Contribution of early SPECT/CT to 99mTc-MIBI double phase scintigraphy in primary hyperparathyroidism: Diagnostic value and correlation between uptake and biological parameters / Aportación del SPECT/TC precoz a la gammagrafía de doble fase con 99mTc-MIBI en pacientes con hiperparatiroidismo primario: valor diagnóstico y correlación de la captación con parámetros biológicos

Aim. To evaluate the value of 99mTc-MIBI double-phase scintigraphy (DPS) and early SPECT/CT in the pre-surgical assessment of patients with primary hyperparathyroidism (PHPT). Also, to calculate the correlation between uptake and some biological parameters. Material and methods. Forty patients with PHPT were included: 37 solitary adenomas, 1 hyperplasia, and 2 double adenomas. Fifteen patients had ectopic glands. DPS and early SPECT/CT were acquired in all patients. Ultrasound was performed in 31/40. All patients underwent surgery, intra-operative iPTH measurements, and histopathological examinations. Qualitative DPS uptake was assessed and correlated to pre-surgical calcium, iPTH levels, gland weight, and maximum diameter. Results. In the planar study, there were 23 positive cases, 8 doubtful, and 9 negatives. With the SPECT/CT, 8/9 negatives cases were located. All doubtful cases were confirmed as positives. Gland location improved in 16 cases (12 ectopic). DPS+SPECT/CT failed to detect a solitary adenoma and at least one gland in three cases of multiglandular disease (MGD). The sensitivity by patient was: DPS 72.5%, DPS+SPECT/CT 90%, and ultrasound 42%. Ultrasound and scintigraphy (DPS+SPECT/CT) were concordant in 16/31 patients. For the rest of them, scintigraphy proved correct in 14/15, and both techniques failed in one case. There was a significant correlation between level of uptake and iPTH level, gland weight, and maximum diameter. Conclusion. Early SPECT/CT improves sensitivity and the locating of parathyroid pathological glands and increases diagnostic confidence. iPTH level, glandular size, and weight are related to the qualitative assessment of 99mTc-MIBI uptake in early DPS (AU)

Objetivo. Evaluar la gammagrafía de doble fase con 99mTc-MIBI (GDF) y el SPECT/TC precoz, en la valoración prequirúrgica del hiperparatiroidismo primario (HPTP), calculando la correlación entre grado de captación y algunos parámetros biológicos. Material y métodos. Se incluyeron 40 pacientes: 37 adenomas solitarios, dos adenomas dobles, una hiperplasia. Quince tenían glándulas ectópicas. En 40 pacientes se realizaron GDF y SPECT/TC; en 31/40, ecografía. Todos los pacientes fueron intervenidos, realizando determinación de PTHi intraoperatoria y examen histopatológico. Se evaluó cualitativamente la captación en la GDF, correlacionándose con calcio y PTHi prequirúrgicos, peso y diámetro máximo glandulares. Resultados. En el estudio planar se obtuvieron 23 casos positivos, 8 dudosos, y 9 negativos. Con SPECT/TC se localizaron 8/9 de los negativos. Todos los dudosos se confirmaron como positivos. La localización glandular mejoró en 16 casos (12 ectópicos). La GDF+SPECT/TC fallaron en la detección de un adenoma solitario y en la visualización de alguna de las glándulas en tres casos de enfermedad multiglandular (EMG). La sensibilidad por pacientes fue: GDF 72,5%, GDF+SPECT/TC 90%, ecografía 42%. Ecografía y gammagrafía (GDF+SPECT/TC) concordaron en 16/31 pacientes. De los no concordantes, la gammagrafía acertó en 14/15 y ambas técnicas fallaron en uno. Hubo correlación significativa entre captación y PTHi, peso y diámetro máximo glandulares. Conclusion. El SPECT/TC precoz mejora la sensibilidad y la localización de las paratiroides patológicas y aumenta la confianza diagnóstica. PTHi, tamaño y peso glandulares se correlacionan con la valoración cualitativa de la captación precoz de 99mTc-MIBI en la GDF (AU)

Parathyroid Hormone Polymorphism RS6254 is Associated with the Development and Severity of Osteoporosis in Asymptomatic but not Normocalcemic Hyperthyroidism.

Although normocalcemic and asymptomatic hyperparathyroidism (HPT) are becoming more common, they remain only partially understood. Parathyroid hormone (PTH) polymorphisms have been associated with disease severity in classical HPT. The aim of the present study was to evaluate the clinical effect of PTH polymorphism (rs6254) in normocalcemic and asymptomatic HPT. A prospective study of 61 consecutive patients with normocalcemic or asymptomatic HPT was carried out. Secondary causes of HPT were ruled out. All patients were followed for≥1 year. Calcium and phosphorus metabolism parameters were assessed at least twice during the follow-up period to classify as normocalcemic or asymptomatic HPT. Bone mineral density (BMD) and the rs6254 polymorphism genotype were also assessed. Genotype rs6254GG was observed in 23 patients (37.7%) whereas GA and AA genotypes were presented in 29 (47.5%) and 9 (14.8%) patients, respectively. Age, sex and genotype distributions were comparable in both groups. In asymptomatic but not normocalcemic HPT patients, the GG genotype was associated with a significantly higher level of intact PTH [200.2 (SD 76.5) vs. 113.3 (SD 25.9) pg/ml; p<0.01], and significantly lower Z-score densitometry at the femoral neck, proximal femur, and lumbar spine. Both remained significant after adjusting for major confounding factors by multiple linear regression. The present study supports the independent pathogenic effect of rs6254GA polymorphism on the development and severity of BMD complications in patients with asymptomatic but not normocalcemic HPT. Further studies are needed to confirm this finding and to assess the effect of other polymorphisms in normocalcemic and asymptomatic HPT.

The Calcium-Sensing Receptor in Health and Disease.

The extracellular calcium-sensing receptor (CaSR) is a unique G protein-coupled receptor (GPCR) activated by extracellular Ca2+ and by other physiological cations including Mg2+, amino acids, and polyamines. CaSR is the most important master controller of the extracellular Ca2+ homeostatic system being expressed at high levels in the parathyroid gland, kidney, gut and bone, where it regulates parathyroid hormone (PTH) secretion, vitamin D synthesis, and Ca2+ absorption and resorption, respectively. Gain and loss of function mutations in the CaSR are responsible for severe disturbances in extracellular Ca2+ metabolism. CaSR agonists (calcimimetics) and antagonists (calcilytics) are in use or under intense research for treatment of hyperparathyroidism secondary to kidney failure and hypocalcemia with hypercalciuria, respectively. Expression of the CaSR extends to other tissues and systems beyond the extracellular Ca2+ homeostatic system including the cardiovascular system, the airways, and the nervous system where it may play physiological functions yet to be fully understood. As a consequence, CaSR has been recently involved in different pathologies including uncontrolled blood pressure, vascular calcification, asthma, and Alzheimer's disease. Finally, the CaSR has been shown to play a critical role in cancer either contributing to bone metastasis and/or acting as a tumor suppressor in some forms of cancer (parathyroid cancer, colon cancer, and neuroblastoma) and as oncogene in others (breast and prostate cancers). Here we review the role of CaSR in health and disease in calciotropic tissues and others beyond the extracellular calcium homeostatic system.

Contribution of early SPECT/CT to 99mTc-MIBI double phase scintigraphy in primary hyperparathyroidism: Diagnostic value and correlation between uptake and biological parameters.

AIM: To evaluate the value of 99mTc-MIBI double-phase scintigraphy (DPS) and early SPECT/CT in the pre-surgical assessment of patients with primary hyperparathyroidism (PHPT). Also, to calculate the correlation between uptake and some biological parameters. MATERIAL AND METHODS: Forty patients with PHPT were included: 37 solitary adenomas, 1 hyperplasia, and 2 double adenomas. Fifteen patients had ectopic glands. DPS and early SPECT/CT were acquired in all patients. Ultrasound was performed in 31/40. All patients underwent surgery, intra-operative iPTH measurements, and histopathological examinations. Qualitative DPS uptake was assessed and correlated to pre-surgical calcium, iPTH levels, gland weight, and maximum diameter. RESULTS: In the planar study, there were 23 positive cases, 8 doubtful, and 9 negatives. With the SPECT/CT, 8/9 negatives cases were located. All doubtful cases were confirmed as positives. Gland location improved in 16 cases (12 ectopic). DPS+SPECT/CT failed to detect a solitary adenoma and at least one gland in three cases of multiglandular disease (MGD). The sensitivity by patient was: DPS 72.5%, DPS+SPECT/CT 90%, and ultrasound 42%. Ultrasound and scintigraphy (DPS+SPECT/CT) were concordant in 16/31 patients. For the rest of them, scintigraphy proved correct in 14/15, and both techniques failed in one case. There was a significant correlation between level of uptake and iPTH level, gland weight, and maximum diameter. CONCLUSION: Early SPECT/CT improves sensitivity and the locating of parathyroid pathological glands and increases diagnostic confidence. iPTH level, glandular size, and weight are related to the qualitative assessment of 99mTc-MIBI uptake in early DPS.

Clinical Expression of Calcium Sensing Receptor Polymorphism (A986S) in Normocalcemic and Asymptomatic Hyperparathyroidism.

Normocalcemic and asymptomatic hyperparathyroidism diagnosis are becoming more common. However, their pathophysiology is incompletely known. The aim of the present study was to evaluate the clinical effect of calcium-sensing receptor polymorphism (A986S) in normocalcemic and asymtomatic HPT. Prospective study conducted with 61 consecutive normocalcemic and asymptomatic HPT patients was followed up during a minimum period of 1 year. Secondary causes of hyperparathyroidism were ruled out. Calcium and phosphorus metabolism parameters were evaluated in at least 2 determinations during follow-up to classify as normocalcemic or asymptomatic hyperparathyroidism. Bone mineral density and A986S polymorphism genotype were also analyzed. Thiry-eight patients (62.3%) had the genotype A986A, and 23 (36.7%) patients had A986S (20 patients, 32.8%) or S986S (3 patients, 4.9%). Age, sex, and genotype distributions were comparable in both normocalcemic and asymptomatic hyperparathyroidism. In normocalcemic patients, S allele genotype was associated to statistically significant higher level of intact PTH: 92.0 (SD 18.5) vs. 110.6 (SD 24.4) pg/ml, p<0.05; and remained significant after adjustment by multiple linear regression. In asymptomatic hyperparathyroidism, A986A genotype resulted in a statistically significant higher level of intact PTH, alkaline phosphatase and procollagen amino-terminal propeptide; but only serum calcium remained as an independent predictor of serum intact PTH levels after a multiple linear regression. Bone mineral densitometry between genotypes did not show statistically significant differences. A986S polymorphism of CaSR is an independent predictor of PTH level in normocalcemic hyperparathyroidism patients, but not in asymptomatic hyperparathyroidism. More studies are needed to evaluate the effect of other polymorphisms in normocalcemic and asymptomatic hyperparathyroidism.

Effects of a High-Protein/Low-Carbohydrate versus a Standard Hypocaloric Diet on Weight and Cardiovascular Risk Factors during 9 Months: Role of a Genetic Variation in the Cannabinoid Receptor Gene (CNR1) (G1359A Polymorphism).

OBJECTIVE: We decided to investigate the role of this polymorphism on cardiovascular risk factors and weight loss secondary to a high-protein/low-carbohydrate vs. a standard hypocaloric diet (1,000 kcal/day) over a period of 9 months. MATERIAL AND METHODS: A nutritional evaluation was performed at the beginning and at the end of a 9-month period in which subjects received 1 of 2 diets (diet HP: high protein/low carbohydrate vs. S: standard diet). RESULTS: One hundred and four patients (54.7%) had the genotype G1359G and 86 (45.3%) patients had G1359A (77 patients, 25.8%) or A1359A (9 patients, 3.7%) (A-allele-carriers). In subjects with both genotypes, the body mass index, weight, fat mass, waist circumference and systolic blood pressures decreased with both diets. After the diet type HP and in subjects with both genotypes, the glucose, leptin, total cholesterol, LDL-cholesterol, insulin and HOMA-R levels decreased. After diet S and in all subjects, the total cholesterol, LDL cholesterol and leptin levels decreased, too. CONCLUSION: Our interventional study didn't show a relationship between the rs1049353 CNR-1 polymorphism and body weight response after two different hypocaloric (low carbohydrate/high protein vs. standard) diets over a period of 9 months. However, a low-carbohydrate/high-protein diet for 9 months improved glucose metabolism in subjects with both genotypes.

Efficacy and safety of long term treatment of unresponsive hypoparathyroidism using multipulse subcutaneous infusion of teriparatide.

Vitamin D nonresponsive hypoparathyroidism is uncommonly seen in the clinical practice. The use of new treatment modalities, including teriparatide administration, provides an alternative requiring its validation. We report the first case of hypoparathyroidism refractory to vitamin D that was successfully controlled for 5 years by teriparatide treatment. A 53-year-old woman presented severe hypoparathyroidism after thyroidectomy. No therapeutic response was obtained with oral and i. v. calcium and magnesium, or even with 5 µg calcitriol/day. Digestive disorders were ruled out and heterologous parathyroid transplant was ineffective. Subcutaneous (s. c.) recombinant human PTH 1-34 (rhPTH-teriparatide) plus oral calcitriol, calcium, and magnesium, were partially effective, but effectiveness of 20 µg teriparatide lasted less than 4 h and stable calcemia was not possible even with 4-6 injections/day. Multipulse s. c. pump driven infusion of teriparatide achieved complete normalization of serum calcium, phosphate, magnesium, calciuria, and magnesuria with relatively low teriparatide doses (25-35 µg/day) after the first day of treatment. Effectiveness of this treatment modality was maintained for 5 years. The only significant side effect observed during these years was the development of subcutaneous nodules with occasional insufficient control of calcemia. A gain in bone mineral density was observed after the first year of treatment, which had remained stable and within normal values, thereafter until now. No abnormalities in bone scintigraphy were detected in the follow-up. Vitamin D unresponsive hypoparathyroidism maybe safely and effectively controlled at long term by s. c. multipulse pump treatment recombinant human PTH.

Do thyroid cancer patients with basal undetectable Tg measured by current immunoassays require rhTSH testing?

OBJECTIVE: To evaluate the predictive value of disease free status of basal thyroglobulin (Tg) in differentiated thyroid carcinoma (DTC). DESIGN: Basal and recombinant human TSH (rhTSH) stimulated Tg measured with a commercial immunoassay (Liaison DiaSorin, Italial), neck ultrasonography (US) and fine needle aspiration cytology if required were performed in DTC patients followed prospectively for 6.8 years in a university hospital. 92 consecutive DTC patients were included. 74 patients with basal and stimulated Tg <1.0 ng/ml and Tg antibodies and US negative were considered as disease-free and persistent/recurrent disease was detected in 18 patients. In 25/74 disease-free patients rhTSH test was repeated within one year. RESULTS: 63/92 patients had undetectable basal Tg (<0.5 ng/ml), with rhTSH-Tg <0.5 ng/ml in 52, in 6 rhTSH-Tg between 0.5 and 1 ng/ml, in 2 between 1-2 ng/ml (disease-free after 3 years of follow-up) and >2.0 ng/ml (mean 4.1±2.4 ng/ml) in another 3, with US lymphatic metastasis confirmed histologically. Disease-free state was predicted with a sensitivity (S) of 66.7% and specificity (Sp) of 75.7% for basal Tg-0.5 ng/ml, and S 100% and Sp 85.1% for stimulated Tg-0.92. rhTSH test and US were repeated within one year in 25 disease-free patients with Tg<1.0 ng/ml. No further elevation below 1 ng/ml was observed. CONCLUSIONS: Low risk patients with undetectable basal Tg measured with current commercially available immunoassays should be followed with at least one rhTSH stimulated Tg and neck US because of the insufficient predictive value for recurrence/persistent disease of basal Tg.