Juan Carlos Galofré

Body Adiposity and Type 2 Diabetes: Increased Risk With a High Body Fat Percentage Even Having a Normal BMI

Obesity is the major risk factor for the development of prediabetes and type 2 diabetes. BMI is widely used as a surrogate measure of obesity, but underestimates the prevalence of obesity, defined as an excess of body fat. We assessed the presence of impaired glucose tolerance or impaired fasting glucose (both considered together as prediabetes) or type 2 diabetes in relation to the criteria used for the diagnosis of obesity using BMI as compared to body fat percentage (BF%). We performed a cross‐sectional study including 4,828 (587 lean, 1,320 overweight, and 2,921 obese classified according to BMI) white subjects (66% females), aged 18–80 years. BMI, BF% determined by air‐displacement plethysmography (ADP) and conventional blood markers of glucose metabolism and lipid profile were measured. We found a higher than expected number of subjects with prediabetes or type 2 diabetes in the obese category according to BF% when the sample was globally analyzed (P < 0.0001) and in the lean BMI‐classified subjects (P < 0.0001), but not in the overweight or obese‐classified individuals. Importantly, BF% was significantly higher in lean (by BMI) women with prediabetes or type 2 diabetes as compared to those with normoglycemia (NG) (35.5 ± 7.0 vs. 30.3 ± 7.7%, P < 0.0001), whereas no differences were observed for BMI. Similarly, increased BF% was found in lean BMI‐classified men with prediabetes or type 2 diabetes (25.2 ± 9.0 vs. 19.9 ± 8.0%, P = 0.008), exhibiting no differences in BMI or waist circumference. In conclusion, assessing BF% may help to diagnose disturbed glucose tolerance beyond information provided by BMI and waist circumference in particular in male subjects with BMI <25 kg/m2 and over the age of 40.

Clinical Usefulness of a New Equation for Estimating Body Fat

OBJECTIVE To assess the predictive capacity of a recently described equation that we have termed CUN-BAE (Clínica Universidad de Navarra-Body Adiposity Estimator) based on BMI, sex, and age for estimating body fat percentage (BF%) and to study its clinical usefulness. RESEARCH DESIGN AND METHODS We conducted a comparison study of the developed equation with many other anthropometric indices regarding its correlation with actual BF% in a large cohort of 6,510 white subjects from both sexes (67% female) representing a wide range of ages (18–80 years) and adiposity. Additionally, a validation study in a separate cohort (n = 1,149) and a further analysis of the clinical usefulness of this prediction equation regarding its association with cardiometabolic risk factors (n = 634) was carried out. RESULTS The mean BF% in the cohort of 6,510 subjects determined by air displacement plethysmography was 39.9 ± 10.1%, and the mean BF% estimated by the CUN-BAE was 39.3 ± 8.9% (SE of the estimate, 4.66%). In this group, BF% calculated with the CUN-BAE showed the highest correlation with actual BF% (r = 0.89, P < 0.000001) compared with other anthropometric measures or BF% estimators. Similar agreement was found in the validation sample. Moreover, BF% estimated by the CUN-BAE exhibits, in general, better correlations with cardiometabolic risk factors than BMI as well as waist circumference in the subset of 634 subjects. CONCLUSIONS CUN-BAE is an easy-to-apply predictive equation that may be used as a first screening tool in clinical practice. Furthermore, our equation may be a good tool for identifying patients at cardiovascular and type 2 diabetes risk.

Advantage of salivary cortisol measurements in the diagnosis of glucocorticoid related disorders

OBJECTIVE Salivary cortisol in the assessment of glucocorticoid related disorders. DESIGN-METHODS: Serum and salivary cortisol were measured in 189 patients (22 Cushings syndrome, 67 pseudo-Cushing, 11 Addisons disease, 89 controls) at 8:00 and 24:00 h. RESULTS Serum and salivary cortisol correlated in the whole study population (r=0.62, p=0.000). Morning serum and saliva cortisol in Addisons disease were lower than in controls (6.74+/-1.69 vs 22.58+/-1.78 microg/dL, and 0.15+/-0.25 vs 0.67+/-0.12 microg/dL) (p<0.001). Morning serum cortisol was similar in controls and patients with Cushings syndrome or pseudo-Cushing (22.58+/-1.78 vs 13.96+/-6.02 vs 16.13+/-1.69 microg/dL). Morning serum and salivary cortisol at 8:00 had the same sensitivity to distinguish patients with Addisons disease from healthy controls. 24:00 am serum cortisol in controls (2.61+/-0.20 microg/dL) was lower than in the pseudo-Cushing group (6.53+/-0.77 microg/dL, p<0.001) and in Cushings syndrome (10.90+/-2.36 microg/dL, p=0.003). 24:00 am salivary cortisol in controls (0.0025+/-0.001 microg/dL) was lower than in patients with Cushings syndrome (0.58+/-0.11 microg/dL, p<0.001) and those higher than in patient with pseudo-Cushing (0.10+/-0.06 microg/dL, p=0.001). Both salivary cortisol and serum cortisol presented high specificity (82% and 100%) to detect Cushings syndrome but salivary cortisol higher sensitivity (saliva 88% and serum 50%). CONCLUSION Morning salivary cortisol is as good as serum as screening test for patients with Addisons disease and nighttime salivary cortisol is more adequate than serum in the screening of Cushings syndrome.

Autoimmune Thyroid Disease in Pregnancy: A Review

The maternal physiological changes that occur in normal pregnancy induce complex endocrine and immune responses. During a normal pregnancy, thyroid gland volume may enlarge, and thyroid hormone production increases. Hence, the interpretation of thyroid function during gestation needs to be adjusted according to pregnancy-specific ranges. The elevated prevalence of gestation-related thyroid disorders (10%-15%) and the important repercussions for both mother and fetus reported in multiple studies throughout the world denote, in our opinion, the necessity for routine thyroid function screening both before and during pregnancy. Once thyroid dysfunction is suspected or confirmed, management of the thyroid disorder necessitates regular monitoring in order to ensure a successful outcome. The aim of treating hyperthyroidism in pregnancy with antithyroid drugs is to maintain serum thyroxine (T(4)) in the upper normal range of the assay used with the lowest possible dose of drug, whereas in hypothyroidism, the goal is to return serum thyroid-stimulating hormone (TSH) to the range between 0.5 and 2.5 mU/L.

Genetics of pheochromocytoma and paraganglioma in Spanish pediatric patients

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare neuroendocrine tumors that arise from the adrenal medulla or from the extra-adrenal sympathetic and parasympathetic paraganglia respectively. Now we know that more than 30% of patients develop extra-adrenal tumors (Cascon et al. 2009b, Mannelli et al. 2009), the percentage of malignant cases depends on tumor location and/or genetic background (from w3% in RETor VHL-related cases to 31% described for SDHB mutation carriers; Welander et al. 2011), and the probability of carrying a germline mutation in one of the PCC/PGL susceptibility genes is approaching 50%. Regarding the latter, up to four genes (SDHAF2, SDHA, TMEM127, and MAX) have recently been incorporated into the ‘catalog’ of PCC/PGL susceptibility genes (Hao et al. 2009, Burnichon et al. 2010, Qin et al. 2010, Comino-Mendez et al. 2011). Before the discovery of these genes, 30–40% of PCC/PGL cases were thought to be hereditary with autosomal inheritance caused by germline mutations affecting one of six major susceptibility genes: RET, VHL, SDHB, SDHC, SDHD, and NF1 (Cascon et al. 2009b, Mannelli et al. 2009). Recent international collaborations, focused on establishing the involvement of the novel identified genes, suggested that overall they could explain an additional 6% of the negative-tested patients (Bayley et al. 2010, Yao et al. 2010, Burnichon et al. 2012). In addition to this high and heterogeneous genetic predisposition, there is a unknown percentage of familial cases (i.e. with familial antecedents of PCC/PGL and/or with other clinical characteristics suggesting a hereditary disease) that do not harbor mutations in any of the susceptibility genes mentioned earlier. Although PCCs/PGLs are infrequently diagnosed during childhood, it is possible to find pediatric patients (diagnosed under the age of 18 years) either carrying germline alterations in the major susceptibility genes or without known mutations (Welander et al. 2011). The identification of a genetic predisposition in children has

Increased postpartum thyroxine replacement in Hashimoto's thyroiditis.

BACKGROUND The thyroidal response of pregnant patients with established Hashimotos thyroiditis remains poorly described. The aim of this study was to determine the impact of pregnancy on Hashimotos thyroiditis as revealed by changes in postpregnancy levothyroxine requirements. METHODS We performed a retrospective study of 799 hypothyroid patients in a university hospital. We reviewed the clinical records and selected a group of well-documented pregnant (n = 34) and nonpregnant (n = 32) hypothyroid women for study. We reviewed levothyroxine intake and serum thyrotropin (TSH) levels during three consecutive 9-month time intervals that were immediately before, during, and after pregnancy. We compared the percent change in levothyroxine dose between the prepregnancy level and each trimester during and after pregnancy. RESULTS There were two patterns of levothyroxine supplementation during gestation. In pattern 1 (n = 11) there was either no change or a single levothyroxine dose increase with no subsequent changes in each trimester (T1 = T2 = T3). In pattern 2 (n = 18), multistep levothyroxine dose increases were required throughout pregnancy (T1 < T2 < T3) to maintain desired TSH levels (<2.0 mU/L). Women with pattern 2 had mean TSH levels during gestation that differed significantly from pattern 1 (2.8 +/- 0.5 vs. 1.3 +/- 0.1 mU/L respectively; p < 0.03). Further, in multivariate logistic regression, women with pattern 2 were 62 times more likely than women with pattern 1 to have a levothyroxine dose at least 20% above baseline at 3 months postpartum (p = 0.04). CONCLUSIONS We showed that >50% of hypothyroid women with Hashimotos thyroiditis experienced an increase in levothyroxine requirements in the postpartum compared to pregestational doses. This pattern of enhanced levothyroxine need was most likely dependent on the preexisting thyroid functional reserve and postpartum progression of autoimmune destruction.

A cross-sectional study of the association between circulating TSH level and lipid profile in a large Spanish population

Some evidence suggests that high serum TSH levels are associated with an adverse lipid profile, but this association is not clear when plasma TSH is within the reference range. Nevertheless, these studies have never been conducted in Spain, a country with a strong adherence to the Mediterranean diet. The study aim was to analyse the association between blood TSH levels and circulating lipids in a large Spanish population and set up a TSH reference range in different age, gender and Body Mass Index (BMI) subpopulations from our cohort.

PheoSeq: A Targeted Next-Generation Sequencing Assay for Pheochromocytoma and Paraganglioma Diagnostics

Genetic diagnosis is recommended for all pheochromocytoma and paraganglioma (PPGL) cases, as driver mutations are identified in approximately 80% of the cases. As the list of related genes expands, genetic diagnosis becomes more time-consuming, and targeted next-generation sequencing (NGS) has emerged as a cost-effective tool. This study aimed to optimize targeted NGS in PPGL genetic diagnostics. A workflow based on two customized targeted NGS assays was validated to study the 18 main PPGL genes in germline and frozen tumor DNA, with one of them specifically directed toward formalin-fixed paraffin-embedded tissue. The series involved 453 unrelated PPGL patients, of whom 30 had known mutations and were used as controls. Partial screening using Sanger had been performed in 275 patients. NGS results were complemented with the study of gross deletions. NGS assay showed a sensitivity ≥99.4%, regardless of DNA source. We identified 45 variants of unknown significance and 89 pathogenic mutations, the latter being germline in 29 (7.2%) and somatic in 58 (31.7%) of the 183 tumors studied. In 37 patients previously studied by Sanger sequencing, the causal mutation could be identified. We demonstrated that both assays are an efficient and accurate alternative to conventional sequencing. Their application facilitates the study of minor PPGL genes, and enables genetic diagnoses in patients with incongruent or missing clinical data, who would otherwise be missed.

Management of subclinical hyperthyroidism.

The ideal approach for adequate management of subclinical hyperthyroidism (low levels of thyroid-stimulating hormone [TSH] and normal thyroid hormone level) is a matter of intense debate among endocrinologists. The prevalence of low serum TSH levels ranges between 0.5% in children and 15% in the elderly population. Mild subclinical hyperthyroidism is more common than severe subclinical hyperthyroidism. Transient suppression of TSH secretion may occur because of several reasons; thus, corroboration of results from different assessments is essential in such cases. During differential diagnosis of hyperthyroidism, pituitary or hypothalamic disease, euthyroid sick syndrome, and drug-mediated suppression of TSH must be ruled out. A low plasma TSH value is also typically seen in the first trimester of gestation. Factitial or iatrogenic TSH inhibition caused by excessive intake of levothyroxine should be excluded by checking the patient’s medication history. If these nonthyroidal causes are ruled out during differential diagnosis, either transient or long-term endogenous thyroid hormone excess, usually caused by Graves’ disease or nodular goiter, should be considered as the cause of low circulating TSH levels. We recommend the following 6-step process for the assessment and treatment of this common hormonal disorder: 1) confirmation, 2) evaluation of severity, 3) investigation of the cause, 4) assessment of potential complications, 5) evaluation of the necessity of treatment, and 6) if necessary, selection of the most appropriate treatment. In conclusion, management of subclinical hyperthyroidism merits careful monitoring through regular assessment of thyroid function. Treatment is mandatory in older patients (> 65 years) or in presence of comorbidities (such as osteoporosis and atrial fibrillation).

Spanish consensus for the management of patients with advanced radioactive iodine refractory differentiated thyroid cancer.

BACKGROUND Approximately one third of the patients with differentiated thyroid cancer (DTC) who develop structurally-evident metastatic disease are refractory to radioactive iodine (RAI). Most deaths from thyroid cancer occur in these patients. The main objective of this consensus is to address the most controversial aspects of management of these patients. METHODS On behalf of the Spanish Society of Endocrinology & Nutrition (SEEN) and the Spanish Group for Orphan and Infrequent Tumors (GETHI), the Spanish Task Force for Thyroid Cancer, consisting of endocrinologists and oncologists, reviewed the relevant literature and prepared a series of clinically relevant questions related to management of advanced RAI-refractory DTC. RESULTS Ten clinically relevant questions were identified by the task force. In answering to these 10 questions, the task force included recommendations regarding the best definition of refractoriness; the best therapeutic options including watchful waiting, local therapies, and systemic therapy (e.g. kinase inhibitors), when sodium iodide symporter (NIS) restoration may be expected; and how recent advances in molecular biology have increased our understanding of the disease. CONCLUSIONS In response to our appointment as a task force by the SEEN and GHETI, we developed a consensus to help in clinical management of patients with advanced RAI-refractory DTC. We think that this consensus will provide helpful and current recommendations that will help patients with this disorder to get optimal medical care.