Combined Effects of Vitamin D Status, Renal Function and Age on Serum Parathyroid Hormone Levels.

Background: Vitamin D status and renal function are well-known independent predictors of serum parathyroid hormone (PTH) levels. We aimed to describe the combined effects of 25-hydroxy vitamin D (25(OH)D), glomerular filtration rate (GFR) and age on serum PTH levels across the whole clinical spectrum. Methods: We retrieved from our endocrinology center database all PTH measurement between 2012 and 2020 for which a simultaneous measurement of serum 25(OH)D, calcium and creatinine was available. Age, sex and diagnosis were available for all subjects. Intact PTH was measured using the same electrochemiluminescence assay. Results: There were 6,444 adults and 701 children without a diagnosis of hyper- or hypoparathyroidism or abnormal serum calcium levels. In adults with 25(OH)D≥12 ng/mL multiple regression models showed that serum PTH was negatively correlated with both 25(OH)D and GFR. Regression (-0.68 and -1.59 vs. -0.45 and -0.22 respectively), partial correlation (-0.16 and -0.35 vs. -0.12 and -0.10 respectively) and determination coefficients (0.14 vs. 0.031) were higher in CKD than in normal renal function. In subjects with 25(OH)D<12 ng/mL, GFR was the only significant predictor in those with CKD (ß-coefficient=-2.5, r=-0.55) and 25(OH)D was the only significant predictor in those with normal renal function (ß-coefficient=-2.05, r=-0.11). Increasing age was associated with higher PTH levels only in those with normal renal function and 25(OH)D≥12 ng/mL. Conclusions: We showed that declining vitamin D and renal function have additive effects on serum PTH in subjects without vitamin D deficiency. In vitamin D deficient subjects this dependency is stronger but is not additive anymore.

The Interplay Between the Renin-Angiotensin-Aldosterone System and Parathyroid Hormone.

The renin-angiotensin-aldosterone system (RAAS) is the regulatory system by which renin induces aldosterone production. Angiotensin II (Ang II) is the main effector substance of the RAAS. The RAAS regulates blood pressure and electrolyte balance by controlling blood volume and peripheral resistance. Excessive activation of the RAAS is an important factor in the onset of cardiovascular disease and the deterioration of this disease. The most common RAAS abnormality is primary aldosteronism (PA). Parathyroid hormone (PTH) is a peptide secreted by the main cells of the parathyroid gland, which promotes elevated blood calcium (Ca2+) levels and decreased blood phosphorus (Pi) levels. Excessive secretion of PTH can cause primary hyperparathyroidism (PHPT). Parathyroidism is highly prevalent in postmenopausal women and is often associated with secondary osteoporosis. PA and PHPT are common endocrine system diseases. However, studies have shown a link between the RAAS and PTH, indicating a positive relationship between them. In this review, we explore the complex bidirectional relationship between the RAAS and PTH. We also point out possible future treatment options for related diseases based on this relationship.

Normocalcemic Hyperparathyroidism: Study of its Prevalence and Natural History.

CONTEXT: Normocalcemic hyperparathyroidism (NPHPT) is characterized by persistently normal calcium levels and elevated parathyroid hormone (PTH) values, after excluding other causes of secondary hyperparathyroidism. The prevalence of the disease varies greatly and the data on the natural history of this disease are sparse and inconclusive. OBJECTIVES: The objectives of this study are to describe the prevalence of NPHPT and its natural history in a referral population and to compare the variability of serum calcium with a group of patients with primary hyperparathyroidism (PHPT). DESIGN: A retrospective study was conducted over 5 years. SETTING: The setting for this study was a metabolic bone referral center. PATIENTS: A total of 6280 patients were referred for a bone mineral density measurement (BMD). MAIN OUTCOME MEASURES: The prevalence and natural history of NPHPT and variability of calcium were the main outcome measures. RESULTS: We identified NPHPT patients using data from the day of the BMD measurement. We excluded patients with low estimated glomerular filtration rate (eGFR) or vitamin D, or with no measurements available. Based on the evaluation of their medical files, we identified 11 patients with NPHPT (prevalence 0.18%). Only 4 patients had consistent normocalcemia throughout their follow-up, with only 2 also having consistently high PTH. None had consistently normal eGFR or vitamin D.Intermittent hypercalcemia was present in 7 of the 11 NPHPT patients. The mean adjusted calcium was found to be significantly lower in the NPHPT group compared with the PHPT group but higher than the control group. PTH was similar for NPHPT and PHPT. These 2 groups had similar variability in serum calcium. CONCLUSIONS: NPHPT patients often have episodes of hypercalcemia. We believe that NPHPT is a mild form of PHPT.

Comparison of Pre- and Post-transplant Parathyroidectomy in Renal Transplant Recipients and the Impact of Parathyroidectomy Timing on Calcium Metabolism and Renal Allograft Function: A Retrospective Single-Center Analysis.

BACKGROUND: The effect of parathyroidectomy (PTx) timing on serum calcium (Ca) levels and renal functions in renal transplant recipients with severe hyperparathyroidism (HPT) remains unclear. We retrospectively aimed to investigate and compare the clinical data of patients who underwent pre- and post-transplant PTx and elucidated the impact of PTx timing on serum Ca levels and renal graft outcomes after renal transplantation (RTx). METHODS: During January 2000-December 2016, 53 and 55 patients underwent post-transplant PTx (Post-RTx group) and pretransplant PTx (Pre-RTx group), respectively. The serum Ca levels and estimated glomerular filtration rate (eGFR) were assessed in both groups. RESULTS: At the end of the follow-up, the serum Ca levels were significantly higher and the incidence of hypocalcemia was significantly lower in the Pre-RTx group than in the Post-RTx group [9.5 vs. 8.9 mg/dL, P < 0.001; 14.5% vs. 34.0%, P = 0.024]. The decrease in the eGFR 12-36 months after RTx was more significant in the Post-RTx group than in the Pre-RTx group (-13.8% vs. -0.9%; P = 0.001). A logistic regression involving age, sex, dialysis period, and serum parathormone level revealed that post-transplant PTx is an independent risk factor for persistent hypocalcemia at the end of the follow-up (P = 0.034) and for a >20% decrease in the eGFR 12-36 months after RTx (P = 0.029). CONCLUSIONS: In renal transplant candidates with severe HPT, pretransplant PTx should be considered to prevent persistent hypocalcemia and deterioration of the renal graft function.

Pregnant Patient on Hemodialysis Who Showed Remarkable Improvement of Severe Hyperparathyroidism by Strict Serum Phosphorus Control.

We encountered a pregnant hemodialysis patient with severe hyperparathyroidism (HPT). Although her disease was considered to be refractory to medical treatment, the serum intact parathyroid hormone (PTH) level remarkably improved without manifestation of hypercalcemia through only strict serum phosphorus control, mainly via intensification of dialysis. The very strong correlation between the serum phosphorus level and serum intact PTH level suggested the possibility of secondary HPT. She ultimately gave birth to a healthy baby. The clinical course of the patient's HPT and the growth of the child have been good for more than six years.

Musculoskeletal manifestations in end-stage renal disease patients on hemodialysis and relation to parathyroid dysfunction.

End-stage renal disease (ESRD) is associated with chronic kidney disease-mineral and bone disorder (CKD-MBD); including renal osteodystrophy, and biochemical changes reflecting mineral and hormonal abnormalities. CKD-MBD can lead to serious musculoskeletal manifestations with an impact on the functional status of patients. The objective is to find the frequency of the musculoskeletal manifestations in dialysis patients, to determine the impact on the functional ability of patients, and to detect the relation between parathyroid hormone (PTH) level and musculoskeletal manifestations. The sample size included 53 adult patients on hemodialysis (HD), three times weekly, divided into two groups as follows; (Group A) included 15 patients (10 males and 5 females) on HD for a year or <1 year and (Group B) included 38 patients (24 males and 14 females) on HD for >1 year. All patients were subjected to a full history and physical examination plus a comprehensive assessment of patient's disability was done with a health assessment questionnaire (HAQ)-disability index. The most common neurological manifestations are uremic polyneuropathy (43.4%) and carpal tunnel syndrome. Arthralgia is the most common musculoskeletal manifestation (83%).The most common radiological signs of SHPT is the subperiosteal resorption of the terminal phalanges (67.9%). The most common MSUS abnormalities are Achilles tendinopathy (67.9%). Osteoporosis is detected in 24.5% of patient. There are highly positive significant correlations between HAQ score and age, HD duration, serum PTH, T-score, and X-ray findings. Musculoskeletal system involvement remains a common problem which decreases the physical function of patients with ESRD.

Perioperative hyperkalemia in hemodialysis patients undergoing parathyroidectomy for renal hyperparathyroidism.

The present study investigates the incidence of perioperative hyperkalemia and the influence factors of serum potassium levels during and after parathyroidectomy (PTX) in hemodialysis patients with renal hyperparathyroidism (rHPT). A total of 204 hemodialysis patients with refractory rHPT undergoing successful total parathyroidectomy with autotransplantation (tPTX + AT) were analyzed retrospectively. Hyperkalemia was defined as serum potassium levels ≥ 5.5 mmol/L. The preoperative baseline level of serum potassium (K base+ ) was defined as a mean of the three preoperative prehemodialysis serum potassium levels. The higher levels of serum potassium during and immediately after surgery were recorded as K d0+ and the peak prehemodialysis serum potassium levels 3 days after surgery as K d3+ . 136/204 (66.7%) patients suffered from hyperkalemia during or immediately after surgery and 65/204 (31.9%) patients were affected with prehemodialysis hyperkalemia 3 days after surgery. K base+ was the only influencing factor for K d0+ . Serum K base+ , preoperative serum alkaline phosphatase, and total calcium supplement dosage during intravenous calcium supplement were the influencing factors for K d3+ . In the case of PTX, the serum potassium levels of patients with higher serum K base+ and severe postoperative hypocalcemia need to be monitored with extended attention perioperatively.

Protocol driven outcomes in renal parathyroid surgery.

BACKGROUND: Patients who require surgery for renal hyperparathyroidism represent a special population that is at high risk for postoperative complications. To optimize their treatment, we developed a multidisciplinary approach to the perioperative management of these patients undergoing parathyroidectomy. METHODS: The Augusta University endocrine surgery parathyroid database was interrogated to identify dialysis-dependent patients undergoing parathyroidectomy from 2005 to 2015. Numerous clinical parameters were quantified. Patients were stratified into protocol patients and nonprotocol patients. RESULTS: A total of 42 patients undergoing renal parathyroidectomy who met the inclusion criteria were identified. Serious adverse events were nearly twice as common in the patients not treated on protocol. The length of stay was nearly 2 days shorter in the protocol group. Lowest calcium level and ionized calcium was higher in the protocol cohort despite a lower postoperative parathyroid hormone. The protocol group had fewer laboratory draws. CONCLUSION: Implementation of a multidisciplinary renal hyperparathyroidism protocol has resulted in improved perioperative outcomes.

Inherited Deletion of 1q, Hyperparathyroidism and Signs of Y-chromosomal Influence in a Patient with Turner Syndrome

We report a detailed phenotypic, cytogenetic and molecular characterization of a patient prenatally diagnosed with Turner syndrome (TS). In addition to having typical TS clinical characteristics including webbed neck, high arched palate and coarctation of the aorta, the patient had features less frequently seen in TS. These included recurrent parathyroid adenomas, growth along the 75th-90th centiles on the TS height curve despite minimal treatment with growth hormone, behavioral problems and evidence of gonadal dysgenesis with testicular-like structures, such as seminiferous tubules lined by Sertoli cells and a contiguous nodule of Leydig cells. While fluorescence in situ hybridization (FISH) failed to detect Y-chromosome material in gonadal tissue or blood samples, chromosomal microarray analysis (CMA) confirmed X monosomy and a 4.69 Mb copy number loss on 1q31.2q31.3 (bp 192,715,814 to 197,401,180). This region contains the CDC73 gene which has been associated with hyperparathyroidism-jaw tumor syndrome, features of which include recurrent, functional parathyroid adenomas and behavioral issues. This case illustrates how atypical features in a TS patient, such as robust growth and recurrent parathyroid adenomas, may suggest an underlying molecular etiology that should be explored by additional genetic diagnostic modalities. It is therefore appropriate in such cases to conduct further genetic testing, such as CMA and FISH, to explore other diagnostic possibilities and possibly prevent further complications.

The efficacy of fluorine-18-choline PET/CT in comparison with 99mTc-MIBI SPECT/CT in the localization of a hyperfunctioning parathyroid gland in primary hyperparathyroidism.

AIM: The aim of this study was to determine the role of fluorine-18-choline (F-FCH) PET/CT in comparison with technetium-99m-methoxyisobutylisonitrile (Tc-MIBI) single-photon emission computed tomography/computed tomography (SPECT/CT) in primary hyperparathyroidism and to investigate whether maximum standardized uptake value (SUVmax) may be indicative of disease severity. PATIENTS AND METHODS: Thirty-five primary hyperparathyroidism patients (24 females, 11 males, mean age: 55.31±12.27, range: 25-72 years) who underwent Tc-MIBI SPECT/CT and F-FCH PET/CT and had inconclusive neck ultrasonography (USG) were studied. The diagnostic power of both modalities and the relationship between SUVmax and biochemical [serum parathormone (PTH), calcium, phosphorus, vitamin D3 levels, urinary calcium excretion/24 h] and clinical (bone mineral densitometry and urinary USG results) parameters were analyzed. RESULTS: In 29 of 35 patients, Tc-MIBI SPECT/CT and F-FCH were concordant (κ=0.64, P=0.001). In five of 35 patients with a negative SPECT/CT, F-FCH PET/CT accurately localized parathyroid adenomas. In one patient, F-FCH was false negative and Tc-MIBI SPECT/CT showed the lesion. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of Tc-MIBI SPECT/CT and F-FCH PET/CT were calculated to be 78, 100, 100, 70, 86%, and 96, 100, 100, 93, and 97%, respectively. SUVmax was correlated with lumbal T scores (P=0.026). The mean serum PTH levels were significantly higher (P=0.026) and lumbal and femur T scores were significantly lower (P=0.04 and 0.008) in patients with SUVmax greater than 4.4 (i.e. the mean SUVmax calculated in positive cases). CONCLUSION: F-FCH PET/CT has a high diagnostic power in primary hyperparathyroidism and can be used for further evaluation of patients with inconclusive neck USG and Tc-MIBI SPECT/CT. SUVmax of the hyperfunctioning parathyroid gland seems to be predictive of disease severity in terms of serum PTH and bone mineral densitometry results. Studies with larger patient groups are needed to support these data.

The effect of vitamin D3 supplementation on markers of cardiovascular health in hyperparathyroid, vitamin D insufficient women: a randomized placebo-controlled trial.

PURPOSE: Emerging data supports an association between parathyroid hormone (PTH) and aldosterone. It has been speculated, that potential adverse cardiovascular effects of vitamin D insufficiency may partly be caused by the development of secondary hyperparathyroidism with increased activity of the renin-angiotensin-aldosterone system (RAAS). We aimed to investigate the effect of normalizing vitamin D status and/or reducing PTH levels on RAAS activity and other markers of cardiovascular health. METHODS: In a double-blinded study during wintertime, we randomized 81 healthy postmenopausal women with secondary hyperparathyroidism (PTH > 6.9 pmol/l) and 25-hydroxy-vitamin D (25(OH)D) levels < 50 nmol/l to 12 weeks of treatment with vitamin D3 70 µg/day (2800 IU/day) or identical placebo. Markers of cardiovascular health were defined as changes in the plasma RAAS, glycated hemoglobin, lipids, and lipoproteins, blood pressure, vascular stiffness, heart rate, and cardiac conductivity. RESULTS: Compared to placebo, vitamin D3 treatment significantly increased plasma levels of 25(OH)D and 1,25(OH)2D by 230% (95% CI: 189-272%) and 58% (190-271%), respectively. Vitamin D3 treatment reduced PTH by 17% (11-23%), but did not reduce RAAS activity. Compared to placebo, vitamin D3 treatment increased plasma levels of high-density lipoproteins (HDL) by 4.6% (0.12-9.12%), but did not affect other measured indices. CONCLUSIONS: Vitamin D3 supplementation normalized vitamin D levels and reduced PTH. The supplement increased levels of HDL, but had no effects on RAAS activity or other indices of cardiovascular health.

Relationship between bone turnover and left ventricular function in primary hyperparathyroidism: The EPATH trial.

Observational studies suggested a link between bone disease and left ventricular (LV) dysfunction that may be pronounced in hyperparathyroid conditions. We therefore aimed to test the hypothesis that circulating markers of bone turnover correlate with LV function in a cohort of patients with primary hyperparathyroidism (pHPT). Cross-sectional data of 155 subjects with pHPT were analyzed who participated in the "Eplerenone in Primary Hyperparathyroidism" (EPATH) Trial. Multivariate linear regression analyses with LV ejection fraction (LVEF, systolic function) or peak early transmitral filling velocity (e', diastolic function) as dependent variables and N-terminal propeptide of procollagen type 1 (P1NP), osteocalcin (OC), bone-specific alkaline phosphatase (BALP), or beta-crosslaps (CTX) as the respective independent variable were performed. Analyses were additionally adjusted for plasma parathyroid hormone, plasma calcium, age, sex, HbA1c, body mass index, mean 24-hours systolic blood pressure, smoking status, estimated glomerular filtration rate, antihypertensive treatment, osteoporosis treatment, 25-hydroxy vitamin D and N-terminal pro-brain B-type natriuretic peptide. Independent relationships were observed between P1NP and LVEF (adjusted ß-coefficient = 0.201, P = 0.035) and e' (ß = 0.188, P = 0.042), respectively. OC (ß = 0.192, P = 0.039) and BALP (ß = 0.198, P = 0.030) were each independently related with e'. CTX showed no correlations with LVEF or e'. In conclusion, high bone formation markers were independently and paradoxically related with better LV diastolic and, partly, better systolic function, in the setting of pHPT. Potentially cardio-protective properties of stimulated bone formation in the context of hyperparathyroidism should be explored in future studies.

Diseases associated with calcium-sensing receptor.

The calcium-sensing receptor (CaSR) plays a pivotal role in systemic calcium metabolism by regulating parathyroid hormone secretion and urinary calcium excretion. The diseases caused by an abnormality of the CaSR are genetically determined or are more rarely acquired. The genetic diseases consist of hyper- or hypocalcemia disorders. Hypercalcaemia disorders are related to inactivating mutations of the CASR gene either heterozygous (autosomal dominant familial benign hypercalcaemia, still named hypocalciuric hypercalcaemia syndrome type 1) or homozygous (severe neonatal hyperparathyroidism). The A986S, R990G and Q1011E variants of the CASR gene are associated with higher serum calcium levels than in the general population, hypercalciuria being also associated with the R990G variant. The differential diagnosis consists in the hypocalciuric hypercalcaemia syndrome, types 2 (involving GNA11 gene) and 3 (involving AP2S1 gene); hyperparathyroidism; abnormalities of vitamin D metabolism, involving CYP24A1 and SLC34A1 genes; and reduced GFR. Hypocalcemia disorders, which are more rare, are related to heterozygous activating mutations of the CASR gene (type 1), consisting of autosomal dominant hypocalcemia disorders, sometimes with a presentation of pseudo-Bartter's syndrome. The differential diagnosis consists of the hypercalciuric hypocalcaemia syndrome type 2, involving GNA11 gene and other hypoparathyroidism aetiologies. The acquired diseases are related to the presence of anti-CaSR antibodies, which can cause hyper- or especially hypocalcemia disorders (for instance in APECED syndromes), determined by their functionality. Finally, the role of CaSR in digestive, respiratory, cardiovascular and neoplastic diseases is gradually coming to light, providing new therapeutic possibilities. Two types of CaSR modulators are known: CaSR agonists (or activators, still named calcimimetics) and calcilytic antagonists (or inhibitors of the CasR). CaSR agonists, such as cinacalcet, are indicated in secondary and primary hyperparathyroidism. Calcilytics have no efficacy in osteoporosis, but could be useful in the treatment of hypercalciuric hypocalcaemia syndromes.

MicroRNAs in parathyroid physiopathology.

Parathyroid glands regulate calcium homeostasis through synthesis and secretion of parathormone (PTH). They sense the extracellular calcium concentration through the G-protein coupled calcium sensing receptor (CASR) and release PTH in order to preserve calcium concentration in the physiological range. Tumors of the parathyroid glands are common endocrine neoplasia associated with primary or secondary/tertiary hyperparathyroidisms. Small non-coding RNAs are regulators of gene expression able to modulate hormone synthesis, hormone release and endocrine cell proliferation. In this scenario, microRNA (miRNA) expression profiles have been investigated in parathyroid tumors, while miRNAs are involved in hypocalcemia and uremia-induced PTH release from normal parathyroid cells. Here we reviewed data about the role of miRNAs in the regulation of: 1) PTH synthesis and secretion; 2) CASR expression; 3) parathyroid cell tumorigenesis. Though studies about miRNAs in parathyroid gland pathophysiology are limited, they contribute in elucidating regulatory pathways involved in PTH release and parathyroid cell tumorigenesis.

Hyperparathyroidism and increased fractional excretion of phosphate predict allograft loss in long-term kidney transplant recipients.

BACKGROUND: After kidney transplantation, fibroblast growth factor-23 (FGF-23) normally returns to baseline within 1 year whereas hyperparathyroidism persists in most kidney transplant (KT) recipients. As a result, serum phosphate remains relatively low in association with increased serum calcium and urinary phosphate excretion when compared to chronic kidney disease patients. The relationship between mineral metabolism and outcomes in long-term KT recipients has not been extensively studied. This study investigated whether the alteration in mineral metabolism influenced graft survival in long-term KT recipients. METHODS: This study included 273 KT recipients after 1 year of transplantation. Mineral parameters were obtained at the time of enrolment and patients were followed prospectively for an average of 71 months. RESULTS: Graft loss (death-censored) occurred in 41 (15%) patients. In univariate analysis, deceased donor transplantation, decreased serum albumin and estimated glomerular filtration rate, increased serum phosphate, parathyroid hormone (PTH), FGF-23 and fractional excretion of phosphate (FePi) predicted future allograft loss. After adjustments for cardiovascular disease risk factors, donor type, dialysis vintage, serum albumin and allograft function, only increased PTH and FePi remained associated with the outcome. Relationships between increased serum phosphate and FGF-23 with graft survival were lost after adjustments. Adjusted survival curves revealed the association between PTH > 90 pg/mL and FePi > 20% with worse graft survival. CONCLUSIONS: Hyperparathyroidism and increased FePi predicted allograft loss in long-term KT recipients.

Rara localización de tumor pardo en paciente pediátrico / Rare brown tumor location in chronic renal failure

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