Wermers, Robert A.

Abstract Bisphosphonates frequently provoke a cytokine-driven acute clinical response (ACR) characterized by fever, chills, arthralgias, and myalgias. More rarely, an association between aminobisphosphonates, such as alendronate and zoledronic acid, and rheumatologic and/or immune-mediated syndromes (RIMS) has been described. Herein we report 2 patients, one with a prior history of rheumatic disease and one without, who developed giant cell arteritis meeting the American College of Rheumatology 2022 criteria following zoledronic acid infusion. We subsequently review existing mechanistic and clinical literature supporting this link. The duration of symptoms and elevation of inflammatory markers may serve as indicators for differentiating between the more common ACR and less frequent but potentially morbid RIMS. Although the benefit of bisphosphonates will outweigh the risk of RIMS for most patients with high fracture risk, clinicians should be aware of this phenomenon to assist earlier diagnosis and treatment in affected individuals.

Abstract Disclosure: S. Mohan: None. M.T. Sheehan: None. P.J. Tebben: None. R.A. Wermers: None. Introduction: Elevated 1,25-dihydroxyvitamin D (1,25(OH)2D) is a rare cause of non-parathyroid hormone (PTH) mediated hypercalcemia. An increase in the activating enzyme 1-alpha hydroxylase is seen in granulomatous diseases and lymphoma, while mutations in the CYP24A1 gene leads to reduced catabolism of 1,25(OH)2D. Cinacalcet has been shown to successfully treat 1,25(OH)2D-mediated hypercalcemia of malignancy. Extrapolating this, we report 3 patients with non-malignant 1,25(OH)2D-mediated hypercalcemia treated with cinacalcet. Case Series: The patients (2 male and 1 female) were 55-71 years old. At presentation to our clinic, all had hypercalcemia with serum calcium concentrations between 10.6-11.5 mg/dL (normal, 8.8-10.2 mg/dL). PTH ranged between 16-35 pg/ml (normal 15-65 pg/ml), PTH-related peptide was normal in all patients, 25-hydroxyvitamin D was 32-51 ng/ml, and 1,25(OH)2D was inappropriately normal between 31-77 pg/ml (normal 18-78 pg/mL) in the setting of hypercalcemia and chronic kidney disease in 2 patients with estimated glomerular filtration rates 35-42 ml/min. Other causes of hypercalcemia including sarcoidosis, tuberculosis and malignancy were ruled out. The female patient had hypercalciuria (288 mg/24 hours) without nephrolithiasis and both male patients had severe hypercalciuria (400-660 mg/24 hours) with recurrent nephrolithiasis. One male patient had biallelic variants in the CYP24A1 gene, while the other male patient was suspected to have similar mutations, but not identified on genetic testing. The female patient with a PTH of 35 pg/mL on our initial measurement had documented 1,25(OH)2D level of 82 pg/mL with PTH <20 pg/mL while previously hypercalcemic. Upon cinacalcet initiation all patients demonstrated normalization of calcium levels (8.6-9.5 mg/dl) with doses between 30-90 mg daily. The patient with CYP24A1 gene mutations experienced symptomatic hypocalcemia with calcium of 8.1 mg/dL requiring dose reduction and eventual discontinuation of cinacalcet due to limited clinical benefit. There were no consistent changes in 24-hour urine calcium or fractional excretion of calcium. Levels of 1,25(OH)2D increased and PTH decreased on cinacalcet while serum calcium levels were maintained within normal range, including 2 subjects with continued normocalcemia after 2 years of therapy. Conclusion: Cinacalcet may be a therapeutic option in non-malignant 1,25(OH)2D-mediated hypercalcemia. Further evaluation is needed to confirm efficacy, understand risks and benefits, and elucidate potential mechanisms of action. Mild decrease in PTH may lead to reduced skeletal calcium efflux while the maintenance of normocalcemia despite rising 1,25(OH)2D, which was also seen in our reported patients with malignant 1,25(OH)2D-mediated hypercalcemia, suggests cinacalcet may decrease intestinal calcium absorption. Presentation: Saturday, June 17, 2023

Abstract Primary hyperparathyroidism (PHPT) is classically characterized by hypercalcemia with elevated or inappropriately normal parathyroid hormone (PTH) levels. Elevated PTH levels in the presence of normal calcium levels are not infrequently found during the evaluation of metabolic bone disorders or kidney stone disease. This can be caused by secondary hyperparathyroidism (SHPT) or normocalcemic primary hyperparathyroidism (NPHPT). NPHPT is due to autonomous parathyroid function whereas SHPT is caused by a physiologic stimulation to PTH secretion. Many medical conditions and medications can contribute to SHPT, and differentiation between SHPT and NPHPT may be difficult. Cases are presented to illustrate examples. In this paper, we review the distinction between SHPT and NPHPT as well as end organ effects of NPHPT and outcomes of surgery in NPHPT. We suggest that the diagnosis of NPHPT be made only after careful exclusion of causes of SHPT and consideration of medications that can increase PTH secretion. Further, we advise a conservative approach to surgery in NPHPT.

Background: There is limited long-term follow-up of patients undergoing parathyroidectomy. Recurrence is described as 4% to 10%. This study evaluated persistence and recurrence of hypercalcemia in primary hyperparathyroidism after parathyroidectomy. Methods: Single-institution retrospective (1965–2010) population-based cohort from Olmsted County (MN) of patients undergoing surgery for primary hyperparathyroidism. Patients’ demographic data, preoperative and postoperative laboratory values, clinical characteristics, surgical treatment, and follow-up were noted. Results: A total of 345 patients were identified, 75.7% female, and median age 58.4 years [interquartile range (IQR): 17.6]. In all, 68% of patients were asymptomatic and the most common symptoms were musculoskeletal complaints (28.4%) and nephrolithiasis (25.6%). Preoperative median serum calcium was 11 mg/dL (IQR: 10.8–11.4 mg/dL), and median parathyroid hormone was 90 pg/mL (IQR: 61–169 pg/dL). Bilateral cervical exploration was performed in 38% and single gland resection in 79% of cases. Median postoperative serum calcium was 9.2 mg/dL (IQR: 5.5–11.3). Nine percent of patients presented persistence of hypercalcemia, and recurrence was found in 14% of patients. Highest postoperative median serum calcium was 10 mg/dL (IQR: 6–12.4), and median number of postoperative calcium measurements was 10 (IQR: 0–102). Postoperative hypercalcemia was identified in 37% of patient. Fifty-three percent were attributed to secondary causes, most commonly medications, 22%. Three percent of patients required treatment for postoperative hypercalcemia. Median time to recurrence and death were 12.2 and 16.7 years, respectively. Conclusion: Recurrent hypercalcemia after successful parathyroidectomy is higher than previously reported. Most cases are transient and often associated to other factors with only the minority requiring treatment. Long-term follow-up of serum calcium should be considered in patients after successful parathyroidectomy.

ABSTRACT In this narrative review, we present data gathered over four decades (1980–2020) on the epidemiology, pathophysiology and genetics of primary hyperparathyroidism (PHPT). PHPT is typically a disease of postmenopausal women, but its prevalence and incidence vary globally and depend on a number of factors, the most important being the availability to measure serum calcium and parathyroid hormone levels for screening. In the Western world, the change in presentation to asymptomatic PHPT is likely to occur, over time also, in Eastern regions. The selection of the population to be screened will, of course, affect the epidemiological data (ie, general practice as opposed to tertiary center). Parathyroid hormone has a pivotal role in regulating calcium homeostasis; small changes in extracellular Ca++ concentrations are detected by parathyroid cells, which express calcium-sensing receptors (CaSRs). Clonally dysregulated overgrowth of one or more parathyroid glands together with reduced expression of CaSRs is the most important pathophysiologic basis of PHPT. The spectrum of skeletal disease reflects different degrees of dysregulated bone remodeling. Intestinal calcium hyperabsorption together with increased bone resorption lead to increased filtered load of calcium that, in addition to other metabolic factors, predispose to the appearance of calcium-containing kidney stones. A genetic basis of PHPT can be identified in about 10% of all cases. These may occur as a part of multiple endocrine neoplasia syndromes (MEN1–MEN4), or the hyperparathyroidism jaw-tumor syndrome, or it may be caused by nonsyndromic isolated endocrinopathy, such as familial isolated PHPT and neonatal severe hyperparathyroidism. DNA testing may have value in: confirming the clinical diagnosis in a proband; eg, by distinguishing PHPT from familial hypocalciuric hypercalcemia (FHH). Mutation-specific carrier testing can be performed on a proband's relatives and identify where the proband is a mutation carrier, ruling out phenocopies that may confound the diagnosis; and potentially prevention via prenatal/preimplantation diagnosis. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). Abstract The prevalence and incidence of PHPT vary around the world and depend on a number of factors, the most important being availability of serum calcium (and parathyroid hormone) measurement for screening, which in the Western world has shifted its presentation to an asymptomatic disorder. Clonally dysregulated overgrowth of one or more parathyroid glands together with reduced expression of CaSRs is the most important pathophysiologic basis of PHPT, which may also occur as a part of inherited syndromes or as a nonsyndromic isolated endocrinopathy in 10% of cases. Genetic testing has roles in establishing the clinical diagnosis, although its value requires assessments using GRADE(176) methodology, which is recommended for future consideration.

Background In Jan 2018, we began routinely obtaining neck ultrasound (US) with 123I/99Tc-sestamibi (MIBI) for parathyroid gland localization and to identify thyroid pathology in the setting of primary hyperparathyroidism (1HPT). The aim of this study is to assess if routine neck US is a useful adjunct to 123I/99Tc-MIBI in 1HPT. Methods Patients undergoing surgery for 1HPT with both 123I/99Tc-MIBI and US at our institution after implementation of routine US were reviewed. Biopsy and surgical management of thyroid pathology was evaluated. 123I/99Tc-MIBI and US results were compared to intraoperative findings to determine sensitivity and positive predictive value (PPV) for parathyroid localization. Results From January 2018 to September 2019, there were 423 patients (mean, 61 years) that met inclusion criteria (80% women). Thyroid nodules were found on US in 57%, mean size 1.3 + 0.8 cm. Fine needle aspiration (FNA) was performed in 87 patients with nodules (36%). 35 patients (8.5%) required total or partial thyroidectomy for diagnoses/treatment. Papillary thyroid cancer (PTC) was found in 3.5% of the cohort with micro-PTC 53% and PTC 1-2 cm 40%. A successful parathyroid operation for 1HPT was achieved in 98.6% of patients. Positive predictive value for localization of abnormal parathyroid glands was 97% when US and 123I/99Tc-MIBI had concordant findings. Discussion Routine use of US in 1HPT commonly identifies nodules that are benign or low-risk PTC. Ultrasound is less sensitive for parathyroid localization but when used with 123I/99Tc-MIBI, concordant imaging has a high PPV.

ABSTRACT Inactivating mutations of the ENPP1 gene are associated with generalized arterial calcification of infancy (GACI) and less often autosomal-recessive hypophosphatemic rickets type 2 (ARHR2). We aimed to investigate the spectrum of phenotypes in a family with monoallelic and biallelic mutations of ENPP1 after identification through whole exome sequencing of a 54-year-old female with biallelic mutation of ENPP1, c.323G > T; p.Cys108Phe and c.1441C > T; p.Arg481Trp. Including the proband, 2 subjects had biallelic mutations, 5 had monoallelic mutations, and 2 had no mutation of ENPP1. The maternal mutation, a known pathogenic variant associated with GACI, was found in 3 subjects with monoallelic mutations, while the paternal mutation, which was not previously reported, was present in 2 subjects with monoallelic mutations. Both subjects with biallelic mutations had bowing of bilateral femurs, periarticular mineral deposition, normocalcemic primary hyperparathyroidism with multigland parathyroidectomy, increased carotid intima-media thickness, and enthesopathy was also noted in one subject. Intact FGF23 was elevated in both subjects with biallelic mutations, while C-terminal FGF23 was only elevated in one and PPi was reduced in one. Subjects with monoallelic mutations did not have periarticular calcifications or bone deformities. To conclude, patients with biallelic GACI causing mutations can survive well into adulthood, and despite the same biallelic ENPP1 pathogenic variants, clinical and biochemical manifestations can significantly differ, and include enthesopathy and primary hyperparathyroidism, which have not been previously described. Although carriers of monoallelic ENPP1 variants appear unaffected by classic disease manifestations, there may be subtle biochemical and clinical findings that warrant further investigation. © 2019 American Society for Bone and Mineral Research.

Abstract Objective Several studies indicate that patients with primary hyperparathyroidism (PHPT) undergoing parathyroid surgery have improvement in mood and neuropsychological functioning. The current analysis aims to examine the relationship between biochemical and clinical variables and the improvement in depression scores and in specific symptoms, after parathyroidectomy. Design A prospective observational case‐control study at a referral centre. Patients Patients with PHPT undergoing parathyroidectomy (n = 88) or thyroid surgery (n = 85). Measurements The Patient Health Questionnaire‐9 (PHQ‐9) was utilized to obtain depression scores at enrolment and 12 months after surgery. The changes in PHQ‐9 were analysed and correlated with baseline clinical and biochemical parameters. Results At enrolment, there was no difference between the groups in the number with a depression diagnosis (PHPT 34.1%, thyroid surgery, 35.5%, P = 0.86). However, baseline PHQ‐9 scores were significantly higher in PHPT (median 7.5, range 0‐27) than thyroid surgery patients (median 3.0, range 0‐18, P < 0.0001). Following surgery, all PHQ‐9 scores, total and symptom group (cognitive, somatic) improved and were no longer different between PHPT (total PHQ‐9 median 2, range 0‐16) and thyroid (median 1, range 0‐14, P = 0.31) groups. Baseline parathyroid hormone level, but not calcium, had a weak relationship with change in PHQ‐9 score after parathyroid surgery ( P = 0.003). Baseline PHQ‐9 score was correlated with change in PHQ‐9 score at 12 months after parathyroid surgery ( P < 0.001). Conclusions Depression scores improve in both somatic and cognitive domains after parathyroidectomy for PHPT and baseline severity of depression predicts the response.