High PTH Research Articles

Short and long-term effects of kidney donation on mineral and bone metabolism

BackgroundLiving kidney donors (LKD) experience an abrupt decline in glomerular filtration rate (GFR) resulting in abnormalities of mineral and bone metabolism (MBD), and this may have implications for skeletal health. We prospectively studied acute and long term MBD adaptation of LKD from two kidney transplant centers (São Paulo, Brazil and Miami, USA).MethodsRenal function and MBD parameters longitudinally after kidney donation (baseline – D0, day 1, 14, 180 and 360 post-operatively) were measured in 74 patients (40 y, 73% female, 54% Brazilian). A subset of 20 donors from Brazil were reassessed after 10 years of nephrectomy.ResultsAt baseline, Brazilian donors presented lower intact FGF23 (20.8 vs. 80.1 pg/mL, P < 0.01) and higher PTH (47.4 vs. 40.1, P = 0.04) than their US counterparts. GFR decreased to 63% of its baseline levels just after donation but improved 10% during the first year. PTH levels increased on D1, returning to baseline levels on D14, while FGF23 remained higher than baseline over the first year. LKD had a significant reduction of serum phosphate on D1, which returned to baseline levels on D180. A higher fractional excretion of phosphate (FEP) was noted since D14. After 10 years of donation, 20 LKD presented a sustained reduction in GFR (74.8 ± 14mL/min). There was a return to baseline in serum FGF23 [21.8 (18–30) pg/mL] and FEP, accompanied by an increase in serum calcium. PTH remained elevated (57.9 ± 18 pg/mL), whereas serum calcitriol and Klotho were lower than before the donation.ConclusionsThe abrupt decline in kidney mass is associated with an increase in PTH and FGF23 that is not explained by phosphate retention. In a long-term evaluation, LKD showed a sustained drop in GFR, with lower serum calcitriol and Klotho, and higher PTH. The effects of these changes should be investigated in further studies.

6408 Familial Hypoparathyroidism With Elevated Parathyroid Hormone Due To A PTH Mutation Responsive To Teriparatide

Abstract Disclosure: N. Mukhtar: None. B. Alghamdi: None. M. Alswailem: None. A.S. Alzahrani: None. Introduction: Apart from vitamin D disorders, causes of congenital hypocalcemia (HypoCa) include genetic defects causing familial hypoparathyroidism (FH), and defects in PTH receptor or its signalling pathway (PTH resistance). The former is typically characterized by low plasma PTH and the latter by elevated PTH levels. In this report, we describe a family with FH but with significant elevation of functionally inactive PTH due to a PTH mutation. We also show a positive therapeutic impact of recombinant human PTH (teriparatide) therapy on HypoCa in one of these siblings who was not well controlled on calcitriol and calcium replacement. Case description: The proband is a 34-year-old lady who has history of chronic HypoCa since birth with several admissions for severe HypoCa and recurrent seizures during childhood. She and her three brothers (a 32-year-old male twin and an 18-year-old male) were diagnosed to have Pseudohypoparathyroidism type 1b based on the presence of chronic HypoCa (serum Ca 1.6-1.85 mmol/l) since birth associated with significantly elevated plasma PTH levels in the range of 310-564 pg/dl (normal range 10-65) and absence of signs of Albright hereditary osteodystrophy. Laboratory workup of the proband recently showed: PTH 514 ng/L (NR 15-65) , calcium 1.81 mmol/l (NR 2.1-2.6), phosphate 1.67mmol/L (NR 0.8-1.4), magnesium 0.73 mmol/L (NR 0.7-1.0), albumin 38 g/L (NR 40-50), Alkaline phosphatase 56 U/L, eGFR &amp;gt;60 ml/min/1.73 m2, creatinine 78 umol/L and 25-hydroxyvitamin D 77 nmol/l (NR 50-120). Daily excretion of calcium was normal at 3.38 mmol and an ultrasound of the kidneys suggest nephrocalcinosis. Skeletal X-rays and bone mass densitometry were normal. Molecular studies: WES showed no potentially pathogenic variants in GNAS, PTHR, CASR, VDR, and CYP27B1 but a previously reported homozygous variant in the PTH, exon 3 (NM_000315.4: c.128G&amp;gt;A, p.Gly43Glu). This was confirmed by Sanger sequencing in the patient and two of her brothers. This variant was assessed to be likely pathogenic or likely damaging by several in silico analysis tools including Polyphen2, MutPred, PROVEAN, DEOGEN2 and VUS by ACMG, SIFT, Mutation Assessor and FATHMM. Management: Because the patient’s HypoCa was not controlled on large doses of calcitriol and calcium carbonate, a trial of teriparatide 20 mcg SC daily resulted in normalization of calcium and PTH levels. The patient reported significant improvement in her general wellbeing with loss of numbness, tingling, muscle spasms and tetany of the fingers. She has been on teriparatide for the last year with excellent improvement in her quality-of-life Conclusion: High PTH in the presence of congenital hypoCa is not always due to receptor or post-receptor defect and can be due to a mutated biologically inactive PTH. In such cases, treatment with Teriparatide may result in stabilization of biochemical profile and improve quality of life. Presentation: 6/2/2024

7200 A Unique Case Of Hypercalcemia From Primary Hyperparathyroidism With Thymoma And Concurrent Pulmonary Tuberculosis

Abstract Disclosure: S. Jing Hang Randy: None. L. Huiling: None. Background: Several case reports have reported the rare association of thymoma with primary hyperparathyroidism. We describe a unique case of hypercalcemia with such association but was also found to have concurrent pulmonary tuberculosis. Clinical Case: A 50-year-old Indian female with a significant history of anterior mediastinal mass underwent median sternotomy with mass resection and was found to have peri-operative hypercalcemia. Her only complaint was chronic cough. Initial investigations showed high adjusted calcium 2.78 mmol/L (2.15– 2.50 mmol/L), normal phosphate 1.1 mmol/L (0.8– 1.4 mmol/L) and high PTH 24.7 pmol/L (1.6– 6.9 pmol/L). Apart from the mediastinal mass, a whole-body CT scan showed multiple prominent mediastinal lymph nodes with non-specific subcentimetre lung nodules. The post-operative finding was a Type AB thymoma with necrotizing granulomatous inflammation in adjacent station I lymph node. Differentials for patient’s hypercalcemia included primary hyperparathyroidism, malignancies such as lymphomas and infectious causes in particular tuberculosis. Her 25-OH Vitamin D was low at 9 ug/L (30 - 100 ug/L), 1,25-dihydroxyvitamin D was elevated at 205 pg/mL (18-64 pg/mL) while creatinine, ALP, serum ACE and PTHrP were unremarkable. She was subsequently admitted for worsening hypercalcemia, fever and left pleural effusion with generalized lymphadenopathy where she underwent an Endobronchial Ultrasound-guided Transbronchial Needle Aspirate of station IV lymph nodes before being started on tuberculosis treatment. The AFB culture showed Mycobacterium Tuberculosis Complex thereafter. Parathyroid sonography revealed a 2.2cm x 0.9cm x 0.8cm lobulated hypoechoic lesion posterior to the inferior pole of left thyroid lobe. However, a confirmatory sestamibi scan could only be done 6 weeks post-thymectomy given the raw surgical bed, with a possibility of false-negative result for cervical parathyroid adenoma given a recent thymectomy. It subsequently showed a hyperfunctioning left inferior parathyroid nodule with no other suspicious focal uptake in the neck or mediastinum. Patient underwent a focused left parathyroidectomy. Histology showed features consistent with parathyroid adenoma. A stepwise trajectory of her calcium normalization was observed with hydration, intravenous zoledronic acid for her osteoporosis, tuberculosis treatment, adjuvant radiation therapy for her thymoma with margins involvement, and parathyroidectomy. Conclusion: This case illustrates the challenges faced while considering localizing scans for primary hyperparathyroidism with recent thymectomy given the common embryological origin of inferior parathyroid and thymus. It also demonstrates the possible co-existence of separate pathologies in hypercalcemia and the need to exercise prudent clinical judgement to further evaluate for these various etiologies. Presentation: 6/2/2024

6463 A Case of Tumour-Induced Osteomalacia Which Remitted After Treatment of Metastatic Prostate Cancer

Abstract Disclosure: J. Chua: None. M. Chuah: None. A case Tumour-induced osteomalacia (TIO) which remitted after treatment of metastatic prostate cancer. Dr Chua Jia Min, Dr Matthew Chuah Bingfeng Abstract Case report: A 69-year-old gentleman with a known history of bladder cancer presented to the emergency department with fatigue, lower back pain and bilateral lower limb weakness worsening over the past one month. MRI and bone scan revealed extensive osteoblastic bone metastases across the skeletal system. This gentleman was referred to the Endocrinology service for the evaluation of high PTH. His corrected calcium was normal at 2.17mmol/L (2.09-2.46mmol/L) and iPTH was raised at 8.74pmol/L (1.60-6.90pmol/L). He was noted to have severe hypophosphatemia 0.34mmol/L (0.94-1.50mmol/L). Bicarbonate levels were normal, there was no glycosuria or proteinuria. There was no history of IV ferrous carboxymaltose use. Further investigations were consistent with urinary phosphate loss - TRP was 0.398 and TMP-GFR was 0.199. ALP was elevated at 282ug/L (39-99ug/L). 25-hydroxyvitamin D was low at 12 ug/L, which accounted for the high PTH levels (secondary hyperparathyroidism). FGF-23 levels returned high at 1293 RU/ml (&amp;lt;180 RU/ml). BMD showed osteoporosis with T-score of -2.6 at the left femoral neck. He was subsequently diagnosed with metastatic prostate adenocarcinoma, based on histology from a bone biopsy of an affected vertebrae. PSA was markedly raised at 606ug/L. A diagnosis of TIO secondary to metastatic prostate cancer was made. The patient was started on PO sodium-phosphate solution 4ml TDS (approximately 3mmol/kg/day of elemental phosphorus), calcitriol 0.25mcg BD and vitamin D was replaced. After phosphate was replete, the patient's weakness and fatigue improved. He was subsequently started on androgen deprivation therapy with leuprorelin acetate injection once every 3 months and apalutamide daily. SC denosumab 60mg Q6monthly was also commenced in view of extensive bone metastases. Repeat imaging showed response to treatment with decrease in the size of the prostate and bone lesions. His PSA levels are now undetectable and TMP-GFR has normalised. His oral phosphate and calcitriol doses were gradually reduced and subsequently stopped. His calcium and phosphate levels remain within normal limits on no supplementation, suggesting remission of his TIO. PTH levels normalised after vitamin D repletion. Learning points TIO is a rare paraneoplastic syndrome usually associated with mesenchymal tumours, and treatment involves resection of the causative tumour. Cases of TIO secondary to prostate cancer (an epithelial cancer) are exceedingly rare. Despite metastatic disease, this patient responded exceedingly well to his cancer therapy. Suppression of the tumour cells with androgen deprivation therapy resulted in the lack of phosphotonin production and remission of his TIO. Presentation: 6/1/2024

5043 Skeletal Microstructure in Men with Celiac Disease

Abstract Disclosure: A. Rubenstein: None. A. Kondapalli: None. S. Agarwal: None. M. Bucovsky: None. I. Colon: None. N. Kil: None. S. Lewis: None. B. Lebwohl: None. P. Green: None. M. Walker: Advisory Board Member; Self; Alexion Pharmaceuticals, Inc.. The pathophysiology of osteoporosis related to celiac disease (CD) remains incompletely understood. High resolution peripheral quantitative computed tomography (HRpQCT) has revealed microarchitectural deficits in women with CD, but no data exist in men. We prospectively studied bone health using DXA and HRpQCT in 17 men with duodenal biopsy-confirmed CD (mean age 43±16 years; 82% white, 6% Asian, 12% other) and 5 male controls (mean age 40±12 years; 80% white, 20% Asian). Compared to controls, men with CD had lower self-rated health scores (p&amp;lt;0.05), but age, BMI, alcohol use, physical activity, acid blocker use, and vitamin D intake did not differ. Among patients with CD, 23.5% had other autoimmune diseases (type 1 diabetes, hypothyroidism, vitiligo, systemic sclerosis). At CD diagnosis, mean age was 34.3 ± 14.8. CD patients had a mean CD and gluten-free diet duration of 8 years. 29% of patients (n=5/17) were enrolled within 13 months of CD diagnosis. Mean tissue transglutaminase IgA, serum calcium, PTH, Vitamin D, and alkaline phosphatase were normal, but vitamin D levels were &amp;lt; 30 ng/mL in 36% (n=5/14) and PTH was elevated in 11% (n=1/9). T- (-0.5±1.5 vs. 0.8±0.8, p=0.03) and Z-scores (-0.1±1.4 vs. 1.1±0.9, p=0.05) by DXA were normal at all sites but tended to be lower at the 1/3-radius only in CD compared to controls. By HRpQCT, there were no differences. Compared to a larger control group including HRpQCT data from an additional 14 normative database controls (n=19), CD had lower radial cortical (-4.7%, p=0.02) and tibial trabecular (-13.3%, p=0.04) vBMD and a trend toward lower cortical volumetric BMD (vBMD; -3.5%, p=0.06) at the tibia. Within the CD group, longer CD duration was associated with worse tibial cortical vBMD at (r=-0.55, p=0.02). Higher PTH (n=9) correlated with lower lumbar spine areal BMD (r=-0.75, p=0.02), tibial trabecular thickness (Tb.Th; r=-0.77, p=0.02) as well as radial cortical vBMD (r=-0.81, p&amp;lt;0.01), trabecular Tb.Th (r=-0.78, p=0.01), and cortical thickness (r=-0.75, p=0.02). Those with greater dietary vitamin D intake had higher total vBMD (r=0.50, p=0.04) and trabecular thickness at the tibia (r=0.51, p=0.04). Similarly, higher 25-hydroxy vitamin D levels were associated with higher total hip aBMD (r=0.58, p=0.03). In summary, CD in men is associated with lower areal BMD at the 1/3-radius by DXA and lower vBMD at the radius and tibia by HRpQCT. Low vitamin D levels and secondary hyperparathyroidism may contribute. Further work is needed to understand the extent and pathophysiology of skeletal disease in men with CD. Presentation: 6/3/2024

7630 Incidental Calvarial Brown Tumor in an ESRD patient with seizures

Abstract Disclosure: K.N. Pereira: None. V. mehta: None. S. Sekaran: None. M. Renzu: None. Brown Tumor [BT], also known as Osteitis fibrosa cystica [OFC], is a rare tertiary manifestation of hyperparathyroidism [HPTH]. BT commonly affects the maxilla/mandible, long bones and spine and presents as lytic bone lesions on imaging. Among the crania-facial bones, the maxilla, palate, temporal bone, nasal cavity, orbital bone and paranasal sinuses are affected. We describe a case of a 37 year old African-American female with extensive medical history including ESRD on hemodialysis who initially presented to the hospital with hypertensive emergency in the setting of 1 week of missed dialysis. During her presentation, she had an unexplained seizure which led to further workup with imaging. CT head revealed findings suspicious of renal osteodystrophy as well as a discrete lucency at the calvarial vertex suggestive of a brown tumor. Endocrinological studies were noted to have very high PTH levels with hypercalcemia, hyperphosphatemia and vitamin D deficiency indicative of tertiary hyperparathyroidism. Based on her clinical presentation, labs and imaging, her bone disease including BT and pathologic fractures, was deemed to be due to tertiary hyperparathyroidism in the setting of ESRD, which were not amenable to surgical intervention. Extensive literature review did not reveal any reported BTs in the calvarial vertex. This case emphasizes on the holistic approach to diagnosis of BTs and underlines that fact that BT can occur in any cortical bone including unusual presentation sites like the calvarial vertex. Presentation: 6/3/2024

7254 An Unusual Case Of Hypercalcemia

Abstract Disclosure: S. Shushtarian: None. M. Balogun: None. T. Kaur: None. Hypercalcemia varies depending on severity. Higher serum calcium levels and more severe symptoms may indicate primary hyperparathyroidism or a malignant cancer. This is a case of a 32 year old female who presented with recurrent history of nephrolithiasis, found to have hypercalcemia of 13.4 mg/dL and parathyroid hormone of 1928.9 pg/mL, with phosphorus of 1.5 mg/dL. Ultrasound of her thyroid revealed a complex nodule arising from the right parathyroid gland measuring 2.2 X 2.0 cm. CT chest revealed diffuse osseous sclerosis secondary to metabolic disorder. Sestamibi scan did not localize any parathyroid adenoma. MRI of the thoracic and lumbar spine showed multiple small enhancing lesions throughout the pelvis and in the left rib, likely brown tumors related to hyperparathyroidism. X-ray of bony prominence on the patient’s left knee revealed a large lytic lesion of the proximal tibial diaphysis measuring 5.1 X 1.9 cm, concerning for aggressive neoplasm. Subsequent left tibial bone biopsy revealed giant cell rich lesions consistent with brown tumor of hyperparathyroidism. Due to our patient’s high calcium levels and large nodule size, she was referred to a tertiary center as the concern for parathyroid carcinoma and post-op hungry bone syndrome was high. Pre-op PTH level was 1408 pg/mL and post-op PTH was 96 pg/mL. The tumor removed was 2.1 cm. Post surgical pathology was consistent with atypical parathyroid adenoma. Patient was referred for genetic testing. An atypical parathyroid adenoma (APA) only accounts for 1.2 to 1.3% of cases of primary hyperparathyroidism. 80-85% of primary hyperparathyroidism is due to typical adenoma, and 10 to 15% of cases are due to hyperplasia or multiple gland disease. APA can often be confused with parathyroid carcinoma (PC), as they both have a 1:1 male to female ratio, high serum calcium levels, symptomatic hypercalcemia, high PTH levels, and fragility fractures. There are studies showing that both APA and PC have loss of nuclear parafibromin immunoreactivity. In addition, neither APA nor PC have any correlation with menopause, hormones, or gene deletions, unlike typical adenomas. Biopsy is necessary for diagnosis as the histological and immunohistochemical differences can differentiate APA vs PC. Histological features include pseudo-capsular invasion, bands of fibrosis, pronounced trabecular growth, nuclear atypia, and prominent nucleoli. Also, APA has a strong membranous staining pattern of E-cadherin, whereas PC has a loss of membranous staining. These differences are essential as although APA and PC clinically present similarly, APA lacks the invasive growth and possibility for metastatic disease that PC has. The likelihood for relapse of APA is low. Presence of malignancy criteria are indicative that a mass is actually PC and not APA. Despite this, APA is still considered a tumor of uncertain malignant potential and requires follow up. Presentation: 6/3/2024

Short-term momentum and reversals, turnover, and a stock’s price-to-52-week-high ratio

We show that short-term reversal behavior declines with a stock’s turnover and the prior month’s price-to-52-week-high ratio (PTH), shifting to momentum for stocks with both a relatively high turnover and PTH. This behavior of consecutive one-month individual stock returns is robust to subperiod analysis, risk adjustments, and alternative methodologies. Our findings suggest opposing channels. First, promoting short-term momentum, our evidence implies a PTH-anchoring underreaction to recent news, consistent with the short-term contrarian price-dampening channel of Atmaz et al. (2024) with higher turnover implying a stronger contrarian-induced underreaction. Second, promoting short-term reversals, our evidence reinforces the importance of the well-known liquidity-provision-compensation channel. Reversals are especially strong for low-PTH, low-turnover stocks, where the lower PTH implies a generally smaller-cap, less-liquid stock and the lower turnover implies a weaker contrarian-induced underreaction. We also find that the return behaviors vary with dispersion in analysts’ earnings forecasts and with market-wide sentiment, in a manner consistent with these channels.

#1451 Calcimimetics reduce the progression of high-phosphate diet-induced tubular damage

Abstract Background and Aims During chronic kidney disease (CKD) progresses, there is an increased phosphate load and the concentration of the phosphaturic hormones PTH and FGF23 rises. In patients, phosphate and FGF23 are discussed as risk factors for CKD progression. We have recently shown that mice with high phosphate, PTH and FGF23 levels develop Stat3/Kim-1-mediated proximal tubule damage and tubulointerstitial fibrosis associated with increased MCP-1 expression and accumulation of macrophages. Calcimimetics lower PTH and FGF23 levels in hemodialysis patients and are thought to have both cardio- and nephroprotective effects. In a preclinical study, cinacalcet was shown to stabilize podocyte function in proteinuric mice. Therefore, we postulate that calcimimetics also have a positive effect on the progression of tubular damage in mice with high phosphate, PTH and FGF23 levels. Method For the induction of phosphaturic hormones with concomitant tubule damage, male C57BL/6 mice were fed a 2.0% high phosphate diet (HPD) and compared to animals on a 0.8% control phosphate diet (CPD). After four months, one HPD group was additionally treated with 1 mg/kg body weight/day etelcalcetide (KP-2326). Six months after the start of the trial, blood and urine samples as well as kidneys were taken for biochemical, histological and molecular biological examinations. Results KP-2326 treatment reduced HPD-induced PTH and FGF23 levels, but had no effect on increased phosphate excretion or elevated serum phosphate levels. Histologically, tubular damage was not as pronounced in the KP-2326-treated HPD animals as in the HPD group without therapy. The increased BUN levels caused by HPD and the albuminuria were significantly reduced by KP-2326. KP-2326 reduced HPD-mediated activation of Stat3 in proximal tubule cells and decreased Kim-1 synthesis at both mRNA and protein levels. Moreover, KP-2326 significantly reduced the mRNA expression of Ccl2 and the macrophage-specific marker Adgre1 compared to the untreated HPD group, which was histologically reflected in a lower accumulation of F4/80+ macrophages around the damaged tubules. Conclusion Treatment with KP-2326 was able to reduce the progression of HPD-induced tubule damage, at least in part due to the reduction in PTH and FGF23 levels.

#3065 Factors associated with recurrence or persistently high parathormone levels after parathyroidectomy in patients with CKD

Abstract Factors associated with recurrence or persistently high parathormone levels after parathyroidectomy in patients with secondary hyperparathyroidism receiving renal replacement therapy Background and Aims Resistant hyperparathyroidism that indicates surgery usually occurs in patients with CKD who receive renal replacement therapy (RRT). This study aims to evaluate the factors associated with persistent or recurrent high levels of PTH after parathyroidectomy due to SHPT in patients receiving RRT. Method In this retrospective study, we included 66 adult patients (mean age: 46.86 ± 13.79) with parathyroidectomy for SHPT receiving renal replacement therapy. Clinicopathological features, laboratory parameters (preoperatively, at the first hour of surgery, at least every three months for at least two years after surgery), type of surgery and pathologic diagnosis were recorded from the medical records. Persistence was defined as failure to achieve a decrease in PTH level of more than fifty percent of preoperative PTH level. Recurrence was defined as elevated PTH levels after six months post-operation (&amp;gt;600 pg/mL). Results The demographics and clinical characteristics of the study population are described in Table 1. High PTH levels were observed in nineteen patients, while recurrence was observed in nine. Persistence was associated with lower preoperative ALP levels (455.27 ± 296.23, 619.72 ± 593.18, p = 0.017). Recurrence was associated with higher preoperative CRP levels (22.89 ± 6.82, 6.82 ± 5.35, p:0,046) and postoperative high phosphorus levels (4.93 ± 0.99, 4.16 ± 1.09, p = .049). Conclusion In our study persistence of high parathormone levels were more common in patients with lower preoperative ALP levels and recurrence was associated with higher preoperative CRP levels and postoperative inadequate phosphorus control. In conclusion, patients with lower ALP and higher CRP levels can be suitable for total parathyroidectomy, which is associated with a lower recurrence rate in SHPT. Also, postoperative phosphorus control can be a key point for preventing the patients' recurrence of high PTH level.

Lytic lesions in bone in a CKD patient, brown tumor is a must on the differential

Brown tumor is a focal lesion of giant cells without neoplastic potential encountered in association with hyperparathyroidism. These lesions can occur anywhere in the skeletal system producing various local symptoms. In this case report, we present a 15-year-old boy with stage 5 chronic kidney disease (CKD) on maintenance hemodialysis who presented with hip pain for 1 week. On investigating, the patient had normal parathyroid levels (PTH) but the previous metabolic bone disorder (MBD) parameters revealed a high PTH. Imaging showed expansile radiolucent lesions involving the left hip. Considering the clinical, metabolic and the radiological picture the patient was diagnosed to have brown tumor with secondary hyperparathyroidism and was treated with Cinancalcet, vitamin D and immobilization with a brace.

Evaluation of Tp-e interval, Tp-e/QT, and Tp-e/QTc ratio in primary hyperparathyroidism before and after parathyroidectomy

Aims: This study aimed to evaluate Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratios, which are new ventricular repolarization (VR) parameters in primary hyperparathyroidism (PHPT) patients, and also investigate the potential effect of parathyroidectomy (PTx) on these parameters. Methods: In total, 27 patients with PHPT who underwent PTx and 25 control subjects were selected for our study. Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratios of patients planned for PTx were compared to healthy matched controls. Electrocardiographic parameters measured 6 months after the surgery were also compared with preoperative values for each patient. Results: Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio were significantly higher in PHPT patients compared to the control group (p&amp;lt;0.001, for all).It was observed that the parameters mentioned after surgery decreased significantly, and there was no statistical difference when compared to the control group.The correlation analysis revealed a significant and positive correlation between corrected calcium (CCa) and PTH levels with Tp-e interval, Tp-e/QT ratio, and Tp-e/QTc ratio (for Ca; r=0.515, p=0.006; r=0.398, p=0.040; r=0.797, p&amp;lt;0.001 respectively vs. for PTH; r=538, p=0.04; r=0.422, p=0.028; r=0.812, p&amp;lt;0.001 respectively). Conclusions: This study showed that Tp-e interval, Tp-e/QT, and Tp-e/QTc ratios were prolonged in PHPT.These values, which are accepted as an indicator of sudden cardiac death after PTx, decreased significantly. In addition, both high PTH and high calcium(Ca) levels appear to have the potential to cause arrhythmogenic effects separately.

Inhibition of RANKL improves the skeletal phenotype of adenine-induced chronic kidney disease in mice.

Skeletal fragility and high fracture rates are common in CKD. A key component of bone loss in CKD with secondary hyperparathyroidism is high bone turnover and cortical bone deterioration through both cortical porosity and cortical thinning. We hypothesized that RANKL drives high bone resorption within cortical bone leading to the development of cortical porosity in CKD (study 1) and that systemic inhibition of RANKL would mitigate the skeletal phenotype of CKD (study 2). In study 1, we assessed the skeletal properties of male and female Dmp1-cre RANKLfl/fl (cKO) and control genotype (Ranklfl/fl; Con) mice after 10wk of adenine-induced CKD (AD; 0.2% dietary adenine). All AD mice regardless of sex or genotype had elevated blood urea nitrogen and high PTH. Con AD mice in both sexes had cortical porosity and lower cortical thickness as well as high osteoclast-covered trabecular surfaces and higher bone formation rate. cKO mice had preserved cortical bone microarchitecture despite high circulating PTH as well as no CKD-induced increases in osteoclasts. In study 2, male mice with established AD CKD were either given a single injection of an anti-RANKL antibody (5mg/kg) 8wk post-induction of CKD or subjected to 3×/wk dosing with risedronate (1.2μg/kg) for 4wk. Anti-RANKL treatment significantly reduced bone formation rate as well as osteoclast surfaces at both trabecular and cortical pore surfaces; risedronate treatment had little effect on these bone parameters. In conclusion, these studies demonstrate that bone-specific RANKL is critical for the development of high bone formation/high osteoclasts and cortical bone loss in CKD with high PTH. Additionally, systemic anti-RANKL ligand therapy in established CKD may help prevent the propagation of cortical bone loss via suppression of bone turnover.

COVID‐19‐Induced Refractory Symptomatic Hypocalcemia in a Patient With Parathyroid Gland Reimplantation

Background: Several cases of severe hypocalcemia in the setting of COVID‐19 have been reported. The proposed mechanisms include direct viral interaction with ACE2 receptors in the parathyroid gland, viral chelation of calcium, worsening hypovitaminosis D, critical illness leading to unbound fatty acids binding calcium, and inflammatory cytokines leading to PTH resistance. Given the life‐threatening nature of hypocalcemia, this underrecognized phenomenon should be on the forefront of the clinician’s attention. This case highlights a rare manifestation of COVID‐19 and further complicated by the patient’s reimplanted parathyroid gland.Presentation: A 73‐year‐old female with primary hyperparathyroidism status post parathyroidectomy with reimplantation in the left forearm presented with 4 days of viral syndrome, found to have tetany and Chvostek’s sign on physical exam. Pertinent laboratory abnormalities included calcium 5.3 mg/dL, ionized calcium 0.44 mmol/L, magnesium 1.4 mg/dL, phosphorous 5.5 mg/dL, PTH 242 pg/mL, and 25‐OH vitamin D 56 ng/mL. Chest CT revealed multifocal pneumonia consistent with positive COVID‐19 testing. She was subsequently admitted to the ICU for severe, symptomatic hypocalcemia and was initiated on a continuous calcium infusion, remdesivir, baricitinib, and steroids. Tetany resolved after 9 g calcium repletion, and she was transferred to the medical floor with an ionized calcium of 0.83 mmol/L. On hospital day 3, repeat ionized calcium was 0.78 mmol/L despite ongoing repletion. Given the persistence of hypocalcemia, a repeat PTH level was obtained which remained high at 487 pg/mL, suggesting ongoing PTH interference in the setting of COVID‐19. PTH was obtained from the right (nonimplanted) arm which was normal at 74 pg/mL. This indicated an appropriate PTH response from the reimplanted gland, and that ongoing hypocalcemia may be due to insufficient PTH function to maintain systemic calcium levels or a peripheral interference with PTH level. With continued calcium supplementation and treatment of COVID‐19, the patient’s calcium stabilized at 8.6 mg/dL. She was discharged on oral calcium supplementation with endocrinology follow‐up.Conclusion: Acute hypocalcemia strongly correlates with a profound inflammatory response in COVID‐19 patients. This case corroborates the cytokine/PTH hypothesis. This patient had a high PTH sampled near the reimplanted gland but an inappropriately normal PTH from the nonimplanted arm, indicating that direct viral interaction interfering with PTH release is an unlikely mechanism. This case represents a scenario where PTH can be sampled directly from the source and this type of model could aid in the process of determining the etiology of hypocalcemia in COVID‐19.

Cross-Disciplinary Approach of Adrenal Tumors: Insights into Primary Aldosteronism-Related Mineral Metabolism Status and Osteoporotic Fracture Risk.

Our objective was to overview the novel aspects in the field of adrenal gland neoplasms, namely, the management of bone status with respect to primary aldosteronism (PA). In the current narrative review, a PubMed study was conducted from inception until June 2023. The inclusion criteria were: human (clinically relevant) studies of any study design (at least 10 patients per study); English papers; and the following combination of key words within the title and/or abstract: "aldosterone" AND "bone", "skeleton", "osteoporosis", "fracture", "calcium", "parathyroid", "DXA", "osteocalcin", "P1NP", "alkaline phosphatase", "bone marker", "trabecular bone score", or "FRAX". The exclusion criteria were in vitro or animal studies, reviews, and case reports/series. We screened 1027 articles and finally included 23 studies (13 of case-control type, 3 cross-sectional, 5 prospective, 1 observational cohort, and 1 retrospective study). The assessments provided in these studies were as follows: nine studies addressed Dual-Energy X-ray Absorptiometry (DXA), another study pointed out a bone microarchitecture evaluation underlying trabecular bone score (TBS), and seven studies investigated the bone turnover markers (BTMs) profile. Moreover, 14 studies followed the subjects after adrenalectomy versus medical treatment, and 21 studies addressed secondary hyperparathyroidism in PA patients. According to our study on published data during a period of almost 40 years (n = 23, N = 3965 subjects aged between 38 and 64, with a mean age 56.75, and a female-to-male ratio of 1.05), a higher PTH in PA versus controls (healthy persons or subjects with essential hypertension) is expected, secondary hyperparathyroidism being associated in almost half of the adults diagnosed with PA. Additionally, mineral metabolism anomalies in PA may include lower serum calcium and higher urinary calcium output, all these three parameters being reversible under specific therapy for PA, regardless medical or surgical. The PA subgroup with high PTH seems at higher cardiovascular risk, while unilateral rather than bilateral disease was prone to this PTH anomaly. Moreover, bone mineral density (BMD) according to central DXA might show a higher fracture risk only in certain adults, TBS being a promising alternative (with a still unknown perspective of diabetes' influence on DXA-TBS results in PA). However, an overall increased fracture prevalence in PA is described in most studies, especially with respect to the vertebral site, the fracture risk that seems correctable upon aldosterone excess remission. These data recommend PA as a cause of secondary osteoporosis, a treatable one via PA intervention. There is still an area of debate the way to address BMTs profile in PA, the case's selection toward specific bone evaluation in every day practice, and further on, the understanding of the potential genetic influence at the level of bone and mineral complications in PA patients.

FRI213 Multiple Endocrine Neoplasia Syndromes: A Rare Case With Variable Presentation

Abstract Disclosure: D.J. Gomez D' Aza: None. M. Kasap: None. T. Zahedi: None. F. Zhang: None. Introduction: Multiple endocrine neoplasia (MEN) syndromes are rare autosomal dominant inherited groups of disorders characterized by the presence of two or more primary endocrine glands tumors. MEN type 1 is usually associated with neoplastic lesions of the pituitary gland, the parathyroid gland, and the pancreas. MEN type 2 typically presents with overgrowth of parathyroid, adrenal glands (pheochromocytoma), and parathyroid hyperplasia (MEN 2A), Marfanoid body habitus, or mucosal neuromas (MEN 2B). It can also manifest with non-endocrine tumors including carcinoid tumors, adrenocortical tumors, meningiomas, facial angiofibromas, collagenomas, lipomas, and germline mutations (MEN type 4). It is extremely rare for MEN type 1 syndrome to have concomitant pheochromocytoma. Case Report: We present a case of a 69 yo female with multiple comorbidities who was hospitalized for heart failure exacerbation. CT scan showed incidental findings of a 4.1 cm right adrenal nodule, a 2.1 cm left anterior mediastinum nodule, and a 1.1 cm oval pituitary mass. She had multiple episodes of hypertension urgency during the last two years. After patient recovered to her base line, workup labs revealed elevated serum Catecholamine with Metanephrine 431.1 pg/mL, Normetanephrine 466.5 pg/mL, Norepinephrine 137 pg/mL, and high PTH 258 pg/mL. Further study was normal for pituitary function tests, aldosterone, renin, cortisol, thyroid, and renal function. PET scan showed mild hypermetabolic activity in bilateral adrenal glands without any abnormal hypermetabolic activity in the chest. Thyroid Ultrasound identified a 1 cm thyroid nodule. Phenoxybenzamine was started due to concern for pheochromocytoma. Patient was monitored closely since she declined surgical intervention. Discussion: MEN syndromes have variable clinical presentation with multiple hormone excess. This patient has imaging and laboratory findings highly suggestive of MEN syndrome with pituitary adenoma, pheochromocytoma, and hyperparathyroidism. Further work up and genetic testing would be helpful to identify the mutation of MEN type 1 or type 2. Clinicians should be aware of the variable presentation of MEN syndrome, and prompt treatment is warranted to prevent life-threatening conditions. Presentation: Friday, June 16, 2023

SAT194 A Rare Case Of Untreated Primary Hyperparathyroidism With Extremely High PTH And Lytic Bone Lesions

Abstract Disclosure: M. Shah: None. K. Akinola: None. M. Bollineni: None. S.A. Milan: None. S. Challagulla: None. Background: Primary hyperparathyroidism (PHPT) typically presents with PTH levels two times above the upper limit of normal. Given the increase in routine calcium measurements, PHPT is usually diagnosed and treated early and skeletal complications are not frequent at presentation. We present a case of PHPT with severely elevated PTH levels and bone lesions mimicking metastatic disease. Clinical Case: A 30-year-old male with a history of untreated primary hyperparathyroidism presented with severe chest wall pain and abdominal pain. Initial laboratory tests revealed a calcium level of 13.3 mg/dL (normal 8.6 to 10.5 mg/dL), alkaline phosphatase (AP) of 747 IU/L (normal 24 to 130 IU/L), and PTH of 2485 pg/mL (normal 9-77 pg/mL). The patient was diagnosed with primary hyperparathyroidism years before this presentation, but was lost to follow up due to lack of insurance. His PTH was first noted to be elevated in 2013 at 266 pg/mL. CT of the chest, abdomen, pelvis showed a 2.8 x 3.0 x 3.3 cm anterior mediastinal mass and diffuse mixed lytic and sclerotic bone lesions consistent with metastatic disease. The patient underwent further imaging with CT 4D parathyroid which revealed a 1.1 cm left inferior thyroid nodule and an anterior mediastinal mass of unclear etiology. Given the high concern for malignancy, a biopsy of the mediastinal mass was performed and returned as hypercellular parathyroid tissue with no atypia. Bone biopsies of the sclerotic lesions of the iliac crest were consistent with osseous tissue with prominent bone remodeling and fibrous tissue; no neoplasm was seen. He was treated with IV fluids and zoledronic acid during this work up which only temporarily improved his high calcium levels. He was then placed on cinacalcet prior to surgery. He ultimately underwent resection of the anterior mediastinal mass and left inferior parathyroid gland via a cervical approach. The patient’s preoperative PTH level was 3455 pg/mL and decreased to 209 pg/mL immediately after resection. Resection of the other parathyroid glands was not done due to the high risk of postoperative hypocalcemia. Pathology of both lesions returned as intrathymic parathyroid adenoma with focal fibrosis. Postoperatively, the patient developed symptomatic hypocalcemia as low as 6.4 mg/dL. He required IV and oral calcium for approximately 3 weeks postoperatively, consistent with hungry bone syndrome. He was discharged on an oral regimen of calcium supplementation. Discussion: Long standing untreated PHPT can present with severely elevated PTH levels and skeletal manifestations commonly mistaken for metastatic lesions. As in this case, parathyroidectomy was the only effective treatment. However, it can be complicated by hungry bone syndrome, especially in a patient with significant bone remodeling as evidenced by high AP and lytic bone lesions. Presentation: Saturday, June 17, 2023

SAT203 Parathyroid Adenoma Masquerading As Parathyroid Carcinoma

Abstract Disclosure: M. Fariduddin: None. A. Lupieri: None. H.L. Calero: None. A. Rubenfeld: None. Y. Eisenberg: None. Case: 22 y/o pregnant female (5 weeks gestation) presented to the endocrinology clinic after a hospital admission for nausea, vomiting, constipation, fatigue and joint pain with labs showing calcium (corrected) of 14 mg/dL and PTH of 1200 pg/ml. Labs in the clinic showed calcium at 16 mg/dL and PTH 1500 pg/ml. She was re-admitted for IV fluids, calcitonin and zoledronic acid. Severe hypercalcemia, young age, and extremely high PTH levels were highly suggestive of parathyroid cancer. CT of neck showed a 2 cm right inferior parathyroid mass abutting the esophagus with concern for esophageal invasion with no evident plane between the mass and the esophagus. No cervical adenopathy was noted. Patient in conjunction with her obstetrician made an informed decision to terminate the pregnancy as this was an undesired pregnancy. She underwent an urgent right inferior gland parathyroidectomy. The mass was not fixed to underlying structures and was resected in-toto. Pathology showed chief cells with clear cytoplasm, and homogeneously round nuclei. There were no atypical mitoses, lymphovascular invasion, perineural invasion, or other invasive features concluding the final pathology as parathyroid adenoma. Discussion: Primary hyperparathyroidism predominantly affects postmenopausal women. Most common cause is parathyroid adenoma (80-85%). Parathyroid carcinoma is a rare cause of primary hyperparathyroidism (1-2%).80% people with parathyroid adenoma and primary hyperparathyroidism are diagnosed incidentally with mildly elevated calcium. PTH elevation is around 1.5-2 times the upper limit of normal. Symptoms are mild sequelae of hypercalcemia. PTH levels 5-10 times upper limit of normal, severe hypercalcemia (Ca &amp;gt; 14 mg/dl) or a hypercalcemia crisis are highly suspicious for parathyroid cancer. Surgical resection is the mainstay of treatment. Clinical criteria play a key role in early identification of parathyroid carcinoma in order to get these patients to surgery before tumor spread and improve long term survival. Our patient with significantly elevated calcium and parathyroid hormone had an atypical presentation of a parathyroid adenoma thus uncovering the limitations of clinical criteria in identifying a parathyroid carcinoma. Most of the patients with a parathyroid adenoma will eventually require surgery, however the technique, extent and urgency of surgery is affected based on clinical situations like these. The timing of the surgery could be detrimental when coupled with a scenario like our patient’s pregnancy wherein you could delay the surgery until the second trimester had the patient wanted to continue the pregnancy. This case highlights the importance of awareness of atypical presentations of parathyroid adenomas and to have a cautious approach in patients with clinical concern for parathyroid carcinoma especially if there is a potential benefit to delay surgery. Presentation: Saturday, June 17, 2023

Parathyroid Retrospective Analysis of Neoplasms Incidence (pTRANI Study): An Italian Multicenter Study on Parathyroid Carcinoma and Atypical Parathyroid Tumour.

Parathyroid cancer (PC) is a rare sporadic or hereditary malignancy whose histologic features were redefined with the 2022 WHO classification. A total of 24 Italian institutions designed this multicenter study to specify PC incidence, describe its clinical, functional, and imaging characteristics and improve its differentiation from the atypical parathyroid tumour (APT). All relevant information was collected about PC and APT patients treated between 2009 and 2021. Among 8361 parathyroidectomies, 351 patients (mean age 59.0 ± 14.5; F = 210, 59.8%) were divided into the APT (n = 226, 2.8%) and PC group (n = 125, 1.5%). PC showed significantly higher rates (p < 0.05) of bone involvement, abdominal, and neurological symptoms than APT (48.8% vs. 35.0%, 17.6% vs. 7.1%, 13.6% vs. 5.3%, respectively). Ultrasound (US) diameter >3 cm (30.9% vs. 19.3%, p = 0.049) was significantly more common in the PC. A significantly higher frequency of local recurrences was observed in the PC (8.0% vs. 2.7%, p = 0.022). Mortality due to consequences of cancer or uncontrolled hyperparathyroidism was 3.3%. Symptomatic hyperparathyroidism, high PTH and albumin-corrected serum calcium values, and a US diameter >3 cm may be considered features differentiating PC from APT. 2022 WHO criteria did not impact the diagnosis.

Bone Mineral Density During and After Lactation: A Comparison of African American and Caucasian Women

During lactation, changes in maternal calcium metabolism are necessary to provide adequate calcium for newborn skeletal development. The calcium in milk is derived from the maternal skeleton through a process thought to be mediated by the actions of parathyroid hormone-related protein (PTHrP) in combination with decreased circulating estrogen concentrations. After weaning, bone lost during lactation is rapidly regained. Most studies of bone metabolism in lactating women have been performed in Caucasian subjects. There are well-documented differences between African American (AA) and Caucasian (C) bone metabolism, including higher bone mineral density (BMD), lower risk of fracture, lower 25-hydroxyvitamin D (25(OH) D), and higher PTH in AA compared to C. In this prospective paired cohort study, BMD and markers of bone turnover were compared in self-identified AA and C mothers during lactation and after weaning. BMD decreased in both AA and C women during lactation, with similar decreases at the lumbar spine (LS) and greater bone loss in the C group at the femoral neck (FN) and total hip (TH), demonstrating that AA are not resistant to PTHrP during lactation. BMD recovery compared to the 2 week postpartum baseline was observed 6 months after weaning, though the C group did not have complete recovery at the FN. Increases in markers of bone formation and resorption during lactation were similar in AA and C. C-terminal telopeptide (CTX) decreased to 30% below post-pregnancy baseline in both groups 6 months after weaning, while procollagen type 1 N-terminal (P1NP) returned to baseline in the AA group and fell to below baseline in the C group. Further investigation is required to determine impacts on long term bone health for women who do not fully recover BMD before a subsequent pregnancy.