Evaluation for primary hyperparathyroidism after radioactive iodine treatment in patients with Graves' disease.

BACKGROUND: Retrospective studies are conflicting regarding the risk of primary hyperparathyroidism after radioactive iodine treatment. We hypothesized that primary hyperparathyroidism rates are greater after radioactive iodine than after thyroidectomy and that patients with hypercalcemia after treatment for Graves' disease are not adequately evaluated for primary hyperparathyroidism, contributing to underdiagnosis of radioactive iodine-associated primary hyperparathyroidism. METHODS: This retrospective review considers patients undergoing radioactive iodine or thyroidectomy for Graves' disease at a tertiary referral center between January 1, 2000, and January 31, 2022. Patients were identified using a hospital-based cohort discovery tool; exclusions included history of head/neck radiation, primary hyperparathyroidism/parathyroidectomy, renal dysfunction diagnoses, or treatment with both radioactive iodine and thyroidectomy. Patients with an elevated calcium (>10.2 mg/dL) level measured after treatment were classified as "incomplete workup" (no parathyroid hormone), "likely primary hyperparathyroidism" (parathyroid hormone >40 pg/dL), or "unlikely primary hyperparathyroidism" (parathyroid hormone <40 pg/dL). RESULTS: Of 900 patients, 468 (52%) had been treated with radioactive iodine and 432 (48%) with thyroidectomy. At a median follow-up of 9.39 years (interquartile range, 5.12-13.25), 25% (n = 224) of patients did not have a serum calcium measured and 52 (8%, n = 676) patients had an elevated calcium level. Hypercalcemia was more common after radioactive iodine (10%) than thyroidectomy (6%, P = .061). Of patients with hypercalcemia, 33 (63%) were "incomplete workup," 5 (10%) were "likely primary hyperparathyroidism," and 14 (27%) were "unlikely primary hyperparathyroidism." There was no difference in primary hyperparathyroidism workup rates between patients treated with radioactive iodine (n = 23) and thyroidectomy (n = 10, P = .389). CONCLUSIONS: Patients treated with radioactive iodine for Graves' disease may experience an elevated rate of hypercalcemia, but the majority are not adequately evaluated for primary hyperparathyroidism. Patients with a history of radioactive iodine should undergo regular calcium screening and, if elevated, appropriate workup for primary hyperparathyroidism.

The Role of Demographic and Clinical Factors in Germline Mutation Testing for Patients with Primary Hyperparathyroidism.

INTRODUCTION: Guidelines recommending genetic counseling in primary hyperparathyroidism (PHPT) vary. To further delineate current recommendations, this study examined genetic counseling referral patterns and rates of mutations in surgical patients with PHPT. PATIENTS AND METHODS: A single-institution review was performed of adult patients who underwent parathyroidectomy for presumed sporadic PHPT. Genetic testing indications of hypercalcemia onset ≤ 40 years, multigland disease (MGD), family history (FHx) of PHPT, or other clinical indications suspicious for a PHPT-related endocrinopathy were examined by demographics and mutation detection rates. RESULTS: Genetic counseling was performed in 237 (37.9%) of 625 patients. Counseling was discussed but not performed in 121 (19.4%) patients. No evidence was noted of genetic referral discussion in the remaining 267 (42.7%). Of these groups, patients who received genetic counseling were youngest, p < 0.001 [median age 55.3 (IQR 43.2, 66.7) years]. The majority of patients with indications of age ≤ 40 years (65.7%), FHx (78.0%), and other clinical indications (70.7%) underwent genetic counseling, while most with MGD (57.0%) did not. Eight mutations were detected in 227 patients (3.5%). Mutations included: MEN1 (n = 2), CDC-73 (n = 4), and CASR (n = 2). Detection was most common in patients with FHx (4/71, 5.6%), then age ≤ 40 years (3/66, 4.5%), and other clinical indications (3/80, 3.8%). No mutations were identified in 48 patients tested solely for MGD. CONCLUSIONS: Most patients with onset of hypercalcemia age ≤ 40 years, positive FHx, or other clinical concerns underwent genetic counseling, while most with MGD did not. As no germline mutations were identified in patients with MGD alone, further investigation of MGD as a sole indication for genetic counseling may be warranted.

Older Patients With Asymptomatic Primary Hyperparathyroidism: Should Criteria for Surgery Be Expanded?

Context: Patients with primary hyperparathyroidism (PHPT) can present with variable signs, symptoms, and end-organ effects. Clinical practice guidelines influence referral for consideration of parathyroidectomy. Objective: This study compared the demographic, biochemical, and symptom profile and examine indications for surgery in patients older than 50 years who underwent parathyroidectomy to determine how changes to current guidelines may affect recommendations for parathyroidectomy. Methods: A retrospective review was conducted of patients age 50 years or older who underwent initial parathyroidectomy for sporadic PHPT from 2012 to 2020. Patients were classified by indications for surgery per guideline criteria (classic, asymptomatic, and no criteria met) and age group (AG): 50 to 59 years; 60 to 69 years; 70 years or older. Patients were treated at a high-volume tertiary medical center by endocrine surgeons. Results: Of 1182 patients, 367 (31%) classic and 660 (56%) asymptomatic patients met the criteria for surgery. The most common indications for surgery were extent of hypercalcemia (51%), osteoporosis (28%), and nephrolithiasis (27%). Of the 155 (13%) patients who did not meet the criteria, neurocognitive symptoms (AG1: 88% vs AG2: 81% vs AG3: 70%; P = .14) and osteopenia (AG1: 53% vs AG2: 68% vs AG3: 68%; P = .43) were frequently observed regardless of patient age. If the age threshold of younger than 50 years was expanded to 60, 65, or 70 years, an additional 61 (5%), 99 (8%), and 124 (10%) patients in the entire cohort would have met the guideline criteria for surgery, respectively. Conclusion: Expanding current guidelines for PHPT to include a broader age range, osteopenia, and neurocognitive symptoms may allow for earlier surgical referral and evaluation for definitive treatment.

Vitamin D status and supplementation before and after Bariatric Surgery: Recommendations based on a systematic review and meta-analysis.

Bariatric surgery is associated with a postoperative reduction of 25(OH) vitamin D levels (25(OH)D) and with skeletal complications. Currently, guidelines for 25(OH)D assessment and vitamin D supplementation in bariatric patients, pre- and post-surgery, are still lacking. The aim of this work is to analyse systematically the published experience on 25(OH)D status and vitamin D supplementation, pre- and post-surgery, and to propose, on this basis, recommendations for management. Preoperatively, 18 studies including 2,869 patients were evaluated. Prevalence of vitamin D insufficiency as defined by 25(OH)D < 30 ng/mL (75 nmol/L) was 85%, whereas when defined by 25(OH)D < 20 ng/mL (50 nmol/L) was 57%. The median preoperative 25(OH)D level was 19.75 ng/mL. After surgery, 39 studies including 5,296 patients were analysed and among those undergoing either malabsorptive or restrictive procedures, a lower rate of vitamin D insufficiency and higher 25(OH)D levels postoperatively were observed in patients treated with high-dose oral vitamin D supplementation, defined as ≥ 2,000 IU/daily (mostly D3-formulation), compared with low-doses (< 2,000 IU/daily). Our recommendations based on this systematic review and meta-analysis should help clinical practice in the assessment and management of vitamin D status before and after bariatric surgery. Assessment of vitamin D should be performed pre- and postoperatively in all patients undergoing bariatric surgery. Regardless of the type of procedure, high-dose supplementation is recommended in patients after bariatric surgery.

The Eucalcemic Patient With Elevated Parathyroid Hormone Levels.

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.

Persistent/Recurrent Primary Hyperparathyroidism: Does the Number of Abnormal Glands Play a Role?

BACKGROUND: Persistent/recurrent hyperparathyroidism occurs in 2%-5% of patients with sporadic primary hyperparathyroidism (PHPT). In this study, the incidence and time to recurrence in patients with single-gland disease (SGD), double adenomas (DAs), or four-gland hyperplasia (FGH) at initial parathyroidectomy were compared. METHODS: This retrospective review included adult patients with sporadic PHPT who underwent initial parathyroidectomy with intraoperative parathyroid hormone monitoring (IOPTH) from 1/2000 to 12/2016 with ≥6 mo follow-up. An abnormal parathyroid was defined by a gland weight of ≥50 mg. A concurrent serum calcium >10.2 mg/dL and parathyroid hormone >40 pg/mL was defined as persistent PHPT if present <6 mo and recurrent PHPT if present ≥6 mo postoperatively after initial normocalcemia. RESULTS: Of 1486 patients, 1203 (81%) had SGD, 159 (11%) DA, and 124 (8%) FGH. Among the 3 groups, there was no difference in the percent decrease from the baseline or time of excision to final postexcision IOPTH levels between groups (79% versus 80% versus 80%, respectively; P = 0.954) or in the proportion of patients with a final IOPTH ≥40 (22% versus 18% versus 14%; P = 0.059). Overall, 22 (1.5%) had persistent PHPT and 26 (1.7%) had recurrent PHPT. Persistent PHPT was more frequent with DAs (6; 3.8%) than other groups (SGD: 16, 1.3%; FGH: 0; P = 0.02). At median follow-up of 33 mo (IQR, 18-60), there was no difference in recurrence rate (1.6% versus 2.5% versus 2.4%; P = 0.57) or median time (mo) to recurrence (SGD: 59 [IQR, 21-86], DAs: 36 [IQR, 29-58], FGH: 23 [IQR, 17-40]; P = 0.46). CONCLUSIONS: Recurrent PHPT occurred in 1.7% of patients who underwent curative initial parathyroidectomy, with no difference in incidence or time to recurrence between groups based on the number of glands removed. Patients with DA more commonly had persistent PHPT, raising the possibility of unrecognized FGH.

OVARIAN GRANULOSA CELL TUMOR IN A PATIENT WITH A PATHOGENIC VARIANT IN THE CDC73 GENE (HYPERPARATHYROIDISM-JAW TUMOR SYNDROME).

OBJECTIVE: To report a patient with the hyperparathyroidism-jaw tumor syndrome (HPT-JT) who was found to have a rare ovarian tumor (granulosa cell tumor [GCT]). HPT-JT is caused by pathogenic variants in the CDC73 gene and results in primary hyperparathyroidism (PHPT), benign fibro-osseous jaw tumors, benign or malignant renal tumors and cysts, and benign or malignant uterine tumors. We believe this is the first reported case of HPT-JT and GCT. METHODS: The patient was a 31-year-old woman with abdominal pain who was found to have adult GCT. Her history was significant for a single gland parathyroidectomy at age 23 for PHPT. Her mother also had PHPT with 1-gland removal, as well as a history of renal cysts. Because of the personal and familial history of PHPT, she underwent germline sequencing of genes associated with PHPT including CASR, CDC73, CDKN1B, MEN1 and RET. RESULTS: Genetic testing revealed a CDC73 gene pathogenic variant (c.687_688dupAG) which creates a premature translational stop signal causing loss-of-function. CONCLUSION: We report a case of ovarian GCT in a young patient with primary hyperparathyroidism and a CDC73 gene mutation. Ovarian granulosa cell tumor may be another CDC73-related tumor.

Parathyroidectomy for primary hyperparathyroidism improves sleep quality: A prospective study.

BACKGROUND: This prospective survey study assessed changes in sleep quality in patients with primary hyperparathyroidism after parathyroidectomy. METHODS: Patients undergoing parathyroidectomy for primary hyperparathyroidism (n = 110) or thyroidectomy for benign euthyroid disease (control group; n = 45) were recruited between June 2013 and June 2015 and completed the Pittsburgh Sleep Quality Index preoperatively and at 1- and 6 months postoperatively. "Poor" sleep quality was defined as a score >5; a clinically important and relevant improvement was a ≥3-point decrease. RESULTS: Preoperatively, parathyroid patients had worse sleep quality than thyroid patients (mean 8.1 vs 5.3; P < .001); 76 (69%) parathyroid and 23 (51%) thyroid patients reported poor sleep quality (P = .03). Postoperatively, only parathyroid patients demonstrated improvement in sleep quality; mean scores did not differ between the parathyroid and thyroid groups at 1 month (6.3 vs 5.3; P = .12) or 6 months (5.8 vs 4.6; P = .11). The proportion of patients with a clinically important improvement in sleep quality was greater in the parathyroid group at 1 month (37% vs 10%; P < .001) and 6 months (40% vs 17%; P = .01). Importantly, there was no difference in the proportion of patients with poor sleep quality between the 2 groups at 1 month (50% vs 40%; P = .32) and 6 months (40% vs 29%; P = .22). CONCLUSION: More than two-thirds of patients with primary hyperparathyroidism report poor sleep quality. After parathyroidectomy, over one-third experienced improvement, typically within the first month postoperatively.

Low 24-hour urine calcium levels in patients with sporadic primary hyperparathyroidism: is further evaluation warranted prior to parathyroidectomy?

BACKGROUND: Low 24-hour urine calcium (uCa) levels in patients with primary hyperparathyroidism (pHPT) raise concern for familial hypocalciuric hypercalcemia. This study evaluated patients with a low 24-hour uCa level for potential differences that may guide the extent of preoperative evaluation needed. METHODS: A retrospective review was conducted of 1,139 sporadic pHPT patients who underwent parathyroidectomy between December 1999 and May 2011. RESULTS: Of the 54 (5%) patients with greater than or equal to one low 24-hour uCa (<100 mg), 28 (52%) patients had only one low level, 9 (17%) had multiple low levels, and 17 (31%) had a repeat 24-hour uCa greater than 100. In the latter group, 4 of the 9 (53%) patients were on a thiazide and had normalization after cessation. Among the groups, differences existed only in serum creatinine (P = .0011) and glomerular filtration rate (P = .0007). CONCLUSION: This study suggests that sporadic pHPT patients with low 24-hour uCa levels may not require further evaluation with genetic testing for familial hypocalciuric hypercalcemia, especially if previous eucalcemia is documented.

Successful treatment of tumor-induced osteomalacia with CT-guided percutaneous ethanol and cryoablation.

CONTEXT: Tumor-induced osteomalacia is a rare condition usually caused by benign mesenchymal tumors. When the tumor can be found, patients are usually managed by wide excision of the tumor. OBJECTIVE: We report a 51-yr-old male with clinical and biochemical evidence of tumor-induced osteomalacia caused by a mesenchymal tumor in the right iliac bone. He declined surgery and appears to have been successfully managed by computed tomography-guided percutaneous ethanol ablation and percutaneous cryoablation. RESULTS: Our patient appears to have had an excellent clinical and biochemical response to computed tomography-guided percutaneous ethanol ablation and percutaneous cryoablation. We found one prior case of image-guided ablation using radiofrequency ablation for tumor-induced osteomalacia. CONCLUSIONS: Although the standard treatment for tumor-induced osteomalacia is wide excision of the tumor, image-guided ablation may be an option in patients who cannot have appropriate surgery or who decline surgery.

Evolution of a pheochromocytoma.

OBJECTIVE: To present a case that demonstrates the evolution of a pheochromocytoma over a several-year period and to emphasize the importance of a thorough work-up for pheochromocytoma in patients with neurofibromatosis type 1 (NF1) and hypertension. METHODS: We review the long-term clinical, biochemical, and imaging findings in a man with a complex medical history of hypertension, NF1, and cardiomyopathy. RESULTS: A 44-year-old man, with a well-documented history of headaches, hypertension, and NF1, was referred for evaluation of a right adrenal enlargement. He had developed cardiomyopathy and undergone an evaluation for cardiac transplantation. Initial computed tomography revealed subtle asymmetry in the upper right adrenal gland. Biochemical studies for pheochromocytoma yielded equivocal findings, with a 1.5-fold elevation in the urinary norepinephrine and near-normal urinary metanephrine level. Because 131I-metaiodobenzylguanidine imaging showed no tracer uptake in the area of the right adrenal gland, the patient was thought not to have a pheochromocytoma. The patient eventually underwent cardiac transplantation and did well. On reassessment 3 1/2 years later, he was found to have a larger right adrenal mass. The second endocrine evaluation demonstrated substantial elevation in the urinary metanephrine level, and the patient underwent laparoscopic right adrenalectomy to remove the tumor (3.5 by 3.0 by 2.5 cm), which proved to be a pheochromocytoma. CONCLUSION: This case shows that a pheochromocytoma can be difficult to diagnose and can evolve to become a large, biochemically active tumor. It is imperative that patients with an adrenal tumor undergo periodic reevaluation to ensure that the tumor remains stable in size. If the tumor enlarges, further biochemical testing is warranted.

Tumoral calcinosis presenting with eyelid calcifications due to novel missense mutations in the glycosyl transferase domain of the GALNT3 gene.

CONTEXT: Familial tumoral calcinosis (TC) is a rare autosomal recessive disorder characterized by metastatic calcifications, often periarticular. Biochemical findings include hyperphosphatemia, high 1,25-dihydroxyvitamin D levels, and elevated tubular maximum for phosphate reabsorption per deciliter of glomerular filtrate (TmP/GFR). TC is caused by biallelic mutations of the genes encoding either fibroblast growth factor 23 (FGF23) or uridine diphosphate-N-acetyl-alpha-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc transferase 3 or GALNT3). OBJECTIVE: The objective was to identify mutations in FGF23 or GALNT3 responsible for a mild TC phenotype by DNA sequencing and to determine serum FGF23 levels by ELISA. PATIENTS OR OTHER PARTICIPANTS: The subject was a 25-yr-old Caucasian woman with eyelid calcifications and biochemical features of TC. RESULTS: Eyelid biopsy revealed superficial dermis calcifications. There was no history of metastatic calcifications, mineral homeostasis abnormalities, or renal dysfunction. Biochemistry revealed normal levels of calcium, creatinine, PTH, and 25-hydroxyvitamin D, with elevated phosphorous, TmP/GFR, and high normal 1,25-dihydroxyvitamin D levels. Intact FGF23 was undetectable (< 3 pg/ml), whereas C-terminal FGF23 was elevated (698.2 RU/ml). Mutation detection revealed compound heterozygosity for two novel mutations in the glycosyl transferase domain of the GALNT3 gene. CONCLUSION: Previously reported GALNT3 mutations in TC have been null mutations. This study shows that missense mutations affecting the glycosyl transferase domain of GalNAc transferase 3 also cause TC. Elevated C-terminal FGF23 fragments with undetectable intact FGF23 suggest that the mutant enzyme lacks the ability to glycosylate FGF23 and that glycosylation by GalNAc transferase 3 is necessary for secretion of functional full-length FGF23.

Sensitivity of fibroblast growth factor 23 measurements in tumor-induced osteomalacia.

CONTEXT: Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome of hypophosphatemia, decreased renal phosphate reabsorption, normal or low serum 1,25-dihydryxyvitamin-D concentration, myopathy, and osteomalacia. Fibroblast growth factor 23 (FGF23) is a phosphaturic protein overexpressed in tumors that cause TIO and is, at least partly, responsible for the manifestations of TIO. OBJECTIVE: The objective of this study was to determine the sensitivity of FGF23 measurements in TIO. DESIGN: FGF23 concentrations were measured on stored samples with three ELISAs. SETTING: This study was conducted at subspecialty referral centers. PATIENTS: Twenty-two patients with suspected TIO, 13 with confirmed tumors, were studied. INTERVENTIONS: There were no interventions in this study. MAIN OUTCOME MEASURE: FGF23 concentration was the main outcome measure of this study. RESULTS: Elevated FGF23 concentrations were detected using the Immunotopics C-terminal assay in 16 of 22 TIO patients (for a sensitivity of 73%), the Immunotopics Intact assay in five of 22 patients (sensitivity, 23%), and the Kainos Intact assay in 19 of 22 patients (sensitivity, 86%). In the 13 patients with confirmed tumors, the sensitivity was higher with all assays: 92% for the Immunotopics C-terminal assay, 38% for the Immunotopics Intact assay, and 100% for the Kainos assay. CONCLUSION: The Kainos Intact assay was the most sensitive, followed by the Immunotopics C-terminal assay. The findings of normal FGF23 concentrations in some patients with TIO may indicate that FGF 23 is not responsible for the hypophosphatemia in these patients or that FGF23 secretion by some tumors is partially responsive to serum phosphate. Normal FGF23 concentrations should be interpreted in relation to the serum phosphate and 1,25-dihydryxyvitamin-D concentrations.

Fanconi's syndrome in HIV+ adults: report of three cases and literature review.

UNLABELLED: We diagnosed Fanconi's syndrome (phosphate depletion and dysfunction of the renal tubules) in three HIV(+) patients. This was temporally related to their HIV treatment. Physicians caring for patients with HIV should recognize the association of this rare syndrome with antiretroviral medications and monitor their patients carefully. INTRODUCTION: Fanconi's syndrome is caused by increased excretion of phosphate, glucose, amino acids, and other intermediary metabolites, and can result in osteomalacia. MATERIALS AND METHODS: We diagnosed this syndrome in three HIV(+) patients. RESULTS: The first was a 43-year-old woman referred for multiple painful stress fractures. She demonstrated hypophosphatemia, metabolic acidosis, phosphaturia, glucosuria, and generalized aminoaciduria. These abnormalities resolved with oral phosphate replacement and discontinuation of the antiretroviral medication tenofovir. The second patient was a 39-year-old man with hypophosphatemia and bone pain. His symptoms improved with discontinuation of adefovir and supplementation of phosphate, potassium, and calcitriol. The third patient was a 48-year-old man who presented with symptomatic tetany caused by hypocalcemia (total serum calcium of 6.5 mg/dl [8.5-10.5 mg/dl]). Nine months before presentation, he had been treated with cidofovir for retinitis caused by cytomegalovirus. With calcium, phosphate, potassium, and calcitriol therapy, his laboratory abnormalities improved substantially, although he continues to require daily electrolyte replacement. CONCLUSIONS: Each patient demonstrated generalized renal tubular dysfunction temporally related to treatment with antiretroviral drugs. The mechanism responsible for these abnormalities is not known; however, physicians caring for patients with HIV disease should recognize the association of Fanconi's syndrome with antiretroviral medications and monitor susceptible patients to prevent potential skeletal and neuromuscular complications.