock NTIS patients in terms of: i) expression of genes and proteins involved in TH metabolism and actions; and ii) NFKB's pathway activation, a responsible factor for some of the phenotypic changes in NTIS. We also investigated whether the patient's serum can induce in vitro the effects observed in vivo.

Methods: Serum samples and SM biopsies from 14 patients with non-septic shock NTIS and 11 controls. Gene and protein expression and NFKB1 activation were analyzed by quantitative PCR and immunoblotting. Human SM cell (HSkMC) cultures to investigate the effects of patient's serum on TH action mediators.

Results: Patients with non-septic shock NTIS showed higher levels of pro-inflammatory cytokines than controls. Expression of TRβ (THRB), TR 1 (THRA), and retinoid X receptor (RXRG) was decreased in NTIS patients. RXRA gene expression was higher, but its protein was lower in NTIS than controls, suggesting the existence of a post-transcriptional mechanism that down-regulates protein levels. NFKB1 pathway activation was not different between NTIS and control patients. HSkMC incubated with patient's serum increased TH receptor and RXRG gene expression after 48 h.

Conclusions: Patients with non-septic shock NTIS showed decreased expression of TH receptors and RXRs, which were not related to increased activation of the NFKB1 pathway. These findings could not be replicated in cultures of HSkMCs incubated in the patient's serum.

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Minimal changes in environmental temperature result in a significant increase in energy expenditure and changes in the hormonal homeostasis in healthy adults

Francesco S Celi, Robert J Brychta, Joyce D Linderman, Peter W Butler, Anna Teresa Alberobello, Sheila Smith, Amber B Courville, Edwin W Lai, Rene Costello, Monica C Skarulis, Gyorgy Csako, Alan Remaley, Karel Pacak and Kong Y Chen.

Objetive: Resting energy expenditure (EE) is a major contributor to the total EE and thus plays an important role in body weight regulation. Adaptive thermogenesis is a major component of EE in rodents, but little is known on the effects of exposure of humans to mild and sustainable reduction in environmental temperature.

Design: To characterize the dynamic changes in continuously measured resting EE, substrate utilization, and hormonal axes simultaneously in response to mild reduction in environmental temperature, we performed a cross-over intervention.

Methods: Twenty-five volunteers underwent two 12-h recordings of EE in whole room indirect calorimeters at 24 and 19 °C with simultaneous measurement of spontaneous movements and hormonal axes.

Results: Exposure to 19 °C resulted in an increase in plasma and urine norepinephrine levels (P<0.0001), and a 5.96% (P<0.001) increase in EE without significant changes in spontaneous physical activity. Exposure to the lower temperature resulted in a significant increase in free fatty acid levels (P<0.01), fasting insulin levels (P<0.05), and a marginal decrease in postprandial glucose levels. A small but significant (P<0.002) increase in serum free thyroxine and urinary free cortisol (P<0.05) was observed at 19 °C.

Conclusions: Our observations indicate that exposure to 19 °C, a mild and tolerable cold temperature, results in a predictable increase in EE driven by a sustained rise in catecholamine and the activation of counter-regulatory mechanisms.

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Newborn TSH concentration and its association with cognitive development in healthy boys

Carmen Freire, Rosa Ramos, Esperanza Amaya, Mariana F Fernández, Piedad Santiago-Fernández, Maria-Jose Lopez-Espinosa, Juan-Pedro Arrebola and Nicolas Olea

Objetive: An association between thyroid function during pregnancy or infancy and neurodevelopment in children has been demonstrated. We aimed to investigate whether newborn TSH concentrations are related to subsequent neurocognitive development.

Design: We conducted a longitudinal study on 178 children from a general population birth cohort in Granada (Spain) born in 2000–2002.

Methods: TSH concentrations were measured in umbilical cord blood, and cognitive functions were assessed at 4 years of age using the McCarthy's scales of children's abilities (MSCA). Organochlorine (OC) compound concentrations and the combined oestrogenicity (total effective xeno-oestrogenic burden (TEXB)) were also determined in the placentae.

Results: Mean newborn TSH was 3.55 mU/l (range=0.24–17 mU/l). In multivariate regression analyses, adjusting for maternal and child characteristics, higher newborn TSH concentrations showed a decrease of 3.51 and 3.15 points on the MSCA general cognitive and executive function scores respectively and were associated with a higher risk of scoring below the 20th percentile (P20) on the quantitative score (odds ratio (OR)=2.64). Children with TSH in the upper quartile (4.19–17.0 mU/l) were at higher risk of scoring

Conclusions: Newborn thyroid hormone status expressed by TSH in cord blood may adversely affect later cognitive function. A more thorough screening for neonatal thyroid deficiency is warranted.

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Accuracy of several parameters of hypothalamic–pituitary–adrenal axis activity in predicting before surgery the metabolic effects of the removal of an adrenal incidentaloma

Cristina Eller-Vainicher, Valentina Morelli, Antonio Stefano Salcuni, Claudia Battista, Massimo Torlontano, Francesca Coletti, Laura Iorio, Elisa Cairoli, Paolo Beck-Peccoz, Maura Arosio, Bruno Ambrosi, Alfredo Scillitani and Iacopo Chiodini

Context: It is unknown whether the metabolic effects of the removal of an adrenal incidentaloma (AI) can be predicted by the assessment of cortisol hypersecretion before surgery.

Objetive: To evaluate the accuracy of several criteria of hypothalamic–pituitary–adrenal axis activity in predicting the metabolic outcome after adrenalectomy.

Design: Retrospective longitudinal study.

Patients: In 55 surgically treated AI patients (Group 1) before surgery and in 53 nontreated AI patients (Group 2) at the baseline, urinary free cortisol (UFC), cortisol after 1 mg overnight dexamethasone-suppression test (1 mg-DST), ACTH, and midnight serum cortisol (MSC) were measured. In Groups 1 and 2, metabolic parameters were evaluated before and 29.6±13.8 months after surgery and at the baseline and after 35.2±10.9 months respectively.

Main outcome measures: The improvement/worsening of weight, blood pressure, glucose, and cholesterol levels (endpoints) was defined by the presence of a >5% weight decrease/increase and following the European Society of Cardiology or the ATP III criteria respectively. The accuracy of UFC, 1 mg-DST, ACTH, and MSC, singularly taken or in combination, in predicting the improvement/worsening of 2 endpoints was calculated.

Results: The presence of 2 among UFC>70 µg/24 h (193 nmol/l), ACTH<10 pg/ml (2.2 pmol/l), 1 mg-DST>3.0 µg/dl (83 nmol/l) (UFC–ACTH–DST criterion) had the best accuracy in predicting the endpoints' improvement (sensitivity (SN) 65.2%, specificity (SP) 68.8%) after surgery. In the nontreated AI patients, this criterion predicted the worsening of 2 endpoints (SN 55.6%, SP 82.9%).

Conclusions: The UFC–ACTH–DST criterion seems to be the best for predicting the metabolic outcome in surgically treated AI patients.

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The role of selective venous sampling in the management of persistent hyperparathyroidism revisited

Janneke E Witteveen, Job Kievit, Arian R van Erkel, Hans Morreau, Johannes A Romijn and Neveen A T Hamdy

Introduction: : Localization studies are mandatory prior to revision surgery in patients with persistent hyperparathyroidism in order to improve surgical outcome and reduce the risk of lengthy explorations. However, in this case, noninvasive localization studies are reported to have a poor sensitivity. The aim of our study is to determine the accuracy of selective venous sampling (SVS) for parathyroid hormone (PTH) in localizing residual hyperactive parathyroid glands in patients with persistent or recurrent hyperparathyroidism.

Patients and methods: We retrospectively evaluated the localizing accuracy of 20 PTH SVS performed prior to revision surgery in 18 patients with persistent or recurrent primary hyperparathyroidism (n=11) or autonomous (tertiary) hyperparathyroidism (n=7). Tc99m-methoxy-isobutyle-isonitrile (MIBI)-single photon emission computed tomography (SPECT) was also performed in all patients prior to revision surgery. Operative and pathological data were obtained from hospital records.

Results: The SVS was able to accurately localize 15 of the 20 pathological glands removed at revision surgery, representing a sensitivity of 75%. This sensitivity is significantly higher than that of Tc99m-MIBI-SPECT, which was only 30% (P=0.012).

Conclusions: Our findings demonstrate that SVS is a valuable localization study in patients with persistent or recurrent hyperparathyroidism, with a sensitivity significantly higher than that of Tc99m-MIBI-SPECT. Our data suggest that SVS represents a useful addition to the preoperative workup of these patients prior to revision surgery.

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New mechanisms involved in paternal 20q disomy associated with pseudohypoparathyroidism

Eduardo Fernández-Rebollo, Beatriz Lecumberri, Intza Garin, Javier Arroyo, Ana Bernal-Chico, Fernando Goñi, Rosa Orduña, Spanish PHP Group, Luis Castaño and Guiomar Pérez de Nanclares

Purpose: Type I pseudohypoparathyroidism (PHP-I) can be subclassified into Ia and Ib, depending on the presence or absence of Albright's hereditary osteodystrophy's phenotype, diminished -subunit of the stimulatory G protein (Gs ) activity and multihormonal resistance. Whereas PHP-Ia is mainly associated with heterozygous inactivating mutations in Gs -coding exons of GNAS, PHP-Ib is caused by imprinting defects of GNAS. To date, just one patient with PHP and complete paternal uniparental disomy (UPD) has been described.

We sought to identify the underlining molecular defect in twenty patients with parathyroid hormone resistance, hypocalcemia and hyperphosphatemia, and abnormal methylation pattern at GNAS locus.

Methods: Microsatellite typing and comparative genome hybridization were performed for proband and parents.

Results: We describe four patients with partial paternal UPD of chromosome 20 involving pat20qUPD in one case, from 20q13.13-qter in two cases, and pat20p heterodisomy plus interstitial 20q isodisomy in one patient.

Conclusions: These observations demonstrate that mitotic recombination of chromosome 20 can also give rise to UPD and PHP, a situation similar to other imprinting disorders, such as Beckwith–Wiedemann syndrome or neonatal diabetes.

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Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations

A Hébrant, W C G van Staveren, C Maenhaut, J E Dumont and J Leclère.

Three syndromes affecting the thyroid gland are described in the literature separately: familial nonautoimmune hyperthyroidism, sporadic congenital nonautoimmune hyperthyroidism, and autonomous adenomas. Recent studies have shown that these three syndromes are caused by similar activating mutations of the TSH receptor gene (TSHR), and that the consequences of these mutations on the physiology and gene expression of the thyroid are qualitatively, but not quantitatively, similar. The three syndromes and two suggested unrecognized variants are in fact facets of the same disease, genetic hyperthyroidism due to TSHR mutations, the expression of which depends on the intensity of activation, its timing, and on the number of affected cells.

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Hypothesis: Extra-hepatic acromegaly: a new paradigm?

Los autores de éste artículo proponen una nueva hipótesis surgida a partir de las observaciones realizadas en el curso del tratamiento combinado con pegvisomant (PEG) y análogos de la somatostatina de acción prolongada (SRL). Los SRL suprimen la secreción de GH, pero también inducen una disminución de los niveles de insulina portal y por ello provocan un estado de relativa resistencia hepática a la GH con disminución de la producción hepática de IGF-I. Como consecuencia, los niveles de IGF-I pueden ser normales sin que ello implique un adecuado control de la hipersecreción de GH en los tejidos periféricos. La adición de PEG al tratamiento con SRL puede permitir no solo la normalización de IGF-I, sino también el control de la “hiperactividad GH residual” en los tejidos periféricos.

Ignacio Bernabeu
Coordinador GNE/SEEN

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Association between thyroid function tests at baseline and the outcome of patients with sepsis or septic shock: a systematic review

Anna G Angelousi, Drosos E Karageorgopoulos, Anastasios M Kapaskelis and Matthew E Falagas

Introduction: The severity of critical illness is associated with various patterns of thyroid hormone abnormalities.We sought to evaluate whether the outcome of patients with, specifically, sepsis or septic shock is associated with the thyroid function tests evaluated at diagnosis or admission in the intensive care unit (ICU).

Methods: We performed a systematic review of relevant studies by searching PubMed.

Results: We included nine studies that all had a prospective cohort design. Seven involved children or neonates, and two involved adults. Mortality was the outcome evaluated in eight studies, while the length of ICU stay was evaluated in the remaining study. In univariate analysis, six of the nine included studies showed that either, free or total, triiodothyronine or thyroxine was lower in the group of patients with sepsis or septic shock who had unfavorable outcome than in those who had favorable outcome. Two other studies showed higher TSH values in the group of patients with unfavorable outcome. No significant relevant findings were observed in the remaining study. Regarding the correlation of sepsis prognostic scoring systems with thyroid function tests, the three studies that provided specific relevant data showed variable findings.

Discussion: Most of the relevant studies identified favor the concept that decreased thyroid function at baseline might be associated with a worse outcome of patients with sepsis or septic shock. Although these findings are not consistent, the role of thyroid function in affecting or merely predicting the outcome of sepsis or septic shock merits further investigation.

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Cardiovascular risk, metabolic profile, and body composition in adult males with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Henrik Falhammar, Helena Filipsson Nyström, Anna Wedell and Marja Thorén

Objective: Lifelong glucocorticoid therapy in patients with congenital adrenal hyperplasia (CAH) or the disease per se may result in increased cardiovascular risk. We therefore investigated cardiovascular and metabolic risk profiles in adult CAH males.

Subjects and methods: We compared CAH males (n=30), 19–67 years old, with age- and sex-matched controls (n=32). Subgroups of different ages (<30 years or older) and CYP21A2 genotypes (null, I2splice, and I172N as the mildest mutation) were studied. Anthropometry, fat and lean mass measured by dual-energy X-ray absorptiometry, lipids, liver function tests, homocysteine, lipoprotein-(a), glucose and insulin during an oral glucose tolerance test (OGTT), urine albumin, adrenal hormones, and 24 h ambulatory blood pressure measurements were studied.

Results: CAH males were shorter. Waist/hip ratio and fat mass were higher in older patients and the I172N group. Heart rate was faster in older patients, the I2splice, and I172N groups. Insulin levels were increased during OGTT in all patients and in the I172N group. -glutamyl transpeptidase was increased in older patients and in the I172N group. Testosterone was lower in older patients. Homocysteine was lower in younger patients, which may be cardioprotective. The cardiovascular risk seemed higher with hydrocortisone/cortisone acetate than prednisolone. Urinary epinephrine was lower in all groups of patients except in I172N.

Conclusions: Indications of increased risk were found in CAH males 30 years old and in the I172N group. In contrast, younger CAH males did not differ from age-matched controls. This is likely to reflect a better management in recent years.

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Serum proteome changes in acromegalic patients following transsphenoidal surgery: novel biomarkers of disease activity

Diana Cruz-Topete, Britt Christensen, Lucila Sackmann-Sala1, Shigeru Okada1, Jens Otto L Jorgensen and John J Kopchick

Context: Transsphenoidal adenomectomy is the primary treatment for acromegaly. However, assessment of the therapeutical outcome remains problematic since the existing biomarkers of disease activity frequently show discordant results.

Objective: To discover novel serum biomarkers of disease activity in acromegalic patients before and after surgery.

Design: Serum samples of eight newly diagnosed acromegaly patients before and after transsphenoidal surgery were analyzed for proteomic changes by two-dimensional gel electrophoresis. Protein spots displaying statistically significant changes, pre- versus post-surgery, were identified by mass spectrometry (MS), tandem MS (MS/MS), and western blot analysis.

Results: Six protein spots displaying decreased intensities after surgery were identified as transthyretin (two isoforms), haptoglobin 2, β-hemoglobin, and apolipoprotein A-1 (two isoforms). One protein spot, identified as complement C4B precursor, was increased after the surgery.

Conclusions: Seven serum protein spots were differentially expressed following surgery in acromegalic patients. The identified proteins represent potential novel biomarkers to assess the effectiveness of surgical treatment in acromegalic individuals. Future studies will validate the use of the identified proteins as biomarkers of disease activity after medical treatment of acromegaly.

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Is it possible to avoid hypopituitarism after irradiation of pituitary adenomas by the Leksell gamma knife?

Josef Marek, Jana Jezková, Václav Hána, Michal Krsek, L'ubomíra Bandúrová, Ladislav Pecen, Vilibald Vladyka and Roman Liscák

Objective: Radiation therapy is one of the treatment options for pituitary adenomas. The most common side effect associated with Leksell gamma knife (LGK) irradiation is the development of hypopituitarism. The aim of this study was to verify that hypopituitarism does not develop if the maximum mean dose to pituitary is kept under 15 Gy and to evaluate the influence of maximum distal infundibulum dose on the development of hypopituitarism.

Design and methods: We followed the incidence of hypopituitarism in 85 patients irradiated with LGK in 1993–2003. The patients were divided in two subgroups: the first subgroup followed prospectively (45 patients), irradiated with a mean dose to pituitary <15 Gy; the second subgroup followed retrospectively 1993–2001 and prospectively 2001–2009 (40 patients), irradiated with a mean dose to pituitary >15 Gy. Serum TSH, free thyroxine, testosterone or 17β-oestradiol, IGF1, prolactin and cortisol levels were evaluated before and every 6 months after LGK irradiation.

Results: Hypopituitarism after LGK irradiation developed only in 1 out of 45 (2.2%) patients irradiated with a mean dose to pituitary <15 Gy, in contrast to 72.5% patients irradiated with a mean dose to pituitary >15 Gy. The radiation dose to the distal infundibulum was found as an independent factor of hypopituitarism with calculated maximum safe dose of 17 Gy.

Conclusions: Keeping the mean radiation dose to pituitary under 15 Gy and the dose to the distal infundibulum under 17 Gy prevents the development of hypopituitarism following LGK irradiation.

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VEGFR1 expression is related to lymph node metastasis and serum VEGF may be a marker of progression in the follow-up of patients with differentiated thyroid carcinoma

Z Karaca, F Tanriverdi, K Unluhizarci, F Ozturk, S Gokahmetoglu, G Elbuken, I Cakir, F Bayram and F Kelestimur

Objective: Vascular endothelial growth factor (VEGF) and VEGF receptor 1 (VEGFR1) are known to be related to thyroid tumorigenesis. The aim of the study was to examine the expressions and serum levels of VEGF, VEGFR1, IGF1, and IGF1 receptor (IGF1R) in patients with differentiated thyroid carcinoma (DTC) compared with patients with nodular goiter (NG).

Methods: We examined 39 patients with DTC who had a clinical history of at least 2 years and compared them with 25 patients who had a pathological diagnosis of NG after thyroidectomy. Serum VEGF, VEGFR1, and IGF1 levels were measured in both patient groups. The expressions of VEGF, VEGFR1, IGF1, and IGF1R were analyzed by the immunohistochemical method in the paraffin blocks of patients' thyroidectomy samples of the patients.

Results: The immunostainings scores for VEGF, VEGFR1, IGF1, and IGF1R were found to be higher in patients with DTC than in those with NG. Only VEGFR1 expression was related to lymph node metastasis at the time of surgery. None of the expressions were related to the long-term prognosis of the patients. Serum VEGF was found to be higher in patients with progressive DTC than in patients in clinical remission.

Conclusions: The expressions of VEGF and VEGFR1 were shown to be correlated with the expression of IGF1 and IGF1R. VEGFR1 expression may be an important index for the presence of lymph node metastasis at the time of thyroidectomy. Increased serum levels of VEGF may reflect disease recurrence in DTC.

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Cardiovascular risk, metabolic profile, and body composition in adult males with congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Z Karaca1, F Tanriverdi, K Unluhizarci, F Ozturk, S Gokahmetoglu, G Elbuken, I Cakir, F Bayram and F Kelestimur

Objective: Lifelong glucocorticoid therapy in patients with congenital adrenal hyperplasia (CAH) or the disease per se may result in increased cardiovascular risk. We therefore investigated cardiovascular and metabolic risk profiles in adult CAH males.

Subjects and methods: We compared CAH males (n=30), 19–67 years old, with age- and sex-matched controls (n=32). Subgroups of different ages (<30 years or older) and CYP21A2 genotypes (null, I2splice, and I172N as the mildest mutation) were studied. Anthropometry, fat and lean mass measured by dual-energy X-ray absorptiometry, lipids, liver function tests, homocysteine, lipoprotein-(a), glucose and insulin during an oral glucose tolerance test (OGTT), urine albumin, adrenal hormones, and 24 h ambulatory blood pressure measurements were studied.

Results: CAH males were shorter. Waist/hip ratio and fat mass were higher in older patients and the I172N group. Heart rate was faster in older patients, the I2splice, and I172N groups. Insulin levels were increased during OGTT in all patients and in the I172N group. {gamma}-glutamyl transpeptidase was increased in older patients and in the I172N group. Testosterone was lower in older patients. Homocysteine was lower in younger patients, which may be cardioprotective. The cardiovascular risk seemed higher with hydrocortisone/cortisone acetate than prednisolone. Urinary epinephrine was lower in all groups of patients except in I172N.

Conclusions: Indications of increased risk were found in CAH males ≥30 years old and in the I172N group. In contrast, younger CAH males did not differ from age-matched controls. This is likely to reflect a better management in recent years.

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Variation in thyroid function in subclinical hypothyroidism: importance of clinical follow-up and therapy

Jesper Karmisholt, Stig Andersen and Peter Laurberg

Abstract: Subclinical hypothyroidism (SCH) is a common condition that is often observed without therapy. However, no evidence-based recommendation exists with regards to how patients with untreated SCH should be monitored.

Monitoring involves regular assessment of symptoms and signs of hypothyroidism (HYPO) and biochemical tests of thyroid function. An important question when repeated tests of thyroid function are performed is how large a difference in test results is needed to be confident that the change is real and not just due to chance variation.

Recent data show that the least significant difference between two tests in SCH is 40% for TSH and 15% for free thyroxine and free triiodothyronine, with 90% confidence. Furthermore, monitoring has to be based on biochemical function testing because serial evaluation of symptoms and signs related to HYPO is rather insensitive in detecting worsening of thyroid insufficiency.

When the presence of thyroid peroxidase auto-antibodies (TPO-Ab) in serum has been demonstrated, repeated measurements do not add much useful information in the monitoring of individual subclinical hypothyroid patients, as levels of TPO-Ab vary in parallel with TSH in these patients.

Lastly, we discuss how differences in the monitoring procedure influence the diagnostic outcome, and we suggest a follow-up approach for untreated subclinical hypothyroid patients.

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Coadministration of lanreotide Autogel and pegvisomant normalizes IGF1 levels and is well tolerated in patients with acromegaly partially controlled by somatostatin analogs alone

Aart-Jan van der Lely, Ignacio Bernabeu, Jan Cap, Philippe Caron, Annamaria Colao, Josef Marek, Sebastian Neggers and Pascal Birman

Objective: To evaluate the efficacy and safety of coadministered lanreotide Autogel (LA; 120 mg/month) and pegvisomant (40–120 mg/week) in acromegaly.

Design: This is a 28-week, multicenter, open-label, single-arm sequential study.

Methods: Patients (n=92) biochemically uncontrolled, on somatostatin analogs (SSAs) or using pegvisomant monotherapy entered a 4-month run-in taking LA (120 mg/month). Patients uncontrolled after the run-in period (n=57) entered a 28-week coadministration period, receiving LA 120 mg/month plus pegvisomant (60 mg once weekly, adapted every 8 weeks based on IGF1 levels to 40–80 mg once weekly or 40 or 60 mg twice weekly).

Results: In total, 33 (57.9%) patients had normalized IGF1 following coadministration (P<0.0001 versus 30% minimum clinically relevant); median pegvisomant dose in normalized patients was 60 mg/week. IGF1 normalized at any time during coadministration in 45 (78.9%) patients (P<0.0001) with median pegvisomant dose at 60 mg/week. Being nondiabetic (odds ratio (OR): 4.65) and older (OR, upper versus lower quartile: 3.40) showed increased likelihood of normalization. Symptom reduction was greatest for arthralgia (–0.6±1.6) and soft tissue swelling (–0.6±1.8). Five patients reported treatment-emergent adverse events causing treatment withdrawal: three serious (treatment related – thrombocytopenia, urticaria; not treatment related – abdominal pain/vomiting) and two nonserious (hepatotoxicity and cytolytic hepatitis, both elevating alanine aminotransferase to >5xupper limit of normal with normalization after withdrawal).

Conclusions: In patients partially controlled by SSAs, LA (120 mg/month) plus pegvisomant normalized IGF1 in 57.9% of patients after 7 months, at a median effective pegvisomant dose of 60 mg/week, and 78.9% at any time. In these patients, results suggest a pegvisomant-sparing effect versus daily pegvisomant monotherapy.

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Expression of functional KISS1 and KISS1R system is altered in human pituitary adenomas: evidence for apoptotic action of kisspeptin-10

Antonio J Martínez-Fuentes, Marcelo Molina, Rafael Vázquez-Martínez, Manuel D Gahete, Luis Jiménez-Reina, Jesús Moreno-Fernández, Pedro Benito-López, Ana Quintero, Andrés de la Riva, Carlos Diéguez, Alfonso Soto, Alfonso Leal-Cerro, Eugenia Resmini, Susan M Webb, Maria C Zatelli, Ettore C degli Uberti, María M Malagón, Raul M Luque1 and Justo P Castaño

Context: KISS1 was originally identified as a metastasis-suppressor gene able to inhibit tumor progression. KISS1 gene products, the kisspeptins, bind to a G-protein-coupled receptor (KISS1R, formerly GPR54), which is highly expressed in placenta, pituitary, and pancreas, whereas KISS1 mRNA is mainly expressed in placenta, hypothalamus, striatum, and pituitary.

Objective and design: KISS1/KISS1R pituitary expression profile, coupled to their anti-tumoral capacities, led us to hypothesize that this system may be involved in the biology of pituitary tumors. To explore this notion, expression levels of KISS1R and KISS1 were evaluated in normal and adenomatous pituitaries. Additionally, functionality of this system was assessed by treating dispersed pituitary adenoma cells in primary culture with kisspeptin-10 and evaluating intracellular calcium kinetics and apoptotic rate.

Results: Both KISS1 and KISS1R were expressed in normal pituitary, whereas this simultaneous expression was frequently lost in pituitary tumors, where diverse patterns of KISS1/KISS1R expression were observed that differed among distinct types of pituitary adenomas. Measurement of calcium kinetics revealed that kisspeptin-10 elicits a remarkable increase in [Ca2+]i in individual cells from four out of the five GH-producing adenomas studied, whereas cells derived from non-functioning pituitary adenomas (NFPA, n=45) did not respond. In contrast, kisspeptin-10 treatment increased the apoptotic rate in cells derived from both GH-producing and NFPA.

Conclusions: These results provide primary evidence that KISS1 and KISS1R expression can be differentially lost in pituitary tumor subtypes, where this system can exert functional, proapoptotic actions, and thereby offer novel insights to investigate the biology and therapeutic options to treat these tumors.

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