Macroprolactin: From laboratory to clinical practice.

Prolactin measurement is very common in standard clinical practice. It is indicated not only in the study of pituitary adenomas, but also when there are problems with fertility, decreased libido, or menstrual disorders, among other problems. Inadequate interpretation of prolactin levels without contextualizing the laboratory results with the clinical, pharmacological, and gynecological/urological history of patients leads to erroneous diagnoses and, thus, to poorly based studies and treatments. Macroprolactinemia, defined as hyperprolactinemia due to excess macroprolactin (an isoform of a greater molecular weight than prolactin but with less biological activity), is one of the main causes of such erroneous diagnoses, resulting in poor patient management when not recognized. There is no unanimous agreement as to when macroprolactin screening is required in patients with hyperprolactinemia. At some institutions, macroprolactin testing by polyethylene glycol (PEG) precipitation is routinely performed in all patients with hyperprolactinemia, while others use a clinically based approach. There is also no consensus on how to express the results of prolactin/macroprolactin levels after PEG, which in some cases may lead to an erroneous interpretation of the results. The objectives of this study were: 1. To establish the strategy for macroprolactin screening by serum precipitation with PEG in patients with hyperprolactinemia: universal screening versus a strategy guided by the alert generated by the clinician based on the absence or presence of clinical symptoms or by the laboratory when hyperprolactinemia is detected. 2. To create a consensus document that standardizes the reporting of prolactin results after precipitation with PEG to minimize errors in the interpretation of the results, in line with international standards.

The triglyceride/glucose index as an insulin resistance marker in the pediatric population and its relation to eating habits and physical activity.

INTRODUCTION: To examine the triglyceride/glucose index (TyG) as an insulin resistance marker in obese children and adolescents and its relation to clinical and biochemical parameters, body composition and lifestyle. PATIENTS AND METHOD: Sixty patients aged 7-16 years of age were enrolled. Anthropometric variables were recorded, together with pubertal stage, blood pressure and body composition assessed by bioimpedance. The TyG index was calculated as ln (fasting glucose (mg/dL) × triglycerides (mg/dL))/2 and the HOMA (homeostatic model assessment) index as fasting insulin (µU/mL) × fasting glucose (mmol/L)/22.5. Feeding habits were documented by adherence to the Mediterranean dietary pattern questionnaire, while physical activity was assessed using the International Sedentary Assessment Tool (ISAT), as well as accelerometry (Actigraph wGT3X+). RESULTS: The mean TyG index was 4.45 ±â€¯0.18, and proved higher in the pubertal group. We found a positive correlation with the HOMA index (r = 0.39; P = 0.03) and TG/HDL-c index (r = 0.53; P < 0.001). The best cut-off point of the TyG index for predicting insulin resistance was 4.21 in prepubertal children (sensitivity 84%, specificity 100%; AUC: 0.84) and 4.33 in pubertal children (sensitivity 89%, specificity 69%; AUC: 0.61). A positive correlation was found with screen time (r = 0.39; P = 0.01), as well as a negative correlation with caloric expenditure (Kcal/day) in the prepubertal group (r = -0.81; P = 0.005). CONCLUSIONS: The TyG index could be a useful insulin resistance marker in the pediatric population. Moderate to vigorous physical activity should be encouraged, as well as restricting screen time for leisure purposes, mainly in the prepubertal group.

Assessment of exposure-response relationship for bevacizumab in patients with metastatic colorectal cancer.

Limited literature is available for bevacizumab exposure-response relationship and there is not a concentration threshold associated with an optimal disease control. This prospective observational study in patients with metastatic colorectal cancer (mCRC) aims to evaluate, in a real-life setting, the relationship between bevacizumab through concentrations at steady state (Ctrough, SS) and disease control. Ctrough, SS were drawn, coinciding with the radiological evaluation of the response (progression or clinical benefit). Generalized estimating equations (GEE) analysis was performed. To test the association between Ctrough, SS in each patient with overall survival (OS) or progression-free survival (PFS), Cox proportional hazard models were developed. Data included 50 bevacizumab Ctrough, SS from 27 patients. The GEE model did not suggest any positive association between bevacizumab Ctrough, SS and clinical benefit (OR 0.99, 95% CI: 0.98-1.02, p = 0.863). The Cox regression showed association between higher median Ctrough, SS with better OS (HR 0.86, 95% CI: 0.73-1.01, p = 0.060), but not with PFS. We cannot confirm a relationship between bevacizumab Ctrough, SS and clinical benefit but this is the first real-world study trying to show a relationship between bevacizumab Ctrough, SS and disease control in mCRC. It was conducted in a small sample size which reduces the level of evidence. Further controlled randomized studies with a sufficient number of patients are required.

Macroprolactin: From laboratory to clinical practice. / Macroprolactina: del laboratorio a la práctica clínica. Recomendaciones del grupo de trabajo de laboratorio de la SEEN y de la comisión de hormonas de la SEQCML sobre la medición e informe del resultado de la macroprolactina.

Prolactin measurement is very common in standard clinical practice. It is indicated not only in the study of pituitary adenomas, but also when there are problems with fertility, decreased libido, or menstrual disorders, among other problems. Inadequate interpretation of prolactin levels without contextualizing the laboratory results with the clinical, pharmacological, and gynecological/urological history of patients leads to erroneous diagnoses and, thus, to poorly based studies and treatments. Macroprolactinemia, defined as hyperprolactinemia due to excess macroprolactin (an isoform of a greater molecular weight than prolactin but with less biological activity), is one of the main causes of such erroneous diagnoses, resulting in poor patient management when not recognized. There is no unanimous agreement as to when macroprolactin screening is required in patients with hyperprolactinemia. At some institutions, macroprolactin testing by polyethylene glycol (PEG) precipitation is routinely performed in all patients with hyperprolactinemia, while others use a clinically based approach. There is also no consensus on how to express the results of prolactin/macroprolactin levels after PEG, which in some cases may lead to an erroneous interpretation of the results. The objectives of this study were: 1. To establish the strategy for macroprolactin screening by serum precipitation with PEG in patients with hyperprolactinemia: universal screening versus a strategy guided by the alert generated by the clinician based on the absence or presence of clinical symptoms or by the laboratory when hyperprolactinemia is detected. 2. To create a consensus document that standardizes the reporting of prolactin results after precipitation with PEG to minimize errors in the interpretation of the results, in line with international standards.

The triglyceride / glucose index as an insulin resistance marker in the pediatric population and its relation to eating habits and physical activity. / El índice triglicéridos-glucosa como marcador de insulinorresistencia en población pediátrica y su relación con hábitos de alimentación y actividad física.

INTRODUCTION: To examine the triglyceride/glucose index (TyG) as an insulin resistance marker in obese children and adolescents and its relation to clinical and biochemical parameters, body composition and lifestyle. PATIENTS AND METHOD: Sixty patients aged 7-16 years of age were enrolled. Anthropometric variables were recorded, together with pubertal stage, blood pressure and body composition assessed by bioimpedance. The TyG index was calculated as ln (fasting glucose (mg/dL)×triglycerides (mg/dL))/2 and the HOMA (homeostatic model assessment) index as fasting insulin (µU/mL)×fasting glucose (mmol/L)/22.5. Feeding habits were documented by adherence to the Mediterranean dietary pattern questionnaire, while physical activity was assessed using the International Sedentary Assessment Tool (ISAT), as well as accelerometry (Actigraph wGT3X+). RESULTS: The mean TyG index was 4.45±0.18, and proved higher in the pubertal group. We found a positive correlation with the HOMA index (r=0.39; P=.03) and TG/HDL-c index (r=0.53; P<.001). The best cut-off point of the TyG index for predicting insulin resistance was 4.21 in prepubertal children (sensitivity 84%, specificity 100%; AUC: 0.84) and 4.33 in pubertal children (sensitivity 89%, specificity 69%; AUC: 0.61). A positive correlation was found with screen time (r=0.39; P=.01), as well as a negative correlation with caloric expenditure (Kcal/day) in the prepubertal group (r=-0.81; P=.005). CONCLUSIONS: The TyG index could be a useful insulin resistance marker in the pediatric population. Moderate to vigorous physical activity should be encouraged, as well as restricting screen time for leisure purposes, mainly in the prepubertal group.

Utilidad para médicos no radiólogos de la clasificación tirads y las características ecográficas de los nódulos tiroideos / Usefulness for non radiologist physicians of tirad classification and ecographic characteristics of thyroid nodules

Dada la mayor accesibilidad a la ecografía tiroidea, se diagnostican más nódulos de forma incidental aumentando su prevalencia al 65% en las tres últimas décadas. Todo ello ha supuesto un aumento de punciones innecesarias. El objetivo de nuestro estudio es identificar la utilidad de la clasificación TIRADS y de las características ecográficas de los nódulos tiroideos para establecer la probabilidad de malignidad de los mismos y seleccionar aquellos sospechosos para realizar la punción y aspiración con aguja fina (PAAF). Se encontró una relación estadísticamente significativa entre la malignidad y nódulo sólido, hipoecogenicidad, márgenes irregulares y microcalcificaciones. Sin embargo, no se encontró relación estadísticamente significativa entre malignidad y número de nódulos, tamaño nodular, diámetro craneocaudal y vascularización central. Asimismo, un 26.1% de los nódulos TIRADS-2 (todos ellos microcarcinomas), un 30% de los TIRADS-3 y un 54 % de los TIRADS-4 fueron malignos (p 0.027). Tanto el TIRADS como las características ecográficas aisladas son útiles para identificar nódulos sugerentes de malignidad.

Owed to the easier accessibility to thyroid ecography, more incidental nodules are discovered reaching their prevalence the 65 % of population in the last three decades. All of it has resulted in a growth of unnecessary fine needle aspirations (FNA). Our study objective is to identify the TIRADS classification utility and the nodules sonographic characteristics to establish their probability of malignancy and to select those suspicious susceptible of FNA. We found a statistically significant relationship between malignancy and solid nodule, hypoechogenicity, irregular margins and microcalcifications. However we didn´t find a relation between malignancy and number, size, shape (taller than wide) and central vascularity. With respect to TIRADS classification, 26,1% of TIRADS-2 (all of them microcarcinomas), 30% of TIRADS-3 and 54% of TIRADS-4 were malignant (p: 0,027). Both of them, TIRADS and individual sonographic characteristics are useful to identify nodules suspicious of malignancy.

Slightly elevated thyrotropin levels in pregnancy in our clinical practice.

OBJECTIVE: The aim of this study was to assess the incidence of obstetric and neonatal complications in pregnant women with "normal" thyroid-stimulating hormone (TSH) levels in the first trimester (group A) and to compare them with those with "slightly elevated" TSH (SET) levels treated with levothyroxine (group B2) or not treated (group B1). METHODS: A total of 2375 women who had been performed laboratory tests in their first trimester of pregnancy were detected at our hospital between April 2015 and August 2017. Of these, 469 patients with SET were prospectively detected and randomized to groups B1 (227) and B2 (242). They were monitored prospectively until 6 months after delivery. Data of the control group (n=1906, group A) were retrospectively reviewed. A total of 1745 women were analyzed. Variables assessed included demographic and clinical characteristics and complications of pregnancy and delivery. RESULTS: A, B1, and B2 had similar clinical characteristics. There were no statistically significant differences in complications between the three groups during pregnancy, except in that natural deliveries were more common in group A as compared to group B1 (76.8% vs. 68.7%, p 0.017) and group B2 (66.3%), p<0.002). There were more induced deliveries in groups B1 (35.8%), and B2 (36.2%) than in group A (18.4%), p<0.01. Although the recommended TSH level was achieved in the second and third trimesters, no benefit could be found of treatment of SET. CONCLUSION: Although there were less natural deliveries and more induced deliveries in patients with SET, treatment with levothyroxine could not reverse this situation, despite achievement of levels considered appropriate in the second and third trimester.

Fasting glucose in the first trimester: An initial approach to diagnosis of gestational diabetes. / Glucemia basal en el primer trimestre como acercamiento inicial al diagnóstico de la diabetes en el embarazo.

OBJECTIVES: To establish whether fasting glucose levels in the first trimester (FGFT)of pregnancy ≥ 92 mg/dL (5.1 mmol/L) (FGFT) anticipate the occurrence of maternal-fetal complications of gestational diabetes mellitus. To assess whether FGFT can replace diagnosis of GDM using the classical two-step oral glucose tolerance test (OGTT). METHODS: A retrospective study of 1425 pregnancies with FGFT and O'Sullivan Test (OST) and/or OGTT according to OST results in the second trimester. FGFT sensitivity and specificity were assessed as compared to the conventional diagnosis of GDM. The relationship between maternal-fetal complications and FGFT was assessed in the total group and after excluding mothers who received specific medical treatment for GDM. RESULTS: Sensitivity and specificity of FGFT levels ≥ 92mg/dL were 46.4% and 88.8% as compared to diagnosis of GDM using Carpenter and Coustan criteria. In the total group, a statistically significant relationship was found between FGFT levels ≥ 92 mg/dL and newborn weight (3228±86 versus 3123±31g; P<.05), as well as a higher rate of macrosomia (6.9% versus 3.5%; P<.05). This association persisted after excluding patients diagnosed with and treated for GDM (weight: 3235±98 versus 3128±31 g; P<.05; percentage of macrosomia: 7.2% versus 3.4%; P<.05). CONCLUSIONS: FGFT is not a good substitute for conventional diagnosis of GDM in the second trimester. Pregnant women with FGFT levels ≥ 92 mg/dL, even with no subsequent diagnosis of GDM, are a risk group for fetal macrosomia and could benefit from dietary measures and physical exercise.

Prevalence of and risk factors for low bone mineral density in Spanish treated HIV-infected patients.

OBJECTIVES: Several studies have involved antiretroviral therapy in the pathogenesis of low bone mineral density (BMD), while others have not confirmed this association. In this study we analyze the impact of HIV status, traditional risk factors and antiretroviral therapy in BMD in an HIV-infected population living in Madrid. MATERIAL AND METHODS: We performed a cross-sectional analysis of 107 individuals infected with HIV and exposed to antiretroviral treatment to estimate the prevalence of decreased BMD. Bone mineral density of lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. In a multivariate analysis variables related with HIV status, antiretroviral drugs and traditional risk factors were included. RESULTS: Low BMD was diagnosed in 63 participants (58.9%), including osteoporosis in 11 (10%). At least one cause of osteoporosis was identified in 43 patients (40%), with a deficiency of vitamin D in 86 (89%) and secondary hyperparathyroidism in 30 (28%). In multivariate analysis, increasing age, a treatment based on boosted PI and tenofovir DF, and previous exposure to tenofovir were identified as independent risk factors for a decreased BMD in both lumbar spine and femoral neck. CONCLUSIONS: We have confirmed a high prevalence of reduced BMD, which is favoured by ritonavir-boosted PI and TDF. Bone safety should continue to be evaluated in clinical trials and cohort studies in order to demonstrate that the new drugs offer additional advantages regarding the impact on BMD.

Hypogonadism associated with muscle atrophy, physical inactivity and ESA hyporesponsiveness in men undergoing haemodialysis.

BACKGROUND: Testosterone deficiency (hypogonadism) is common among men undergoing haemodialysis, but its clinical implications are not well characterized. Testosterone is an anabolic hormone that induces erythrocytosis and muscle synthesis. We hypothesized that testosterone deficiency would be associated with low muscle mass, physical inactivity and higher dosages of erythropoietin-stimulating agents (ESA). METHODS: Single-center cross-sectional study of 57 male haemodialysis patients. None of the patients was undergoing testosterone replacement therapy. Total testosterone was measured in serum. Body composition (by bioelectrical impedance analysis) and physical activity (by the use of pedometers) were assessed. Patients with testosterone levels below the normal range were considered hypogonadal. RESULTS: Mean testosterone level was 321±146ng/dL; 20 patients (35%) were hypogonadal. Hypogonadal patients were older and had lower mean arterial blood pressure, higher interleukin-6 levels, lower lean body mass and higher fat body mass. A negative association between testosterone and normalized ESA dose was found in uni- and multivariate regression analyses. Testosterone levels directly correlated with lean body mass regardless of confounders. Hypogonadal patients had lower physical activity than their counterparts [2753±1784 vs. 4291±3225steps/day (p=0.04)]. The relationship between testosterone and physical activity was independent of age, comorbidities and inflammatory markers, but dependent on the proportion of muscle mass. CONCLUSION: Hypogonadism is common in our male haemodialysis population and is associated with higher ESA doses, reduced muscle mass and lower physical activity. The link between low testosterone levels and physical inactivity may conceivably relate to reduced muscle mass due to inadequate muscle protein synthesis.

Prevalence of vitamin D deficiency and its related risk factor in a Spanish cohort of adult HIV-infected patients: effects of antiretroviral therapy.

We analyzed serum 25(OH) cholecalciferol [25(OH)D] levels and factors related to deficiency (<20 ng/ml) or insufficiency (<30 ng/ml) in a cohort of Spanish HIV-infected patients and compared them with an age- and latitude-matched population from another study. We prospectively assessed 25(OH)D deficiency/insufficiency in a cohort of 352 HIV patients during 2009-2010. Predisposing factors were recorded and their relationship to low levels was assessed by logistic regression; a nutritional survey examined intake, nutritional status, and sunlight exposure in a subgroup of 92 patients. We studied the correlation of 25(OH)D with parathyroid hormone (PTH) and alkaline phosphatase. Age-, sex-, and race/ethnicity-adjusted vitamin D deficiency (<20 ng/ml) was 44.0% (95% CI, 38.8-49.4%) and insufficiency (<30 ng/ml) was 71.6% (95% CI, 66.9-76.3). Deficiency was 16.4% more prevalent in our sample than in non-HIV-infected Spaniards. Lower sunlight exposure was the only factor related to lower levels in the lifestyle and nutritional survey (p=0.045). In multiple logistic regression, higher body mass index (BMI), black race/ethnicity, lower seasonal sunlight exposure, men who have sex with men (MSM), and heterosexual transmission categories, efavirenz exposure and lack of HIV viral suppression were independently associated with deficiency/insufficiency. These variables predicted 79% of cases [AUC=0.872 (95% CI, 0.83-0.91)]. Patients receiving protease inhibitors (PIs) [OR 4.0 (95% CI, 1.3-12.3); p=0.014] or NNRTI [OR 3.6 (95% CI, 1.7-11.2); p=0.025] had higher odds of increased PTH levels; this was significant only in 25(OH)D-deficient patients (p=0.004). As in less insolated areas, the prevalence of vitamin D deficiency/insufficiency was high in HIV-infected patients in Spain; among treated patients, levels were higher with PIs than with efavirenz.

Prevalence of insulin resistance in a young adult population. Relationship with weight status.

AIM: To estimate the prevalence of insulin resistance using both the Homeostatic Model Assessment (HOMA) index and basal insulinemia, and to analyze its relationship to overweight, as measured by body mass index (BMI) and waist circumference (WC). PATIENTS AND METHODS: A series of 118 non-diabetic young adults aged 18 and 19 years attending a primary care health center were studied. They were contacted by telephone, and their BMI, WC, HOMA and basal insulinemia were measured, among other parameters. RESULTS: HOMA values ≥ P90 (HOMA ≥3.15) were found in 9.3% of the sample (50% in the obesity group). Insulinemia ≥ P90 (16,9) was found in 11%. Based on BMI, 17.8% were overweight (26.5% of men, 11.6% of women), and 6.8% were obese (6.1% of men, 7.2% of women). Based on WC, 5.71% were obese when waist was measured at the midpoint and 15.38%, when measured at the iliac crest. HOMA was found to be significantly correlated to weight increase, BMI, WC, systolic blood pressure, triglycerides, and blood glucose, while correlation was only found between insulinemia and increased WC and decreased high lipoprotein cholesterol (HDL) levels. CONCLUSION: In this young adult sample, increased BMI and WC were associated to increased insulin resistance. High HOMA values were found in 9.3% of subjects.

Vitamin D deficiency in dialysis patients: effect of dialysis modality and implications on outcome.

OBJECTIVE: Vitamin D deficiency has been linked to cardiovascular disease and mortality in hemodialysis (HD) patients. The purpose of the present cross-sectional study was to analyze the Vitamin D status of dialysis patients from a single center, study determinants of Vitamin D deficiency, and assess its implications on outcome. METHODS: A prospective observational study of 115 prevalent dialysis patients was carried out, in which clinical and dialysis-related characteristics including routine biochemistry were studied in relation to levels of 25-hydroxyvitamin-D (25[OH]D, chemiluminescence). Survival was assessed after a median follow-up period of 413 days. RESULTS: 25(OH)D deficiency and insufficiency was present in 51% and 42% of the patients, respectively. Only 7% of the patients showed normal 25(OH)D levels. Peritoneal dialysis patients presented the lowest 25(OH)D levels. Also, a significant difference was found between on-line hemodiafiltration (OL-HDF) and conventional HD (11 [6 to 16] versus 19 [13 to 27] ng/mL; P < 0.001; 25th to 75th percentiles, conventional HD versus OL-HDF respectively). In multinomial logistic regression analysis, patients on conventional HD had 8.35 greater odds (95% CI [2.04 to 34.20]) of 25(OH)D deficiency than OL-HDF even after adjustment for sex, parathyroid hormone, pH, and Charlson comorbidity index. During the follow-up period, 18 patients died. Both crude and adjusted (hazard ratio, 6.96; 95% CI [1.44 to 33.64]) Cox analysis identified 25(OH)D deficiency as a mortality risk factor. CONCLUSION: This observational study underlines the high prevalence of hypovitaminosis D in dialysis patients and its strong implications on outcome. Furthermore, our results suggest that OL-HDF was associated with a better preservation of the vitamin D status as compared with conventional HD.

Intragenic GNAS deletion involving exon A/B in pseudohypoparathyroidism type 1A resulting in an apparent loss of exon A/B methylation: potential for misdiagnosis of pseudohypoparathyroidism type 1B.

CONTEXT: Several endocrine diseases that share resistance to PTH are grouped under the term pseudohypoparathyroidism (PHP). Patients with PHP type Ia show additional hormone resistance, defective erythrocyte G(s)alpha activity, and dysmorphic features termed Albright's hereditary osteodystrophy (AHO). Patients with PHP-Ib show less diverse hormone resistance and normal G(s)alpha activity; AHO features are typically absent in PHP-Ib. Mutations affecting G(s)alpha coding exons of GNAS and epigenetic alterations in the same gene are associated with PHP-Ia and -Ib, respectively. The epigenetic GNAS changes in familial PHP-Ib are caused by microdeletions near or within GNAS but without involving G(s)alpha coding exons. OBJECTIVE: We sought to identify the molecular defect in a patient who was diagnosed with PHP-Ia based on clinical presentation (hormone resistance and AHO) but displayed the molecular features typically associated with PHP-Ib (loss of methylation at exon A/B) without previously described genetic mutations. METHODS: Microsatellite typing, comparative genome hybridization, and allelic dosage were performed for proband and her parents. RESULTS: Comparative genome hybridization revealed a deletion of 30,431 bp extending from the intronic region between exons XL and A/B to intron 5. The same mutation was also demonstrated, by PCR, in the patient's mother, but polymorphism and allele dosage analyses indicated that she had this mutation in a mosaic manner. CONCLUSION: We discovered a novel multiexonic GNAS deletion transmitted to our patient from her mother who is mosaic for this mutation. The deletion led to different phenotypic manifestations in the two generation and appeared, in the patient, as loss of GNAS imprinting.