Suppressed Parathyroid Hormone Levels Research Articles

Paraneoplastic Hypercalcaemia as a Cause of Unexplained Renal Impairment in a Patient With Seminoma: A Case Report

A 44-year-old otherwise healthy male who had undergone left high inguinal orchidectomy, with histopathology suggestive of classical seminoma, was referred to the authors’ oncology centre for evaluation of persistently deranged renal function tests and initiation of chemotherapy. They had a large retroperitoneal mass encasing their left kidney and their creatinine was 4.2 mg/dL. Even 1 week after double J stenting, they had persistently elevated creatinine of 3.1 mg/dL, which was precluding their curative chemotherapy with bleomycin/cisplatin/etoposide regimen. In a desperate situation, to prevent further progression of disease, pre-phase chemotherapy with carboplatin and etoposide was considered. In anticipation of tumour lysis syndrome, considering the large mass and compromised renal function, a tumour lysis profile was requested, which revealed elevated serum calcium levels (15.4 mg/dL, which goes against the tumour lysis syndrome). Considering the large retroperitoneal lymph nodal mass, suppressed parathyroid hormone levels (4.1 pg/mL) and vitamin D3 being within normal range, a paraneoplastic cause of hypercalcaemia was considered. Correction of hypercalcaemia with medical measures as well as treatment of seminoma was instituted, which led to normalisation of renal function tests within the next 10 days. Here, the authors report a rare case of testicular seminoma with persistently deranged renal function, likely due to paraneoplastic hypercalcaemia, which improved after successful chemotherapy along with anti-hypercalcaemic measures, including aggressive hydration, diuretics, calcitonin, dexamethasone, and denosumab. This report shows that it is important to treat the cause along with medical management in this oncologic metabolic emergency. It also highlights the value of pre-phase chemotherapy with carboplatin and etoposide in the setting of acute renal impairment.

A Therapeutic Approach to Primary Hyperparathyroidism: A Collaborative Evaluation Between Endocrinology and Surgery.

Introduction Primary hyperparathyroidism (PHPT) is a disorder in which one or more parathyroid glands overproduce parathyroid hormone, leading to hypercalcemia. It may present with symptoms likeconstipation, abdominal pain, psychiatric complaints as well as signs of nephrolithiasis, and osteoporosis that may need surgical treatment. PHPT is often underdiagnosed and undertreated. Our study aimed to review hypercalcemia in a single center to evaluate forundiagnosed PHPT. Methods A group of 546 patients from Southwest Virginia was selected using the EMR Epic (Epic Systems, Verona, USA)who had adiagnosis of hypercalcemia in the previous six months.Charts were manually reviewed, and patients were excluded based on the lack of hypercalcemia as well as previous testing of parathyroid hormone (PTH) levels. One hundred and fifty patients were excluded because of a lack of documented hypercalcemia. Letters were sent to the patients advising the patients to discuss whether a PTH would be indicated with their primary care provider (PCP). These patients' charts were re-examined six months later and a determination of whether a PTH level was performed as well as any referrals explicitly for hypercalcemia or PHPT was done. Results A total of 20 (5.1%) patients had a new PTH test during the time assessed. Of these patients, five received referrals to surgical treatment and six received referrals to endocrinology for treatment (no patients received referrals to both). Of those who obtained a PTH level, 50% of them had significantly elevated PTH levels consistent with the diagnosis of primary hyperparathyroidism. An additional 45% had levels of parathyroid hormone that were in the normal range but or most likely inappropriately normal for the concurrent level of calcium. Only one patient (5%) had a suppressed PTH level. Conclusion The impact of an intervention on clinician evaluation and treatment of patients with hypercalcemia has been previously tested and shown to be beneficial. In this study, the method of directly sending a letter to patients yielded clinically significant results, with 20 patients out of 396 (5.1%) having a PTH level tested. A majority had an overt or suspected parathyroid disease, and out of them, 11 underwent referral for treatment.

LBODP020 Treatment Of Hypercalcemia Due To Prolonged, Excessive Vitamin D Intake

Abstract Case A 66-year-old man with history of anxiety, depression, and complex regional pain syndrome presented to a psychiatric hospital with suicidal ideation. Admission laboratory studies demonstrated hypercalcemia (Ca 14.2 mg/dL) with kidney injury (Cr 3.26). He endorsed taking 5 to 16 (average 8-9) tablets of 1000 IU Vitamin D daily for 10 years. He had heard about the health benefits of Vitamin D and believed it gave him a euphoric effect. Work-up demonstrated elevated ionized calcium (1.63 mmol/L), normal serum phosphorus (3.8 mg/dL), low total protein (6.24 g/dL), normal total albumin (3.42 g/dL), and negative serum protein electrophoresis. Intravenous hydration with normal saline at 200 cc/hr was initiated along with intravenous furosemide. Additional work up demonstrated a suppressed parathyroid hormone level (10pg/ml). 25-hydroxyvitamin D3 (25-(OH)D3) levels were elevated beyond the measurable range (> 155.9 pg/mL). The plasma 1α,25-dihydroxyvitamin D3 (1α,25 (OH)2D3) was normal at 44 pg/mL (range 18-64 pg/mL). With intravenous fluid administration, the patient's ionized calcium level decreased and his creatinine improved. However, 48 hours after the fluids were discontinued on hospital day 3, the ionized calcium and serum creatinine rose once again. Due to the long half-life of Vitamin D and the up-trending calcium levels, he received 60mg of intravenous Pamidronate on hospital day 8. On discharge on hospital day 11, his renal function was stable (Cr 2.24) with normal ionized calcium (1.27 mmol/L). His psychiatric symptoms had resolved. Discussion The two most common causes of hypercalcemia are primary hyperparathyroidism and malignancy. Less commonly, vitamin D-mediated hypercalcemia may result from ectopic 1,25-dihydroxyvitamin D production or excessive Vitamin D ingestion. The known upper limit of daily Vitamin D intake in an adult that will cause no adverse risk is 4000 IU per day. Vitamin D is a fat-soluble vitamin with a half-life of approximately 2 months. The liver converts Vitamin D3 to the metabolite 25-(OH)D3, which has a half-life of 15 days, and the kidney further metabolizes this to 1α,25 (OH)2D3, which has a half-life of 15 hours. Therefore, this patient's 25-(OH)D3 was expected to remain at toxic levels for an unknown time period, placing him at risk of prolonged hypercalcemia with further deterioration of his renal function. There is no standard of care established for patients with vitamin D toxicity. Pamidronate, normally contraindicated for GFR <30 mL/min, was administered after nephrology consultation. Information about vitamin D toxicity is primarily gleaned from case reports and series. This case report serves as a model for study of Vitamin D toxicity in humans for understanding the long-term management in patients with chronic vitamin D toxicosis presenting with renal failure. Presentation: No date and time listed

Abstract #1185030: Primary Hyperparathyroidism Corrected by Vitamin D supplementation: A Rare Presentation

Primary hyperparathyroidism (PHTP) is a common endocrine disorder characterized by high parathyroid hormone (PTH) and calcium levels, commonly detected incidentally. A common concurrent finding is vitamin D deficiency, with a reported incidence of as high 91%. Vitamin D administration in PHPT is controversial due to a risk of exacerbating hypercalcemia, though some studies have shown that this may in fact be beneficial by suppressing PTH levels and decreasing bone demineralization. We present an interesting case of a 45-year-old male presenting with asymptomatic PHPT which was successfully managed solely with vitamin D administration.

Childhood Hypercalciuric Hypercalcemia With Elevated Vitamin D and Suppressed Parathyroid Hormone: Long-Term Follow Up.

Purpose: Hypercalcemia with low parathyroid hormone (PTH) level, hypercalciuria, nephrocalcinosis, or nephrolithiasis, was recently reported as caused by mutations in CYP24A1 and SLC34A genes. These encode for vitamin D-24A-hydroxylase and for the renal phosphate transporters NaPiIIa and NaPiIIc, respectively. We aimed to describe the clinical course of these monogenic disorders in patients with and without found mutations during long-term follow-up.Methods: Ten patients with hypercalcemia, hypercalciuria, elevated 1,25-(OH)2D levels and suppressed PTH were followed in our center during 1998–2019. Relevant laboratory and imaging data and results of genetic evaluation were retrieved from medical files.Results: The median age at presentation was 9.5 months (range 1 month−11 years), six were males, and the median follow-up time was 3.8 (1.1–14) years. Mutations in CYP24A1 and SLC34A3 were identified in three and one patients, respectively. Five patients presented with nephrocalcinosis, three with nephrolithiasis, and two had normal renal ultrasound. High blood calcium and 1,25-(OH)2D levels at presentation decreased during follow-up [11.1 ± 1 vs. 9.9 ± 0.5 mg/dl (p = 0.012), and 307 ± 130 vs. 209 ± 65 pmol/l (p = 0.03), respectively]; this paralleled an increase in suppressed PTH levels (5.8 ± 0.9 vs. 11.8 ± 7.3 pg/ml, p = 0.2). Substantial improvements in hypercalciuria and renal sonography findings were not observed. Two patients had impaired renal function (eGFR 84–88 ml/min/1/73 m2) at the last follow up. Interventions included appropriate diet, citrate supplementation, and thiazides.Conclusion: Despite improvement in hypercalcemia and 1,25-(OH)2D levels, not all the patients showed improvements in hypercalciuria and nephrocalcinosis. Deterioration of renal function was also observed. Long-term follow up and intervention to prevent nephrocalcinosis and nephrolithiasis are recommended in these children.

MON-908 Carcinoid Causing Catastrophic Calcemia

Intro: Carcinoid tumors are rare, slow growing, indolent neuroendocrine tumors typically originating from enterochromaffin in the gastrointestinal tract and bronchopulmonary tree1. While often found to be secreting serotonin, many different secretory products have been described2. We present the case of a patient with refractory hypercalcemia due to a carcinoid tumor producing parathyroid hormone related peptide (PTHrP). Case: A 65-year-old male was found to have hypercalcemia of 14.7 mg/dL after presenting for nausea and vomiting. He was treated with Zolendronic acid and intravenous (IV) fluids as initial work-up revealed an appropriately suppressed parathyroid hormone level, no monoclonal spike, and a PTHrP that was dramatically elevated. He refused further work-up initially but was admitted two months later for persistent severe hypercalcemia. Computed tomography imaging showed innumerable liver lesions. Histologic analysis of the largest liver lesion was consistent with carcinoid tumor. For the next two years, he was managed outpatient with Pamidronate, Denosumab, and Sandostatin, along with two liver embolizations. Control of serum calcium levels became more difficult and he had multiple hospitalizations for symptomatic hypercalcemia until chemotherapy, Sunitinib, was initiated. Calcium levels normalized for one year after starting Sunitinib prior to onset of suspected medication-induced pancreatitis. He was switched to Everolimus but did not respond to that and was readmitted mere weeks later for symptomatic hypercalcemia and a combination of Folinic acid, Fluorouracil, and Oxaliplatin (Folfox) was started. He continued to get frequent bisphosphonates and IV fluids along with Folfox but several months later he stopped responding to all medical options. His calcium level climbed to 19.9mg/dL and he underwent a technically complicated surgical procedure in which significant tumor burden was removed from his liver. Since surgery, the patient has remained normocalcemic without additional medical therapy. Discussion: Carcinoid tumors are uncommon with reported incidence of 40 per one million people2. PTHrP is most commonly produced by squamous cell lung cancer, renal cell cancer, gynecologic cancers, and lymphoma3. Carcinoid tumors producing PTHrP with resultant hypercalcemia is rare with a few cases reported in literature4. Our patient had a complex treatment course including IV fluids, anti-resorptive agents, somatostatin analogs, liver embolization, chemotherapeutic agents, and eventual surgical debulking. Surgical intervention is not commonly required for carcinoid tumors5. This patient had a rare tumor, producing an uncommon hormone, and required extensive treatment. This case shows the importance of a multidisciplinary approach in patients with hypercalcemia secondary to carcinoid tumors but refractory to traditional therapy.

Obesity and efficacy of vitamin D3 supplementation in healthy black adults.

Results from recent clinical trials suggest that vitamin D efficacy against cancermay be influenced by body mass index. As suppression of parathyroid hormone (PTH) is one indicator of vitamin D efficacy, we examined to what extent doses of vitamin D3 supplementation suppress PTH levels in individuals with and without obesity. A total of 328 healthy African Americans were randomized into the following four groups and treated for 3months: placebo, 1,000, 2,000, or 4,000IU/day of vitamin D3 supplementation. Among the participants, 250 individuals with PTH measurements were included in the analysis. Obese individuals (n = 141) experienced a steep reduction of 3-month PTH from placebo to 1,000IU/day of vitamin D3 supplementation, but no further reduction at 2,000 or 4,000IU/day. For non-obese individuals (n = 109), the reduction of 3-month PTH was approximately linear for increasing vitamin D3 doses. At supplementation of 2,000 to 4,000IU/day, 3-month 25(OH)vitamin D levels were high in both non-obese and obese individuals, but the 3-month PTH levels remained about 10pg/mL higher in individuals with obesity. Our findings suggest that excess adiposity confers resistance to vitamin D efficacy in suppressing PTH levels, even when given at high doses.

The potential effect of vitamin D against bone loss and vascular calcification in ovariectomized rats: possible association with serum nitric oxide.

Many epidemiological studies have shown an association between osteoporosis and peripheral vascular disease in postmenopausal women. This work was provided to investigate the possible effect of vitamin D against postmenopausal bone loss and vascular calcification in adult rats. This study was carried on 24 Sprague Dawley female rats. Rats were divided into four main groups (6 rats for each group). Group I : control sham-operated rats. Group II : sham operated rats treated with vitamin D . Group III : control ovariectomized (OVX) rats. Group IV : OVX rats treated with vitamin D. Ovariectomized rats were injected intraperitoneal with active vitamin D (calcitriol) 3 times a week for one month in the form of 0.04 μg/kg calcitriol. Serum level of estradiol, calcium, phosphorus and osteoblastic markers (alkaline phosphatase and osteocalcin) were measured. Serum levels of lipid profile, parathormone and nitric oxide were also evaluated. The bone and the aortic wall were prepared for histopathological study. In comparisons to the ovariectomized rats, active vitamin D caused significant attenuation of the bone loss, biomechanical fragility and delayed the onset of vascular calcification in the aortic wall. Also it improved the lipid profile, serum nitric oxide levels and suppressed parathyroid hormone level. This work suggests that the administration of vitamin D has a beneficial effect on the bone quality and also on delaying the onset of aortic vascular calcification in ovariectomized rats. And suggests a possible association with serum nitric oxide.

Etelcalcetide in Patients on Hemodialysis with Severe Secondary Hyperparathyroidism. Multicenter Study in "Real Life".

Etelcalcetide is a new calcimimetic indicated for the treatment of secondary hyperparathyroidism (SHPT) in dialysis patients. Etelcalcetide efficacy in SHPT has been ascertained only in randomized controlled trials. This multicenter study was carried out in “real world” setting that is different from randomized controlled trials (RCTs) to (1) evaluate the effectiveness of etelcalcetide in SHPT, (2) to assess calcium, phosphorus, alkaline phosphatase changes, (3) to register gastrointestinal side effects. Data were collected from twenty-three dialysis units with n = 1190 patients on the charge. From this cohort, n = 168 (14%) patients were on treatment with etelcalcetide, and they were evaluated for statistics. A median weekly dose of etelcalcetide was 15 mg (7.5–45 mg). Patients were either naïve (33%) or switched from cinacalcet to obtain better control of SHPT with reduced side effects or pills burden. Serum parathyroid hormone (PTH) declined over time from a median value of 636 pg/mL to 357 pg/mL. The median time for responders (intact PTH (iPTH) range: two to nine times the upper normal limit) was 53 days; the percentage of responders increased (from baseline 27% to 63%) being similar in switched-patients and naïve-patients. Few patients had symptomatic hypocalcemia requiring etelcalcetide withdrawal (four cases (3%) at 30-day control, two cases (2%) at 60-day, one case (1%) at 90-day control). Side effects with etelcalcetide were lower (3–4%) than that registered during cinacalcet treatment (53%). Etelcalcetide is a new therapeutic option for SHPT with low side effects and pills burden. Etelcalcetide may improve adherence to therapy, avoiding unremitting SHP. It remains to be assessed whether etelcalcetide may reduce parathyroidectomy, vascular calcification, or mortality. Being etelcalcetide very potent in suppressing PTH levels, even in severe SHPT, future studies should evaluate the potential risk of more adynamic bone disease during long-term therapy.

CYP24A1 and SLC34A1 genetic defects associated with idiopathic infantile hypercalcemia: from genotype to phenotype.

Loss of function mutations in the CYP24A1 gene, involved in vitamin D catabolism and in calcium homeostasis, are known to be the genetic drivers of both idiopathic infantile hypercalcemia (IIH) and adult renal stone disease. Recently, also defects in the SLC34A1 gene, encoding for the renal sodium-phosphate transporter NaPi-IIa, were associated with the disease. IIH typically affects infants and pediatric patients with a syndrome characterized by severe hypercalcemia, hypercalciuria, suppressed parathyroid hormone level and nephrolithiasis. In SLC34A1 mutated carriers, hypophosphatemia is also a typical biochemical tract. IIH may also persist undiagnosed into adulthood, causing an increased risk of nephrocalcinosis and renal complication. To note, a clinical heterogeneity characterizes IIH manifestation, principally due to the controversial gene-dose effect and, to the strong influence of environmental factors. The present review is aimed to provide an overview of the current molecular findings on the IIH disorder, giving a comprehensive description of the association between genotype and biochemical and clinical phenotype of the affected patients. We also underline that patients may benefit from genetic testing into a targeted diagnostic and therapeutic workflow.

Prenatal hyperechogenic kidneys in three cases of infantile hypercalcemia associated with SLC34A1 mutations

Prenatal diagnosis of hyperechogenic kidneys is associated with a wide range of etiologies and prognoses. The recent advances in fetal ultrasound associated with the development of next-generation sequencing for molecular analysis have enlarged the spectrum of etiologies, making antenatal diagnosis a very challenging discipline. Of the various known causes of hyperechogenic fetal kidneys, calcium and phosphate metabolism disorders represent a rare cause. An accurate diagnosis is crucial for providing appropriate genetic counseling and medical follow-up after birth. We report on three cases of fetal hyperechogenic kidneys corresponding to postnatal diagnosis of nephrocalcinosis. In all cases, antenatal ultrasound showed hyperechogenic kidneys of normal to large size from 22 gestational weeks, with a normal amount of amniotic fluid. Postnatal ultrasound follow-up showed nephrocalcinosis associated with hypercalcemia, hypercalciuria, elevated 1,25(OH)2-vitamin D, and suppressed parathyroid hormone levels. Molecular genetic analysis by next-generation sequencing performed after birth in the three newborns revealed biallelic pathogenic variants in the SLC34A1 gene, encoding the sodium/phosphate cotransporter type 2 (Npt2a), confirming the diagnosis of infantile hypercalcemia. Nephrocalcinosis due to infantile hypercalcemia can be a cause of fetal hyperechogenic kidneys, which suggests early antenatal anomaly of calcium and phosphate metabolism. This entity should be considered in differential diagnosis. Postnatal follow-up of infants with hyperechogenic kidneys should include evaluation of calcium and phosphate metabolism.

Methotrexate-Induced Lung Injury: A Rare Cause of Significant Hypercalcemia

SESSION TITLE: Drug-induced Lung Disease SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Prolonged methotrexate (MTX) use is known to carry risk of inflammatory and fibrotic lung disease. However, MTX-induced granulomatous pneumonitis with associated hypercalcemia is a very rare complication. CASE PRESENTATION: A 76-year-old Indian male with a past medical history of severe eczema on low-dose MTX for the past three years presented with worsening nonproductive cough, exertional dyspnea, and gastric reflux for one week. Pertinent medications included recent use of calcium carbonate for gastric reflux, and chronic hydrochlorothiazide (HCTZ) use for hypertension. He presented to an urgent care center, where he was found to be hypoxic with diffuse pulmonary infiltrates. Evaluation in the emergency department revealed normal vitals, excepting SpO2 94% on 2L nasal cannula. Physical exam was remarkable for rhonchi in bilateral upper lung fields. Initial labs showed a high corrected total serum calcium at 15.4 mg/dL. MTX and HCTZ were held, and aggressive IV normal saline with empiric ceftriaxone and azithromycin were administered. Additional labs revealed a low parathyroid hormone (PTH) at 4.8 pg/mL and high 1,25-OH2 vitamin D level at 164 pg/mL. Otherwise, phosphorus, PTH-related protein, 25-OH vitamin D, and angiotensin converting enzyme were unremarkable. Bronchoscopy showed mixed inflammatory cells with 90% mononuclear cells. All subsequent workup for atypical infections, plasma cell dyscrasias, neoplasm, and rheumatologic disorders were negative, thus a presumptive diagnosis of subacute MTX-induced pneumonitis was made on day seven of his admission. By this point, the serum calcium had normalized. To treat his lung injury, his antibiotics were discontinued and he was started on a prednisone taper for 2 weeks. At his three month follow-up with pulmonology he was asymptomatic, with normal spirometry and total resolution of his pulmonary infiltrates. DISCUSSION: Although calcium carbonate and HCTZ can lead to hypercalcemia, the extreme elevation here in conjunction with inappropriately elevated 1,25-OH2 vitamin D and suppressed PTH levels support the diagnosis of granulomatous disease. Per Cook et al., macrophages may autonomously produce extrarenal 1,25-OH2 vitamin D unresponsive to normal feedback mechanisms. Thus, along with discontinuation of MTX, glucocorticoid therapy may accelerate recovery from MTX-induced lung injury and reverse hypercalcemia. CONCLUSIONS: Although exceedingly rare, it is important to consider MTX-induced granulomatous injury as a primary cause of hypercalcemia. Reference #1: Jacobs, T, Bilezikian J. Rare Causes of Hypercalcemia. J Clin Endocrinol Metab. 2005;90(11): 6316-6322. Reference #2: Cook NJ, Lake FR. Hypercalcaemia with methotrexate pneumonitis, possible association with pulmonary granulomata. Aust N Z J Med. 1996 Oct;26(5):715. DISCLOSURE: The following authors have nothing to disclose: Prashant Patel, Matthew Siuba, Chris Jacob, Richard Roach No Product/Research Disclosure Information

Serum Parathyroid Hormone Responses to Vitamin D Supplementation in Overweight/Obese Adults: A Systematic Review and Meta-Analysis of Randomized Clinical Trials.

Obesity is often associated with vitamin D deficiency and secondary hyperparathyroidism. Vitamin D supplementation typically leads to the reductions in serum parathyroid hormone (PTH) levels, as shown in normal weight individuals. Meanwhile, the dose of vitamin D supplementation for the suppression of PTH may differ in overweight and obese adults. We conducted a systematic review and meta-analysis of randomized controlled trials to determine the dose of vitamin D supplementation required to suppress PTH levels in overweight/obese individuals. We identified 18 studies that examined overweight or obese healthy adults who were supplemented with varying doses of vitamin D3. The primary outcomes examined were changes in PTH and serum 25-hydroxyvitamin D (25OHD) levels from baseline to post-treatment. The results of the meta-analysis showed that there was a significant treatment effect of vitamin D supplementation on PTH, total standardized mean difference (SMD) (random effects) = −0.38 (95% CI = −0.56 to −0.20), t = −4.08, p < 0.001. A significant treatment effect of vitamin D supplementation was also found on 25OHD, total SMD (random effects) = 2.27 (95% CI = 1.48 to 3.06) t = 5.62, p < 0.001. Data from available clinical trials that supplemented adults with D3 ranging from 400 IU to 5714 IU, showed that 1000 IU of vitamin D supplementation best suppressed serum PTH levels, total SMD = −0.58, while vitamin D supplementation with 4000 IU showed the greatest increase in serum 25OH levels. Vitamin D and calcium supplementation of 700 IU and 500 mg, respectively, also showed a significant treatment effect on the suppression of PTH with a total SMD = −5.30 (95% CI = −9.72 to −0.88). In conclusion, the meta analysis of available clinical trials indicates that 1000 IU vitamin D supplementation can suppress serum PTH levels, while 4000 IU of vitamin D was associated with the largest increase in serum 25OHD levels in the overweight and obese population.

Vitamin D supplementation for 12 months in older people prevents bone loss and suppresses parathyroid hormone levels

Vitamin D supplementation for 12 months in older people prevents bone loss and suppresses parathyroid hormone levels

Vitamin D supplementation for 12 months in older people prevents bone loss and suppresses parathyroid hormone levels

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Life-Threatening Hypercalcemia due to Graves' Disease and Concomitant Adrenal Failure: A Case Report and Review of the Literature.

A 47-year-old woman presented with the complaints of nausea, vomiting, and weight loss. She had a history of bilateral surrenalectomy due to Cushing's syndrome. On examination she had tachycardia and orthostatic hypotension. Laboratory examinations revealed hypercalcemia and suppressed parathyroid hormone levels. She also had thyrotoxicosis due to Graves' disease. The investigations to rule out a malignancy were negative. With steroid, zoledronic acid, and antithyroid drug treatment her symptoms were resolved and calcium level was normalized. This case highlights the importance of recognizing thyrotoxicosis and concomitant adrenal failure as a possible cause of severe hypercalcemia.

Biased allosteric modulation at the CaS receptor engendered by structurally diverse calcimimetics.

Clinical use of cinacalcet in hyperparathyroidism is complicated by its tendency to induce hypocalcaemia, arising partly from activation of calcium-sensing receptors (CaS receptors) in the thyroid and stimulation of calcitonin release. CaS receptor allosteric modulators that selectively bias signalling towards pathways that mediate desired effects [e.g. parathyroid hormone (PTH) suppression] rather than those mediating undesirable effects (e.g. elevated serum calcitonin), may offer better therapies. We characterized the ligand-biased profile of novel calcimimetics in HEK293 cells stably expressing human CaS receptors, by monitoring intracellular calcium (Ca(2+) i ) mobilization, inositol phosphate (IP)1 accumulation, ERK1/2 phosphorylation (pERK1/2) and receptor expression. Phenylalkylamine calcimimetics were biased towards allosteric modulation of Ca(2+) i mobilization and IP1 accumulation. S,R-calcimimetic B was biased only towards IP1 accumulation. R,R-calcimimetic B and AC-265347 were biased towards IP1 accumulation and pERK1/2. Nor-calcimimetic B was unbiased. In contrast to phenylalkylamines and calcimimetic B analogues, AC-265347 did not promote trafficking of a loss-of-expression, naturally occurring, CaS receptor mutation (G(670) E). The ability of R,R-calcimimetic B and AC-265347 to bias signalling towards pERK1/2 and IP1 accumulation may explain their suppression of PTH levels in vivo at concentrations that have no effect on serum calcitonin levels. The demonstration that AC-265347 promotes CaS receptor receptor signalling, but not trafficking reveals a novel profile of ligand-biased modulation at CaS receptors The identification of allosteric modulators that bias CaS receptor signalling towards distinct intracellular pathways provides an opportunity to develop desirable biased signalling profiles in vivo for mediating selective physiological responses.

Vitamin D and bone health: Epidemiologic studies.

Allelic variation in the vitamin D receptor was the first non-structural gene to be associated with osteoporosis, and together with the effects of the vitamin D system on bone homeostasis, suggested that this vitamin might have a strong role in bone health. However, controversy exists regarding what level of serum 25-hydroxyvitamin D (25(OH)D) is optimal. Current data from biochemical, observational and randomized controlled trials (RCTs), indicate serum 25(OH)D levels of at least 50 nmol l(-1) are required for normalization of parathyroid hormone (PTH) levels, to minimize the risk of osteomalacia and for optimal bone cell function. The skeletal consequences of 25(OH)D insufficiency include secondary hyperparathyroidism, increased bone turnover and bone loss and an increased risk of minimal trauma fractures. In large scale epidemiological studies, serum 25(OH)D levels are associated with bone mineral density in both men and women. However, there is mixed evidence on the effectiveness of optimizing serum 25(OH)D levels for the prevention of bone loss and minimal trauma fractures in postmenopausal women and older men. There may be some benefit on primary fracture prevention for those who have inadequate serum levels of 25(OH)D, particularly in institutionalised elderly patients, but only when combined with calcium supplements. For optimal bone health, evidence from RCTs suggests vitamin D may be considered a threshold nutrient with few further bone benefits observed at levels of 25(OH)D above which PTH is normalized. An adequate calcium intake is also imperative to gain optimum benefit from an improved vitamin D status in those with insufficient 25(OH)D levels, with an increased calcium intake being associated with suppression of PTH levels.

Hypercalcemia Due to Giant Cell Myocarditis: A Case Report

Granulomatous diseases are a rare cause of hypercalcemia. The pathogenesis is presumed to be from endogenous production of 1,25-dihydroxyvitamin D by activated macrophages in granulomatous lesions, which harbor the 1α-hydroxylase enzyme. Herein the first case of hypercalcemia associated with giant cell myocarditis, an unusual type of granulomatous process, is reported. In this case, a patient with giant cell myocarditis had development of progressive heart failure and cardiorenal syndrome that required biventricular support. One year later, hypercalcemia associated with a relatively high 1,25-vitamin D level and a concomitantly suppressed parathyroid hormone level developed in the presence of stage 4 chronic kidney disease. Her other workup of hypercalcemia was unrevealing for vitamin D intoxication and multiple myeloma. Computed tomography of her chest showed no signs of hilar lymphadenopathy. Her calcium levels returned to normal with low-dose steroid therapy and have remained normal following a successful heart transplant. This case illustrates an unusual cause of hypercalcemia thought to be due to extrarenal calcitriol production associated with giant cell myocarditis.

Deletion of PTH Rescues Skeletal Abnormalities and High Osteopontin Levels in Klotho−/− Mice

Maintenance of normal mineral ion homeostasis is crucial for many biological activities, including proper mineralization of the skeleton. Parathyroid hormone (PTH), Klotho, and FGF23 have been shown to act as key regulators of serum calcium and phosphate homeostasis through a complex feedback mechanism. The phenotypes of Fgf23−/− and Klotho−/− (Kl−/−) mice are very similar and include hypercalcemia, hyperphosphatemia, hypervitaminosis D, suppressed PTH levels, and severe osteomalacia/osteoidosis. We recently reported that complete ablation of PTH from Fgf23−/− mice ameliorated the phenotype in Fgf23−/−/PTH−/− mice by suppressing serum vitamin D and calcium levels. The severe osteomalacia in Fgf23−/− mice, however, persisted, suggesting that a different mechanism is responsible for this mineralization defect. In the current study, we demonstrate that deletion of PTH from Kl−/− (Kl−/−/PTH−/− or DKO) mice corrects the abnormal skeletal phenotype. Bone turnover markers are restored to wild-type levels; and, more importantly, the skeletal mineralization defect is completely rescued in Kl−/−/PTH−/− mice. Interestingly, the correction of the osteomalacia is accompanied by a reduction in the high levels of osteopontin (Opn) in bone and serum. Such a reduction in Opn levels could not be observed in Fgf23−/−/PTH−/− mice, and these mice showed sustained osteomalacia. This significant in vivo finding is corroborated by in vitro studies using calvarial osteoblast cultures that show normalized Opn expression and rescued mineralization in Kl−/−/PTH−/− mice. Moreover, continuous PTH infusion of Kl−/− mice significantly increased Opn levels and osteoid volume, and decreased trabecular bone volume. In summary, our results demonstrate for the first time that PTH directly impacts the mineralization disorders and skeletal deformities of Kl−/−, but not of Fgf23−/− mice, possibly by regulating Opn expression. These are significant new perceptions into the role of PTH in skeletal and disease processes and suggest FGF23-independent interactions of PTH with Klotho.