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Background: Protein-truncating germline pathogenic variants in the N- and C-terminal exons (2, 9, and 10) of the MEN1 gene may be associated with aggressive pancreatic neuroendocrine tumors. However, the impact of these variants on parathyroid disease is poorly understood. We sought to investigate the effects of genotype and surgical approach on clinical phenotype and postoperative outcomes in patients with multiple endocrine neoplasia type 1 (MEN1)-related primary hyperparathyroidism., Methods: We identified patients with MEN1 evaluated at our institution from 1985 to 2020 and stratified them by genotype, (truncating variants in exons 2, 9, or 10, or other variants), and index surgical approach, (less-than-subtotal parathyroidectomy [

Background: Primary hyperparathyroidism (HPT) is commonly underdiagnosed and undertreated. Joint pain is a nonspecific symptom associated with osteoarthritis or primary HPT. We hypothesize that patients treated for osteoarthritis are underdiagnosed with primary HPT., Methods: Adult patients diagnosed with hip/knee osteoarthritis at the Medical College of Wisconsin from January 2000 to October 2020 were queried. Patients with a calcium level drawn within 1 year of diagnosis of osteoarthritis were included. Patients who had undergone prior parathyroidectomy were excluded. Patients were stratified by serum calcium level, HPT diagnosis, and PTH level. Arthroplasty rates were compared between groups., Results: Of 54,788 patients, 9,967 patients (18.2%) had a high serum calcium level, of whom 1,089 (10.9%) had a diagnosis of HPT. Only 76 (7.0%) patients with HPT underwent parathyroidectomy, 208 (19.1%) underwent knee/hip arthroplasty, and 14 (1.3%) underwent both. Arthroplasty was performed in 1,793 patients without evaluation and/or definitive treatment for HPT. There were higher rates of arthroplasty performed in patients with a high serum calcium level compared with those without (21.2% vs 17.4%, P < .001)., Conclusion: Patients with high serum calcium levels were more likely to undergo arthroplasty than those with normocalcemia. Hypercalcemia in the setting of hip or knee osteoarthritis should prompt a full evaluation for primary HPT., (Published by Elsevier Inc.)

Background: Preventing cervical reoperations is important-especially after parathyroidectomy. We sought to examine early predictors of recurrence of primary hyperparathyroidism after surgical cure., Methods: Adult patients with sporadic primary hyperparathyroidism treated with parathyroidectomy between September 1, 1997, and September 1, 2019, with confirmed eucalcemia at 6 months postoperatively were identified. Recurrence was defined as hypercalcemia (>10.2 mg/dL) with an elevated or nonsuppressed parathyroid hormone level on subsequent follow-up., Results: Parathyroidectomy was performed in 522 patients (median age, 62.1 years, 77% female) with the majority undergoing planned minimally invasive parathyroidectomy (85.4%, n = 446). After a median follow-up of 30.9 months, 13 patients (2.5%) recurred (median time to recurrence 50.2 months, interquartile range 27.9-66.5), all of whom underwent planned minimally invasive parathyroidectomy (n = 13/446, 2.9%). Recurrence was more common in those with higher (but still normal) 6-month calcium (10.1 vs 9.3 mg/dL, P < .001) or parathyroid hormone values (64 vs 46 pg/mL, P < .01). Multivariate analysis revealed that age >66.5 years, calcium ≥9.8mg/dL and parathyroid hormone ≥80 pg/mL at 6 months were associated with increased risk of recurrence. In addition, the presence of at least 1 preoperative imaging study that conflicted with intraoperative findings among minimally invasive parathyroidectomy patients (n = 446) was associated with increased risk of recurrence (hazard ratio 4.93, 95% confidence interval 1.25-16.53, P = .016)., Conclusion: Recurrence of sporadic primary hyperparathyroidism after initial surgical cure in the era of minimally invasive parathyroidectomy is 2.5%. Identification of those at risk for recurrence using 6-month serum calcium ≥9.8 mg/dL, parathyroid hormone ≥80 pg/mL, and/or potentially conflicting localization studies may inform surveillance strategies., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Clinical manifestations and treatment outcomes in children and adolescents with multiple endocrine neoplasia type 1 are not well characterized., Methods: We conducted a retrospective cohort study of 80 patients with multiple endocrine neoplasia type 1 who commenced tumor surveillance at ≤18 years of age., Results: Fifty-six patients (70%) developed an endocrine tumor by age ≤18 years (median age = 14 years, range = 6-18 years). Primary hyperparathyroidism occurred in >80% of patients, with >70% undergoing parathyroidectomy, in which less-than-subtotal (<3-gland) resection resulted in decreased disease-free outcomes versus subtotal (3-3.5-gland) or total (4-gland) parathyroidectomy (median 27 months versus not reached; P = .005). Pancreaticoduodenal neuroendocrine tumors developed in ∼35% of patients, of whom >70% had nonfunctioning tumors, >35% had insulinomas, and <5% had gastrinomas, with ∼15% having metastases and >55% undergoing surgery. Pituitary tumors developed in >30% of patients, and ∼35% were macroprolactinomas. Tumor occurrence in male patients and female patients was not significantly different. Genetic analyses revealed 38 germline MEN1 mutations, of which 3 were novel., Conclusion: Seventy percent of children aged ≤18 years with multiple endocrine neoplasia type 1 develop endocrine tumors, which include parathyroid tumors for which less-than-subtotal parathyroidectomy should be avoided; pancreaticoduodenal neuroendocrine tumors that may metastasize; and pituitary macroprolactinomas., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: It is unclear whether genotype-negative clinical multiple endocrine neoplasia type 1 patients derive equal benefit from prospective surveillance as genotype-positive patients., Methods: In this retrospective cohort study, we compared genotype-negative patients with clinical multiple endocrine neoplasia type 1 with genotype-positive index cases. Primary outcome was age-related penetrance of manifestations; secondary outcomes were disease-specific survival and clinical course of endocrine tumors., Results: We included 39 genotype-negative patients with clinical multiple endocrine neoplasia type 1 (Male: 33%) and 63 genotype-positive multiple endocrine neoplasia type 1 index cases (Male: 59%). Genotype-negative patients with clinical multiple endocrine neoplasia type 1 were 65 years old at last follow-up; genotype-positive multiple endocrine neoplasia type 1 index cases were 50 (P < .001). Genotype-negative patients with clinical multiple endocrine neoplasia type 1 were significantly older at their first and second primary manifestation. Only 1 developed a third primary manifestation. No genotype-negative patients with clinical multiple endocrine neoplasia type 1 with primary hyperparathyroidism and a pituitary adenoma developed a duodenopancreatic neuroendocrine tumor. Disease-specific survival was significantly better in genotype-negative patients with clinical multiple endocrine neoplasia type 1. In genotype-negative patients with clinical multiple endocrine neoplasia type 1, primary hyperparathyroidism was single-gland disease in 47% of parathyroidectomies versus 0% in genotype-positive multiple endocrine neoplasia type 1 index cases. In genotype-negative patients with clinical multiple endocrine neoplasia type 1, 17% of duodenopancreatic neuroendocrine tumors were multifocal versus 68% in genotype-positive multiple endocrine neoplasia type 1 index cases. Genotype-negative patients with clinical multiple endocrine neoplasia type 1 had more pituitary macroadenomas, fewer prolactinomas, and more somatotroph adenomas., Conclusion: Genotype-negative patients with clinical multiple endocrine neoplasia type 1 have a different clinical course than genotype-positive multiple endocrine neoplasia type 1 index cases. This may support a separate classification and a tailored surveillance regimen. Of the genotype-negative patients with clinical multiple endocrine neoplasia type 1 who had parathyroidectomy, almost half had no evidence of multigland disease and may be potential candidates for a more targeted single-gland approach., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: The incidence of primary hyperparathyroidism has increased 300% in the United States in the past 30 years, and secondary hyperparathyroidism is almost universal in patients with end-stage renal disease. We assessed the presence of environmental chemicals in human hyperplastic parathyroid tumors as possible contributing factors to this increase., Methods: Cryopreserved hyperplastic parathyroid tumors and normal human parathyroids were analyzed by gas chromatography and liquid chromatography coupled to ultra-high-resolution mass spectrometry, bioinformatics, and biostatistics., Results: Detected environmental chemicals included polychlorinated biphenyls, polybrominated diphenyl ethers, dichloro-diphenyl-trichloroethane derivatives, and other insecticides. A total of 99% had p,p'-dichlorodiphenyldichloroethylene. More than 50% contained other environmental chemicals, and many classified as endocrine disruptors. Polychlorinated biphenyl-28 and polychlorinated biphenyl-49 levels correlated positively with parathyroid tumor mass. Polybrominated diphenyl ether-47 concentrations in tumors were inversely correlated with patients' serum calcium levels. Cellular metabolites in pathways of purine and pyrimidine synthesis and mitochondrial energy production were associated with tumor growth and with p,p'-dichlorodiphenyldichloroethylene in primary hyperparathyroidism tumors. In normal parathyroids, p,p'-dichlorodiphenyldichloroethylene , polychlorinated biphenyl-28, polychlorinated biphenyl-74, and polychlorinated biphenyl-153, but not p,p'-dichlorodiphenyldichloroethylene or polychlorinated biphenyl-49, were detected., Conclusion: Environmental chemicals are present in human parathyroid tumors and warrant detailed epidemiologic and mechanistic studies to test for causal links to the growth of human parathyroid tumors., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Primary hyperparathyroidism is rare in pediatric patients. Our study aim was to compare primary hyperparathyroidism in pediatric (<19 years) and young adult (19-29 years) patients., Methods: A prospectively collected database from a single, high-volume institution was queried for all patients age <30 years who had initial parathyroidectomy for primary hyperparathyroidism yielding 126/4,546 (2.7%) primary hyperparathyroidism patients representing 39 pediatric and 87 young adult patients. Presenting symptoms, operative data, and postoperative course were compared for patients age 0-19 years and 20-29 years., Results: Sporadic primary hyperparathyroidism was present in 81.7% and occurred less often in pediatric patients than young adult patients (74.4% vs 86.2%, P = .12). Among patients with hereditary primary hyperparathyroidism, multiple endocrine neoplasia type 1 was the most common type. Multiglandular disease was common in both pediatric (30.7%) and young adult (21.8%) patients. Following parathyroidectomy, 3 (2.3%) patients had permanent hypoparathyroidism and none had permanent recurrent laryngeal nerve paralysis. Biochemical cure at 6 months was equally likely in pediatric and young adult patients (97.1% vs 93.6%, P = .44) with comparable follow-up (78.4 months vs 69.1 months, P = .66) and rates of recurrent disease (5.9% vs 10.3%, P = .46). Recurrence was due to multiple endocrine neoplasia 1-related primary hyperparathyroidism in all cases., Conclusion: Although primary hyperparathyroidism is sporadic in most patients <19 years, they are more likely to have multiple endocrine neoplasia type 1-associated primary hyperparathyroidism (23%). Parathyroidectomy for primary hyperparathyroidism can be performed safely in pediatric patients with a high rate of cure. Follow-up for patients with hereditary disease is necessary., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: Fibromyalgia (FM), an ill-defined symptom complex, is characterized by musculoskeletal pain, headache, depression, fatigue, and cognitive decline, symptoms also seen commonly in primary hyperparathyroidism (PHP). Prevalence of concurrent PHP and FM and response to parathyroidectomy (PTX) of those with both conditions are unknown., Methods: We reviewed prospective data of 4,000 patients with sporadic PHP who had PTX from 1995 to 2013 examining perioperative symptoms and medication usage for those with diagnosed FM. Cure was defined by normocalcemia at ≥ 6 months., Results: Of 2,184 patients, 80 (4%) had a prior diagnosis of FM. Of evaluable FM patients, 97.3% had definitive cure of PHP. After PTX, 89% had improvement in ≥ 1 symptom attributed to FM, with improved cognition/memory most common (80%). Improvement in ≥ 2, ≥ 3, and ≥ 4 FM symptoms was appreciated by 71%, 43%, and 25%, respectively. Quality of life and wellness improved in >50%. Postoperative use of drugs prescribed for FM often improved or resolved (narcotics, 77%; anti-inflammatories, 74%; "FM-specific medications," 33%; antidepressants, 30%); 21% discontinued all FM medications postoperatively., Conclusion: FM is common in patients operated on for sporadic PHP. Of those with both conditions, after PTX 89% appreciate symptom response and 77% and 21% had a decrease in or discontinuation or medications, respectively. Before diagnosing FM, providers should exclude PHP, which is surgically correctable., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The electronic medical record (EMR) of a large, tertiary referral center was examined to study the prevalence of undiagnosed and unrecognized primary hyperparathyroidism (PHPT)., Methods: The EMR was queried for outpatient serum calcium >10.5 mg/dL over a 2-year period., Results: Of 2.7 million patients, 54,198 (2%) had hypercalcemia (>10.5 mg/dL). In a 2-year sample of 7,269 patients, 1.3% (95 patients) had a recorded diagnosis of PHPT, and 0.3% (16 patients) had parathyroidectomy. Of the remaining patients, parathyroid hormone (PTH) values were recorded in 32% (2,337 patients). Of patients with PTH measured, 71% (1,662 patients) had PHPT (PTH > 30 pg/mL). Patients with calcium of 11.1–11.5 mg/dL were most likely to have PHPT (55%). Patients with calcium >12 mg/dL were most likely to have PTH measured (52%). Of hypercalcemic patients, 67% never had PTH obtained, 28% of whom were likely to have PHPT. It is estimated that 43% of hypercalcemic patients are likely to have PHPT. The estimated prevalence of PHPT in the general population is 0.86%., Conclusion: PHPT is a more common disorder than previously documented. It is crucial to evaluate even mild hypercalcemia, because 43% of these patients have PHPT. PHPT is underdiagnosed and undertreated.

Background: Previous investigators have reported the incidence of thyroid nodules in patients with primary hyperparathyroidism; others have noted the incidence of primary hyperparathyroidism in patients who underwent thyroidectomy. It is well known that both of these entities coexist. In this article, we present a single-center experience with the incidence of concomitant thyroid nodular disease and primary hyperparathyroidism in patients who underwent parathyroidectomy or thyroidectomy., Methods: From May 2006 to December 2007, 526 patients underwent thyroidectomy, parathyroidectomy, or both. Operations were performed by surgeons in the Johns Hopkins Endocrine Surgery Section after screening preoperatively for concomitant thyroid nodular disease or primary hyperparathyroidism., Results: Among the 200 patients who underwent a parathyroidectomy, 102 (51.0%) were found to have thyroid nodular disease. Six percent of these 200 patients also had a thyroid malignancy. Of the 326 patients who were primarily seen for thyroid disease, the incidence of primary hyperparathyroidism was 3.1%., Conclusion: By implementing a comprehensive approach to patients who present with thyroid disease or primary hyperparathyroidism, concomitant pathology may be elucidated preoperatively. This approach will facilitate the detection of otherwise unsuspected thyroid cancer and hyperparathyroidism as well as prevent unnecessary reoperative surgery.

Background: External radiation is associated with a risk of hyperparathyroidism. We reviewed the outcomes after operation for radiation-induced hyperparathyroidism (R-HPT)., Methods: We conducted a retrospective review of all patients who had operative therapy for R-HPT from 1980 to 2003 in our department with a minimum of 3 years of follow-up after operative therapy., Result: Between 1980 and 2003, 1932 patients underwent parathyroidectomy for primary hyperparathyroidism. Thirty-seven (1.92%) patients had a history of neck irradiation. Thirty-two patients underwent a bilateral exploration (BE), and 5 patients had a focused approach (FA). Thirty-five patients presented with single gland disease, and 2 patients had multiple gland disease. In the BE group, 26 patients remained cured biochemically after a median follow-up of 10.3 years (range, 3-21 years), and 6 patients had recurrence after a median of 13.2 years (range, 7-22 years). In the FA group, all 5 patients remained cured biochemically; however, the median follow-up remained shorter (6.4 years; range, 3-8 years)., Conclusion: In R-HPT, the incidence of multiple gland disease at the time of initial operation was comparable with sporadic HPT. In the absence of thyroid disease, an FA may be proposed for R-HPT. Metachronous pathologic glands may develop several years after successful parathyroidectomy in R-HPT. Hence, lifelong follow-up of these patients is essential.

Background: The use of a targeted, less-invasive approach is changing the operative indications in sporadic primary hyperparathyroidism (SPHPT). Now, patients with "mild" HPT are offered parathyroidectomy. However, the operative findings and outcome of these patients are unknown. This study reports the differences between "mild" and "classic" biochemical SPHPT in incidence of multiglandular disease (MGD) and operative outcome., Methods: All 343 patients underwent parathyroidectomy guided by intraoperative parathyroid hormone (PTH) monitoring (IPM). Among them, 301 patients (88%) had "classic" biochemical SPHPT (hypercalcemia and increased PTH) and 42 patients (12%) had "mild" HPT, which consisted of 28 patients with inappropriate secretion of PTH (ISP-hypercalcemia and normal PTH), and 14 patients with normocalcemic HPT (NCHPT-eucalcemia and increased PTH). Single or MGD was determined by IPM. Operative success is eucalcemia for greater than or equal to 6 months after operation and along with normal PTH levels in NCHPT., Results: Thirty nine of 301 patients (13%) with "classic" biochemical SPHPT had MGD with an operative failure rate of 1% (3/301). In the "mild" HPT group, 14 of 42 patients (33%) had MGD with a failure rate of 5% (2/42). The incidence of MGD was statistically significant (P < .001)., Conclusion: The incidence of MGD and operative failure are higher in patients with "mild" HPT when compared with classic SPHPT. Patients and surgeons should be aware of these consequences when parathyroidectomy is offered to patients with "mild" HPT.