Parathormone decline levels are better markers of symptomatic hypocalcemia following total thyroidectomy than parathormone alone.

Background: We aimed to assess the predictive value of the absolute and relative intact parathormone (iPTH) decline levels as reliable markers of postoperative hypocalcemia. Materials & methods: iPTH levels were measured 4 h after surgery and the following morning after surgery (postoperative day 1). iPTH, absolute iPTH decline (ΔPTH) and relative iPTH decline (ΔPTH%) were calculated and correlated with symptomatic hypocalcemia. Results: Of the 95 patients, 20% of patients (n = 19) developed symptomatic hypocalcemia. The ΔPTH (U = 206; p < 0.001) and ΔPTH% (U = 127; p < 0.001) were significantly higher in patients with symptomatic hypocalcemia. A ΔPTH% of 20% (sensitivity of 84%; specificity of 91%); and an absolute iPTH decline of 3.75 pg/ml (sensitivity of 74%; specificity of 87%) were highly predictive of symptomatic hypocalcemia. Conclusion: Postoperative ΔPTH and ΔPTH% have the potential to be predictors of symptomatic hypocalcemia following thyroidectomy and could facilitate a safe early discharge.

Executive summary of the SEORL CCC-SEEN consensus statement on post-thyroidectomy hypoparathyroidism. / Resumen ejecutivo del documento de consenso SEORL CCC-SEEN sobre hipoparatiroidismo postiroidectomía.

Hypoparathyroidism is the most common complication after total or completion thyroidectomy. It is defined as the presence of hypocalcemia accompanied by low or inappropriately normal parathyroid hormone (PTH) levels. Acute hypocalcemia is a potential lethal complication. Hypocalcemia treatment is based on endovenous or oral calcium supplements as well as oral calcitriol, depending on the severity of the symptoms. The risk of clinical hypocalcemia after bilateral thyroidectomy is considered very low if postoperative intact PTH decrease less than 80% with respect to preoperative levels. These patients could be discharged home without treatment, although this threshold may vary between institutions, and we recommend close surveillance in cases with increased risk (Graves disease, large goiters, reinterventions or evidence of parathyroid gland removal). Long-term treatment objectives are to control the symptoms and to keep serum calcium levels at the lower limit of the normal range, while preserving the calcium phosphate product and avoiding hypercalciuria.

Treatment of hypoparathyroidism.

The goal of the clinical management of hypoparathyroidism is to correct acute and chronic hypocalcemia. Treatment of acute hypoparathyroidism via intravenous infusion of Ca++ salts, is necessary only in symptomatic patients, or in asymptomatic patients in the setting of a rapid decrease in ionized Ca++ levels. The treatment cornerstones of chronic hypoparathyroidism are oral supplementation of calcium and/or active vitamin D, that can be associated with dietary restriction of sodium and phosphates, thiazide diuretics, and phosphate binders. Notably, PTH replacement is emerging as a innovative treatment of chronic hypoparathyroidism. rhPTH (1-84) has been shown to safely reduce calcium and vitamin D dosage, and increase serum calcium levels in hypoparathyroid patients. Therefore, rhPTH (1-84) appears to represent a new option in patients with chronic hypoparathyroidism "resistant" to conventional treatment.

Screening for Vitamin D Deficiency in Black Americans: Comparison of Total, Free, Bioavailable 25 Hydroxy Vitamin D Levels with Parathyroid Hormone Levels and Bone Mineral Density.

OBJECTIVES: There is debate surrounding the adequacy of total and free 25 hydroxy vitamin D [25(OH)D] levels in black Americans who have inherently high bone mineral density [BMD] and low serum concentration of vitamin D binding proteins [VDBP]. DESIGN: Retrospective analysis of serum samples and BMD analyses from the African American Health Study [AAHS] cohort. SETTING: The AAHS is a population-based longitudinal study initiated to examine issues of disability and frailty among urban-dwelling black Americans in the city of Saint Louis, Missouri. PARTICIPANTS: 122 men and 206 women, age 60.2 ± 4.3 years. INTERVENTION: Retrospective analysis. MEASUREMENTS: Total 25(OH)D, VDBP, PTH, and BMD of the lumbar spine and hip by dual energy x-ray photometry (DXA). Free and bioavailable vitamin D levels were calculated using serum concentrations and affinity constants for the VDBP (Gc1F and Gc1S) phenotypes. RESULTS: Serum total 25(OH)D levels were 14.6 ± 8.9 ng/mL (36 ± 22 nmol/L). Vitamin D insufficiency was estimated by compensatory elevations of PTH above the normal range (> 65 pg/mL). PTH levels were within the normal reference range in > 95% of the samples at total 25(OH)D levels ≥ 20 ng/mL (≥50 nmol/L). There was no difference in the correlation of the reciprocal relationship of vitamin D vs parathyroid hormone between the VDBP phenotypes. Receiver operating characteristic curve analyses indicated that serum total 25(OH)D discriminated sufficiency from insufficiency at least as well as the calculated levels of the free and bioavailable vitamin D. Very low levels of total 25(OH)D (≤ 8 ng/mL, ≤20 nmol/L) were associated with decreased BMD (p=0.02), but higher levels of 25(OH)D did not show statistical differences in BMD. CONCLUSION: Total 25(OH)D levels of ≤ 8ng/mL (≤20 nmol/L) are associated with clinically significant changes in BMD, whereas total 25(OH)D levels ≥ 20 ng/mL (≥50 nmol/L) suppressed PTH and were not associated with deficiencies in BMD. Lower levels of 25(OH)D may be acceptable for bone health in black than in white Americans.

Lack of endogenous parathyroid hormone delays fracture healing by inhibiting vascular endothelial growth factor­mediated angiogenesis.

Intermittent low­dose injections of parathyroid hormone (PTH) have been reported to exert bone anabolic effects and to promote fracture healing. As an important proangiogenic cytokine, vascular endothelial growth factor (VEGF) is secreted by bone marrow mesenchymal stem cells (BMSCs) and osteoblasts, and serves a crucial regulatory role in the process of vascular development and regeneration. To investigate whether lack of endogenous PTH causes reduced angiogenic capacity and thereby delays the process of fracture healing by downregulating the VEGF signaling pathway, a PTH knockout (PTHKO) mouse fracture model was generated. Fracture healing was observed using X­ray and micro­computerized tomography. Bone anabolic and angiogenic markers were analyzed by immunohistochemistry and western blot analysis. The expression levels of VEGF and associated signaling pathways in murine BMSC­derived osteoblasts were measured by quantitative polymerase chain reaction and western blot analysis. The expression levels of protein kinase A (PKA), phosphorylated­serine/threonine protein kinase (pAKT), hypoxia­inducible factor­1α (HIF1α) and VEGF were significantly decreased in BMSC­derived osteoblasts from PTHKO mice. In addition, positive platelet endothelial cell adhesion molecule staining was reduced in PTHKO mice, as determined by immunohistochemistry. The expression levels of HIF1α, VEGF, runt­related transcription factor 2, osteocalcin and alkaline phosphatase were also decreased in PTHKO mice, and fracture healing was delayed. In conclusion, lack of endogenous PTH may reduce VEGF expression in BMSC­derived osteoblasts by downregulating the activity of the PKA/pAKT/HIF1α/VEGF pathway, thus affecting endochondral bone formation by causing a reduction in angiogenesis and osteogenesis, ultimately leading to delayed fracture healing.

Causes and pathophysiology of hypoparathyroidism.

Hypoparathyroidism, a disorder characterized by hypocalcemia ensuing from inadequate parathyroid hormone secretion, is a rather rare disorder caused by multiple etiologies. When not caused by inadvertent damage or removal of the parathyroids during neck surgery, it is usually genetically determined. Epidemiological figures of this disease are still scarce and mainly limited to countries where non-anonymous databases are available and to surgical case series. Both the surgical and non-surgical forms pose diagnostic challenges. For surgical hypoparathyroidism, transient forms have to be ruled out even in the long term, in order to avoid unnecessary chronic replacement therapy with calcium and calcitriol. Regarding non-surgical hypoparathyroidism, once referred to as idiopathic, a systematic clinically and genetically-driven approach to define the precise diagnosis have to be pursued. In the case of syndromic hypoparathyroidism, patients have to be screened for associated abnormalities. Autoimmune, non-genetic hypoparathyroidism is still a diagnosis of exclusion, since no specific autoantibodies are specific for this condition.

Resurgence of parathyroidectomy: evidence and outcomes.

PURPOSE OF REVIEW: Parathyroidectomy (PTx) is the definitive therapy for refractory secondary hyperparathyroidism (SHPT). The drastic effects of PTx on biochemical parameters of SHPT increases the possibility that this intervention will lead to a reduction in the adverse outcomes related to uncontrolled SHPT. RECENT FINDINGS: The effect of PTx on mortality and cardiovascular outcomes among dialysis patients with severe SHPT have been evaluated in many observational studies from different regions of the world, including Asia, Europe, North America, and South America. In all but one small study, there was a significant association of PTx with lower all-cause mortality. In addition, in all studies, there was a trend in favor of PTx for cardiovascular morbidity and mortality. The effect of PTx on fractures has been evaluated in only one epidemiological study from the United States, which demonstrated a significant association of PTx and lower hip and combined fractures. SUMMARY: Although randomized evidence is lacking, these highly consistent results may suggest a strong beneficial effect of PTx on long-term clinical outcomes and eliminate the potential concern of low parathyroid hormone after PTx.

Monocrotaline Induces Endothelial Injury and Pulmonary Hypertension by Targeting the Extracellular Calcium-Sensing Receptor.

BACKGROUND: Monocrotaline has been widely used to establish an animal model of pulmonary hypertension. The molecular target underlying monocrotaline-induced pulmonary artery endothelial injury and pulmonary hypertension remains unknown. The extracellular calcium-sensing receptor (CaSR) and particularly its extracellular domain hold the potential structural basis for monocrotaline to bind. This study aimed to reveal whether monocrotaline induces pulmonary hypertension by targeting the CaSR. METHODS AND RESULTS: Nuclear magnetic resonance screening through WaterLOGSY (water ligand-observed gradient spectroscopy) and saturation transfer difference on protein preparation demonstrated the binding of monocrotaline to the CaSR. Immunocytochemical staining showed colocalization of monocrotaline with the CaSR in cultured pulmonary artery endothelial cells. Cellular thermal shift assay further verified the binding of monocrotaline to the CaSR in pulmonary arteries from monocrotaline-injected rats. Monocrotaline enhanced the assembly of CaSR, triggered the mobilization of calcium signaling, and damaged pulmonary artery endothelial cells in a CaSR-dependent manner. Finally, monocrotaline-induced pulmonary hypertension in rats was significantly attenuated or abolished by the inhibitor, the general or lung knockdown or knockout of CaSR. CONCLUSIONS: Monocrotaline aggregates on and activates the CaSR of pulmonary artery endothelial cells to trigger endothelial damage and, ultimately, induces pulmonary hypertension.

Deleción en el gen STX16 asociada a pseudohipoparatiroidismo / STX16 deletion associated to pseudohypoparathyroidism

No disponible

The PTH-Vitamin D-FGF23 axis.

Fibroblast growth factor 23 (FGF23) has emerged as an important regulator of phosphate and vitamin D homeostasis. It is important to understand how FGF23 interacts with vitamin D and parathyroid hormone (PTH) in a FGF23-Vitamin D-PTH axis to regulate mineral homeostasis. In this review, we discuss the genomic structure, and transcriptional, translational, and posttranslational regulation of FGF23. We describe its interaction with PTH and vitamin D, disorders of altered FGF23 states, and emerging therapies for diseases of FGF23 based upon these findings. This discussion helps redefine the role of PTH and vitamin D in relation to a complex bone-kidney-parathyroid loop, and points to areas within this complicated field in need of further clarification and research.

Bilateral Truncal Ligation of the Inferior Thyroid Artery during Bilateral Subtotal Thyroidectomy Causes a Decrease in Parathormone without Clinically Manifest Hypoparathyroidism: A Randomized Clinical Trial.

BACKGROUND: Bilateral truncal ligation (BTL) of the inferior thyroid artery (ITA) is frequently used during subtotal thyroidectomy to reduce the risk of post-operative bleeding as well as to reduce the blood loss intra-operatively. However, its effect on parathyroid function has not been evaluated in relation to age, residual and resected thyroid volume. METHODS: A total of 83 patients were randomized to receive non-BTL or BTL. After bilateral resection, the residual thyroid tissue on each side was measured by intra-operative ultrasonography. Laboratory and clinical examinations were performed the day before operation, intra-operatively and on post-operative days 2 and 5. The primary outcome measure was the difference in intact parathormone (PTHi) on post-operative day 5. Secondary outcomes were laboratory-diagnosed hypocalcaemia or hypoparathyroidism and clinically manifest hypoparathyroidism, respectively. RESULTS: PTHi on post-operative day 5 was significantly lower in the BTL group (29.4 vs. 34.7 ng/l in the non-BTL group, p = 0.033), especially in 61- to 80-year-old patients (0 vs. -7.91 ng/l, p = 0.029). The biggest decline in PTHi was found in the BTL group (-14.067 ng/l PTH, p = 0.018) with a residual thyroid volume of 0.5-1.9 ml. There were two cases of asymptomatic hypoparathyroidism in each group (5.1 vs. 4.8%, respectively, p = 1.000). The only case of clinically manifest hypoparathyroidism was in a BTL group patient aged 64 years (2.4%, p = 1.000). CONCLUSION: BTL of the ITA during subtotal thyroidectomy causes a larger decrease in PTH but does not lead to a significantly higher rate of clinically manifest hypoparathyroidism. BTL of the ITA, age >61 years, and a very small thyroid remnant (<2 ml) may be risk factors for post-operative hypoparathyroidism.

European Society of Endocrinology: European Society of Endocrinology Clinical Guideline: treatment of chronic hypoparathyroidism in adults

Hypoparathyroidism (HypoPT) is a rare (orphan) endocrine disease with low calcium and inappropriately low (insufficient) circulating parathyroid hormone levels, most often in adults secondary to thyroid surgery. Standard treatment is activated vitamin D analogues and calcium supplementation and not replacement of the lacking hormone, as in other hormonal deficiency states. The purpose of this guideline is to provide clinicians with guidance on the treatment and monitoring of chronic HypoPT in adults who do not have end-stage renal disease. We intend to draft a practical guideline, focusing on operationalized recommendations deemed to be useful in the daily management of patients. This guideline was developed and solely sponsored by The European Society of Endocrinology, supported by CBO (Dutch Institute for Health Care Improvement) and based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) principles as a methodological base. The clinical question on which the systematic literature search was based and for which available evidence was synthesized was: what is the best treatment for adult patients with chronic HypoPT? This systematic search found 1100 articles, which was reduced to 312 based on title and abstract. The working group assessed these for eligibility in more detail, and 32 full-text articles were assessed. For the final recommendations, other literature was also taken into account. Little evidence is available on how best to treat HypoPT. Data on quality of life and the risk of complications have just started to emerge, and clinical trials on how to optimize therapy are essentially non-existent. Most studies are of limited sample size, hampering firm conclusions. No studies are available relating target calcium levels with clinically relevant endpoints. Hence it is not possible to formulate recommendations based on strict evidence. This guideline is therefore mainly based on how patients are managed in clinical practice, as reported in small case series and based on the experiences of the authors.(AU)

Hypoparathyroidism - disease update and emerging treatments.

Parathyroid hormone (PTH) is the primary regulator of blood calcium levels and bone metabolism. Insufficient levels of PTH lead to hypoparathyroidism, characterized by low serum calcium and elevated serum phosphate levels. It is most commonly caused by the inadvertent damage to the parathyroid glands during thyroid surgery. Patients with hypoparathyroidism are currently being treated with oral calcium and active vitamin D, and to avoid worsening hypercalciuria, target serum calcium levels are within the lower end of normal. With current treatment, patients may suffer from large swings in serum calcium and are at a substantial risk of chronic renal failure, nephrocalcinosis, and kidney stones. The recent FDA approval of recombinant human (rh) PTH(1-84) for the treatment of hypoparathyroidism adds PTH replacement therapy to the endocrinologist's armamentarium to treat this chronic disease.

Novel activating mutation of human calcium-sensing receptor in a family with autosomal dominant hypocalcaemia.

INTRODUCTION: Autosomal dominant hypocalcaemia (ADH) is caused by activating mutations in the calcium sensing receptor gene (CaR) and characterised by mostly asymptomatic mild to moderate hypocalcaemia with low, inappropriately serum concentration of PTH. OBJECTIVE: The purpose of the present study was to biochemically and functionally characterise a novel mutation of CaR. PATIENTS: A female proband presenting with hypocalcaemia was diagnosed to have "idiopathic hypoparathyroidism" at the age of 10 with a history of muscle pain and cramps. Further examinations demonstrated hypocalcaemia in nine additional family members, affecting three generations. MAIN OUTCOME MEASURE: P136L CaR mutation was predicted to cause gain of function of CaR. RESULTS: Affected family members showed relevant hypocalcaemia (mean ± SD; 1.9 ± 0.1 mmol/l). Patient history included mild seizures and recurrent nephrolithiasis. Genetic analysis confirmed that hypocalcaemia cosegregated with a heterozygous mutation at codon 136 (CCC → CTC/Pro → Leu) in exon 3 of CaR confirming the diagnosis of ADH. For in vitro studies P136L mutant CaR was generated by site-directed mutagenesis and examined in transiently transfected HEK293 cells. Extracellular calcium stimulation of transiently transfected HEK293 cells showed significantly increased intracellular Ca(2+) mobilisation and MAPK activity for mutant P136L CaR compared to wild type CaR. CONCLUSIONS: The present study gives insight about a novel activating mutation of CaR and confirms that the novel P136L-CaR mutation is responsible for ADH in this family.

Measuring vitamin D levels: surrogates are insufficient.

AIMS: With the increasing evidence of adverse consequences because of low vitamin D levels on health demand for vitamin D, screening is increasing. The objective of the study was to assess whether parathyroid hormone (PTH) levels/bone profile is sufficient to identify patients with vitamin D insufficiency or deficiency, or whether vitamin D should be measured directly. METHODOLOGY: A total of 1560 serum specimens, with requests for 25-hydroxyvitamin D (25-OH vitamin D), calcium, phosphate, alkaline phosphatase (ALP), creatinine and PTH on the same sample were analysed at Salford Royal Hospital from November 2010 to November 2012. RESULTS: The prevalence of total vitamin D insufficiency or deficiency (defined as total 25-OH vitamin D < 50 nmol/l) was 62.9% (981/1560) overall, with males having higher proportions (67.2 vs. 59.3 per cent; χ(2) = 8.78, p = 0.003). There was no overall trend in mean serum adjusted calcium across categories of 25-OH vitamin D status but mean serum phosphate was significantly lower (F = 6.53, p < 0.0001) in patients with a 25-OH vitamin D level < 50 nmol/l. However in patients with vitamin D deficiency, a significant proportion had PTH, calcium, phosphate and alkaline phosphatase levels within the laboratory normal range. Even at a 25-OH vitamin D < 10 nmol/l, 71.6% had a normal PTH, 89.8% had normal serum calcium levels, 84.9% had normal phosphate levels and 81.6% had normal serum ALP. CONCLUSIONS: Therefore, despite the costs associated with the measurement of vitamin D, our findings show that no surrogate is adequate for screening for vitamin D deficiency.

Associations between the levels of sclerostin, phosphate, and fibroblast growth factor-23 and treatment with vitamin D in hemodialysis patients with low intact PTH level.

UNLABELLED: Serum sclerostin levels could be closely associated with serum phosphate and fibroblast growth factor-23 levels in hemodialysis patients with low intact parathyroid hormone (PTH) levels. Further study is required to indicate whether these close associations are present in patients with spontaneously low PTH levels without any vitamin D treatment. INTRODUCTION: Intact parathyroid hormone (iPTH) is involved in the interaction between sclerostin and phosphate/fibroblast growth factor-23 (FGF23) in animal models. However, their relationship in patients on hemodialysis (HD) is unclear. METHODS: Data of 102 HD patients were collected regarding clinical and laboratory parameters and mineral bone disorder medications. The patients were divided into subgroups according to the iPTH level (A, <70 pg/mL; B, 70-150 pg/mL; C, 150-300 pg/mL; and D, ≥ 300 pg/mL). RESULTS: The sclerostin level was significantly and positively correlated with phosphate and log of FGF23 levels in subgroups A, B, and combined A and B. Multiple linear regression analysis in the combined A and B subgroup revealed that male sex (t = 3.24, P = 0.01; 95% confidence interval [CI] 11.78 to 50.43) and phosphate level (t = 2.13, P = 0.04; 95% CI, 1.08 to 36.91) were independent factors for serum sclerostin level. The log of serum FGF23 level (t = 1.90, P = 0.06, 95% CI -1.85 to 63.50) appeared to be an important factor for serum sclerostin level. The frequency of patients using vitamin D treatment was not significantly different among subgroups A (93.1%), B (88.0%), C (85.2%), and D (90.5%). CONCLUSION: Serum sclerostin levels were associated with serum phosphate and FGF23 levels in patients with low iPTH levels. Further study is required to indicate whether these close associations are present in patients with spontaneously low iPTH levels without vitamin D treatment.

Oral administration of soluble guanylate cyclase agonists to rats results in osteoclastic bone resorption and remodeling with new bone formation in the appendicular and axial skeleton.

Orally administered small molecule agonists of soluble guanylate cyclase (sGC) induced increased numbers of osteoclasts, multifocal bone resorption, increased porosity, and new bone formation in the appendicular and axial skeleton of Sprague-Dawley rats. Similar histopathological bone changes were observed in both young (7- to 9-week-old) and aged (42- to 46-week-old) rats when dosed by oral gavage with 3 different heme-dependent sGC agonist (sGCa) compounds or 1 structurally distinct heme-independent sGCa compound. In a 7-day time course study in 7- to 9-week-old rats, bone changes were observed as early as 2 to 3 days following once daily compound administration. Bone changes were mostly reversed following a 14-day recovery period, with complete reversal after 35 days. The mechanism responsible for the bone changes was investigated in the thyroparathyroidectomized rat model that creates a low state of bone modeling and remodeling due to deprivation of thyroid hormone, calcitonin (CT), and parathyroid hormone (PTH). The sGCa compounds tested increased both bone resorption and formation, thereby increasing bone remodeling independent of calciotropic hormones PTH and CT. Based on these studies, we conclude that the bone changes in rats were likely caused by increased sGC activity.