Hypercalcemia: A Review.

Importance: Hypercalcemia affects approximately 1% of the worldwide population. Mild hypercalcemia, defined as total calcium of less than 12 mg/dL (<3 mmol/L) or ionized calcium of 5.6 to 8.0 mg/dL (1.4-2 mmol/L), is usually asymptomatic but may be associated with constitutional symptoms such as fatigue and constipation in approximately 20% of people. Hypercalcemia that is severe, defined as total calcium of 14 mg/dL or greater (>3.5 mmol/L) or ionized calcium of 10 mg/dL or greater (≥2.5 mmol/L) or that develops rapidly over days to weeks, can cause nausea, vomiting, dehydration, confusion, somnolence, and coma. Observations: Approximately 90% of people with hypercalcemia have primary hyperparathyroidism (PHPT) or malignancy. Additional causes of hypercalcemia include granulomatous disease such as sarcoidosis, endocrinopathies such as thyroid disease, immobilization, genetic disorders, and medications such as thiazide diuretics and supplements such as calcium, vitamin D, or vitamin A. Hypercalcemia has been associated with sodium-glucose cotransporter 2 protein inhibitors, immune checkpoint inhibitors, denosumab discontinuation, SARS-CoV-2, ketogenic diets, and extreme exercise, but these account for less than 1% of causes. Serum intact parathyroid hormone (PTH), the most important initial test to evaluate hypercalcemia, distinguishes PTH-dependent from PTH-independent causes. In a patient with hypercalcemia, an elevated or normal PTH concentration is consistent with PHPT, while a suppressed PTH level (<20 pg/mL depending on assay) indicates another cause. Mild hypercalcemia usually does not need acute intervention. If due to PHPT, parathyroidectomy may be considered depending on age, serum calcium level, and kidney or skeletal involvement. In patients older than 50 years with serum calcium levels less than 1 mg above the upper normal limit and no evidence of skeletal or kidney disease, observation may be appropriate. Initial therapy of symptomatic or severe hypercalcemia consists of hydration and intravenous bisphosphonates, such as zoledronic acid or pamidronate. In patients with kidney failure, denosumab and dialysis may be indicated. Glucocorticoids may be used as primary treatment when hypercalcemia is due to excessive intestinal calcium absorption (vitamin D intoxication, granulomatous disorders, some lymphomas). Treatment reduces serum calcium and improves symptoms, at least transiently. The underlying cause of hypercalcemia should be identified and treated. The prognosis for asymptomatic PHPT is excellent with either medical or surgical management. Hypercalcemia of malignancy is associated with poor survival. Conclusions and Relevance: Mild hypercalcemia is typically asymptomatic, while severe hypercalcemia is associated with nausea, vomiting, dehydration, confusion, somnolence, and coma. Asymptomatic hypercalcemia due to primary hyperparathyroidism is managed with parathyroidectomy or observation with monitoring, while severe hypercalcemia is typically treated with hydration and intravenous bisphosphonates.

How and when is multiglandular disease diagnosed in sporadic primary hyperparathyroidism?

BACKGROUND: In total, ∼15% of patients with sporadic primary hyperparathyroidism have multiglandular disease, which may be suspected preoperatively but can only be confirmed intra or postoperatively. The study aim is to determine how and when patients are diagnosed with multiglandular disease and to what extent different modalities contribute. METHODS: Consecutive cases of sporadic primary hyperparathyroidism (2013-2019) undergoing initial exploration were reviewed from a single-institution prospective database. Preoperative single-photon emission tomography/computed tomography and neck ultrasound were routinely performed to help direct either bilateral or unilateral exploration guided by intraoperative parathyroid hormone monitoring using the dual criteria. Multiglandular disease was defined as either resection of >1 enlarged parathyroid or hypercalcemia at ≥6 months after single gland resection. RESULTS: Of 1,890 patients with sporadic primary hyperparathyroidism, multiglandular disease was identified in 254 (13.4%); 244 (96.1%) were diagnosed intraoperatively and 10 (3.9%) postoperatively. In these multiglandular disease patients, single gland disease was suggested on single-photon emission tomography/computed tomography in 54.0%, ultrasound in 49.2%, and both were concordant for single gland disease in 29.4%. Intraoperative multiglandular disease diagnosis was prompted by an inadequate intraoperative parathyroid hormone monitoring drop in 38.5%, by surgeon interpretation of imaging in 38.1%, by observing ipsilateral gland enlargement in 11.0%, by finding an initial gland <200 mg in 10.3%, and 2.0% had unexpected multiglandular disease during thyroidectomy. Multiglandular disease was diagnosed by postoperative hypercalcemia in 10 of 254 patients (4.9%). CONCLUSION: To avoid failure at parathyroidectomy for primary hyperparathyroidism, expert surgeons use multiple approaches to diagnose and manage multiglandular disease. Preoperative localization studies alone are insufficient, missing multiglandular disease in at least 30% of cases. All examined adjuncts are informative, including intraoperative parathyroid hormone monitoring, imaging, and intraoperative visual cues.

Stones left unturned: Missed opportunities to diagnose primary hyperparathyroidism in patients with nephrolithiasis.

BACKGROUND: Nephrolithiasis is a sequela of primary hyperparathyroidism and an indication for parathyroidectomy. The prevalence of primary hyperparathyroidism in patients with nephrolithiasis is 3% to 5%; however, recent studies suggest that many hypercalcemic patients with nephrolithiasis never undergo workup for primary hyperparathyroidism. Our goal is to evaluate primary hyperparathyroidism screening rates at a tertiary academic health institution and identify opportunities to increase referral rates in patients presenting with nephrolithiasis. METHODS: We retrospectively reviewed 15,725 patients across an academic health system who presented with nephrolithiasis between 2012 and 2020. Calcium levels measured within 6 months of presentation were identified, and those with hypercalcemia (≥10.3 mg/dL) were reviewed if parathyroid hormone levels were measured. Patients with primary hyperparathyroidism were evaluated to see if they were referred to a specialist for treatment. RESULTS: Of 15,725 patients presenting with nephrolithiasis, 12,420 (79%) had calcium levels measured; 630 patients (4.0%) were hypercalcemic, and 207 (33%) had parathyroid hormone levels measured. Patients were more likely to have parathyroid hormone levels sent if they were older, had higher calcium levels, or presented to an outpatient clinic (P = .028, P = .002, P < .001). We identified 89 patients (0.6%) with primary hyperparathyroidism, of which only 35 (39%) were referred for treatment. CONCLUSION: The proportion of patients presenting with nephrolithiasis ultimately diagnosed with primary hyperparathyroidism was significantly lower than others have reported. Additionally, a substantial number of patients with nephrolithiasis did not have calcium and/or parathyroid hormone levels measured. These missed opportunities for diagnosis are critical as early definitive management of primary hyperparathyroidism can prevent recurrent nephrolithiasis and other primary hyperparathyroidism-related end organ effects.

Recurrence after successful parathyroidectomy-Who should we worry about?

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.

Parathyroidectomy for nephrolithiasis in primary hyperparathyroidism: Beneficial but not a panacea.

BACKGROUND: Nephrolithiasis is a classic indication for parathyroidectomy in primary hyperparathyroidism patients; however, the effects of parathyroidectomy on nephrolithiasis recurrence are not well studied. The aim was to determine effect of parathyroidectomy on time to first nephrolithiasis recurrence and recurrence rate per patient-years. METHODS: A retrospective cohort study of patients diagnosed with primary hyperparathyroidism and at least one episode of nephrolithiasis was performed. The patients were divided into observation, presurgery, and postsurgery groups. Endpoints were time to first recurrence of nephrolithiasis and average recurrence rate per patient-years. RESULTS: The cohort was comprised of 1,252 patients. In addition, 334 (27%) patients underwent parathyroidectomy and 918 (73%) were observed. The surgical and nonsurgical groups differed significantly in age, sex, Charlson, calcium, and primary hyperparathyroidism level. Overall recurrence rate was 31.3%. The 5-, 10-, and 15-year recurrence-free survival rates were 74.4%, 56.3%, 49.5%, respectively (presurgery), 82.4%, 70.9%, 62.8%, respectively (postsurgery; P < .0001), and 86.3%, 77.7%, and 70.6%, respectively (observation). The presurgery group had an increased risk of first recurrence compared with the observation group (hazard ratio 1.89; 95% confidence interval, 1.44-2.47). The average recurrence rates among all surgical patients who recurred were 1 event per 4.3 patient-years presurgery versus 1 event per 6.7 patient-years postsurgery (P = .0001). CONCLUSION: Recurrent nephrolithiasis is a significant problem in patients with primary hyperparathyroidism. Parathyroidectomy prolongs the time to first recurrence and decreases the number of re-recurrences over time but does not eliminate recurrences. Observation may also be a reasonable approach in selected patients.

Serum Phosphate: A Neglected Test in the Clinical Management of Primary Hyperparathyroidism.

BACKGROUND: Although the inverse correlation between serum PTH and phosphate (P) levels in patients with primary hyperparathyroidism (PHPT) is well known, the relationship between P levels and the clinical picture of the disease has not been well investigated. This was thus the aim of this paper. PATIENTS: A total of 472 consecutive patients with PHPT attending our center were retrospectively evaluated at diagnosis. RESULTS: P levels lower than 2.5 mg/dL (HypoP) were found in 198/472 patients (41.9%). HypoP was mild (2-2.5 mg/dL), moderate (1-1.9 mg/dL), and severe (<1 mg/dL) in 168 (84.9%), 30 (15.1%), and 0 cases, respectively. P levels were lower in males than females. Patients with more severe bone density impairment at the radial (but not the vertebral or femoral) site had P levels significantly lower than other patients. PHPT severity was worse in HypoP patients, both clinically (higher prevalence of renal stones, but not of osteoporosis) and biochemically (higher serum calcium and PTH levels). All patients in the moderate HypoP group were either symptomatic or asymptomatic reaching surgical indication according to the latest guidelines. CONCLUSIONS: We observed a relationship between P levels and biochemical and clinical features of PHPT severity. In asymptomatic PHPT patients, even moderate HypoP is predictive of surgical indication, regardless of age and hypercalcemia severity.

Bone Turnover Markers in Response to Ultrasound-Guided Microwave Ablation for Primary Hyperparathyroidism.

Objective: To assess the efficacy and safety of ultrasound-guided microwave ablation (MWA) in the treatment of primary hyperparathyroidism (PHPT), and to investigate whether MWA can improve the bone turnover and renal function. Methods: A total of 20 consecutive PHPT patients with 21 parathyroid lesions treated with MWA in our center from May 2019 to March 2021 were recruited in this study. Serum parathyroid hormone (PTH), calcium and phosphorus levels before MWA and at 20 minutes, 4 hours, 1 day, 3 months, 6 months and 12 months after MWA were measured. Bone turnover biomarkers, renal function and lesion volume with volume reduction rate (VRR) before MWA and at the last follow-up were compared. Any complication related with MWA was evaluated. The technical and clinical success rates of MWA in the treatment of PHPT were calculated. Clinical success was defined as normal serum PTH and calcium without PHPT-associated manifestations at more than 6 months after ablation. Technical success was defined as complete ablation indicated by immediate postoperative contrast-enhanced ultrasound. Results: The serum PTH, calcium and phosphorus levels at their respective follow-up time points dropped significantly after MWA (P <0.05). The volume of parathyroid lesions at the final examination was significantly reduced, compared with pre-ablation volume (P <0.001), with a median VRR reaching 89%. The technical and clinical success rates were 100% and 63.6%, respectively. Substantial changes of bone turnover biomarkers were observed before and after MWA (P <0.05), but the differences in renal function were not statistically significant. No major complications were reported in all cases. Pre-MWA serum PTH, lesion volume, maximum diameter of lesion and ablation time were significantly different between patients with successful and failed MWA. Conclusions: PHPT can be effectively and safely treated by ultrasound-guided MWA, as proven by drop in serum PTH and reduction in the volume of parathyroid adenomas. Besides, MWA can impede bone remodeling to suppress hyperparathyroidism in the condition of PHPT.

Persistent hypercalcemia with similar familial Hypocalciuric hypercalcemia features: a case report and literature review.

BACKGROUND: Primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcemia (FHH) are the most important differential diagnosis of parathyroid hormone (PTH)-dependent hypercalcemia. The clinical features of FHH and PHPT can overlap in some cases. Therefore, these two diseases must be differentiated to prevent unnecessary parathyroidectomy. Here, we present a case that was not entirely matched with any of the known differential diagnoses of hypercalcemia. CASE PRESENTATION: A 19-year-old girl with no history of any disease presented with persistent hypercalcemia without any specific musculoskeletal complaint. We found persistent hypercalcemia in her routine laboratory data from 3 years ago; while no data was available during the childhood period. Her dietary calcium intake was normal. She did not mention any history of renal stone, bone fracture as well as family history of hypercalcemia. Biochemical features showed normal values of serum creatinine, high normal serum calcium (range, 10.3-11.3 mg/dL; (normal range: 8.8-10.4)), and non-suppressed PTH levels (range, 37.2-58.1 pg/mL; (normal range: 10-65)). Serum 25 OH vitamin D level at the first visit was 16.1 ng/mL that treated by vitamin D supplementation. Since then, all 25 OH vitamin D levels were in the acceptable range. After correction of vitamin D deficiency during the follow-up period the calcium creatinine clearance ratio(s) (CCCR) were calculated in the range of 0.009 to 0.014 (means below 1%). The clinical and laboratory data indicate more FHH rather than PHPT. Genetic studies were negative for the common genes associated with FHH (CASR, GNA11, and AP2S1 genes) and multiple endocrine neoplasia type1 (MEN1). On the other hand, no evidence of autoimmunity was found in her to support an autoimmune FHH-like syndrome. Hence, the case did not match completely to any diagnosis of FHH and PHPT, so we decided to follow her. CONCLUSION: We presented a patient with FHH phenotype whose common genetic tests were negative. Further research is needed to ascertain other causes leading to similar manifestations.

Number of cells in parathyroid tissue in primary hyperparathyroidism cases and its relationship with serum calcium value.

BACKGROUND: The relationship between serum calcium (Ca) level to serum parathyroid hormone (PTH), phosphorus (P) levels and tissue properties of the parathyroid gland is unknown in primary hyperparathyroidism cases. Revealing this relationship may be useful for understanding the etiopathogenesis of primary hyperparathyroidism and determining the time of treatment. METHODS: Ninety patients (71 females, 19 males, age range; 27-73 years, average age; 46) who underwent single gland excision with the diagnosis of primary hyperparathyroidism were studied. The patients were divided into 2 groups as serum Ca level <12 and serum Ca level ≥12. Age and sex of the patients, mean cell number of the gland, mean volume of the gland, serum levels of PTH, P, and histopathologic type of hyperplasia were evaluated. RESULTS: The mean cell number per cubic centimeter is 22.9 (10-220 range) million in all glands. Serum Ca level was <12 in 82 (91.1%) of the patients, and ≥12 in 8 (8.9%) cases. Mean cell number of the gland, mean volume of the gland, existence of cystic hyperplasia of the gland, serum levels of PTH and P were statistically significant between the 2 groups (P < .001, P < .001, P < .05, P < .001, P < .05 respectively). CONCLUSION: In primary hyperparathyroidism cases serum Ca level is not related to age and sex but directly related to proportionals to the cell number and volume of the gland and serum levels of PTH, inversely related to cystic hyperplasia and serum levels of P. Early surgical intervention should be planned since the serum Ca level will be high in large adenomas with a noncystic radiological appearance.

Evaluation and Management of Elevated Parathyroid Hormone Levels in Normocalcemic Patients.

Primary hyperparathyroidism is a common endocrine disorder. It used to present as a highly symptomatic disease before the advent of the multichannel autoanalyzer, now usually presenting as mild asymptomatic hypercalcemia. A newer presentation has been increasingly identified in the past two decades, normocalcemic primary hyperparathyroidism, presenting with elevated parathyroid hormone concentrations and consistently normal serum calcium. These patients are usually symptomatic, with parathyroid hormone levels measured in the evaluation for kidney stones or osteoporosis. It is important to exclude causes of secondary hyperparathyroidism. This review will focus on the evaluation and management of elevated parathyroid hormone levels in normocalcemic patients.

The Associations of Serum Osteocalcin and Cortisol Levels With the Psychological Performance in Primary Hyperparathyroidism Patients.

Objectives: The aim of this study was to investigate factors responsible for the psychological performance in primary hyperparathyroidism (PHPT) patients. Methods: A group of 38 PHPT patients receiving questionnaires, including Beck Depression Inventory (BDI), State-Trait Anxiety Inventory (STAI), and 36-Item Short Form Survey (SF-36), was evaluated. The relationships between scores of questionnaires and clinical biomarkers were examined. Collinearity and linear regression model were applied to examine variables determining the scores of the questionnaire. In 192 PHPT patients, bivariate and partial correlation were used to analyze the relationships between serum concentrations of parathyroid hormone (PTH), calcium, osteocalcin (OCN), and cortisol. Results: Among 38 patients receiving questionnaire tests, 50% (19/38) of the patients developed state anxiety, 60.5% (23/38) of the patients had the trait of developing anxiety. In addition, 18.4% (7/38) of the patients developed mild to severe depression. Serum cortisol at 8:00 was negatively and significantly correlated with social function (r = -0.389, p = 0.041) after controlling for age, sex, disease duration, serum PTH, calcium, phosphorus, and 25-hydroxyvitamin D [25(OH)D] concentration. OCN was significantly and negatively correlated with score of STAI-S (r = -0.426, p = 0.027). In the linear regression model for BDI score, variables with statistical significance were serum OCN (ß = -0.422, p = 0.019) and cortisol at 0:00 (ß = 0.371, p = 0.037). In 192 PHPT patients, the serum concentration of OCN (r = 0.373, p = 0.000) was positively correlated with PTH level. After controlling for age, sex, disease duration, serum 25(OH)D, phosphorus, and calcium concentration, the positive correlation between OCN and PTH was still statistically significant (r = 0.323, p = 0.000). The serum concentration of cortisol at 0:00 was significantly and positively correlated with serum calcium (r = 0.246, p = 0.001) in bivariate correlation analysis. After controlling for age, sex, disease duration, serum PTH, 25(OH)D, and phosphorus concentration, serum cortisol at 0:00 was still positively and significantly correlated with serum calcium (r = 0.245, p = 0.001). Conclusion: Serum levels of OCN and cortisol, rather than PTH and calcium, are associated with the development of anxiety and depression symptoms in PHPT patients.

Association between hypomagnesemia and severity of primary hyperparathyroidism: a retrospective study.

BACKGROUND: The occurrence of hypomagnesemia in patients with primary hyperparathyroidism (PHPT) has been noted previously; however, the association of hypomagnesemia and severity of primary hyperparathyroidism remains unknown. The present study aimed to evaluate the association of hypomagnesemia with biochemical and clinical manifestations in patients with PHPT. METHODS: This was a retrospective study conducted at a tertiary hospital. We obtained data from 307 patients with PHPT from January 2010 through August 2020. Data on demographics, history, laboratory findings, bone densitometry findings, and clinical presentation and complications were collected and were compared in normal magnesium group vs hypomagnesemia group. RESULTS: Among the 307 patients with PHPT included in our study, 77 patients (33/102 [32.4%] males and 44/205 [21.5%] females) had hypomagnesemia. Mean hemoglobin levels in the hypomagnesemia group were significantly lower than those in the normal magnesium group in both males and females. In contrast, patients with hypomagnesemia had a higher mean serum calcium and parathyroid hormone than individuals with normal magnesium. The typical symptoms of PHPT, such as nephrolithiasis, bone pain/fractures, polyuria, or polydipsia, were more common in the hypomagnesemia group. In addition, patients with hypomagnesemia had a higher prevalence of osteoporosis, anemia, and hypercalcemic crisis. Even after adjusting for potential confounders, including age, sex, body mass index, estimated glomerular filtration rate, and parathyroid hormone levels, these associations remained essentially unchanged. CONCLUSION: Biochemical and clinical evidence indicates that patients with PHPT with hypomagnesemia have more severe hyperparathyroidism than those without hypomagnesemia. In addition, PHPT patients with hypomagnesemia had a higher prevalence of osteoporosis, anemia, and hypercalcemic crisis.

Factors associated with negative 99mTc-MIBI scanning in patients with primary hyperparathyroidism.

OBJECTIVE: The objective was to evaluate the clinical and biological factors associated with negative 99mTc-MIBI scanning in patients with primary hyperparathyroidism (PHPT). METHODS: A retrospective observational study was designed in 195 patients (mean age: 59.2 ±â€¯13.0 years; 77% woman) with PHPT (calcium: 11,3 ±â€¯1,1 mg/dl and PTH: 218 ±â€¯295 pg/ml) studied in endocrinology setting between 2013 and 2020. An univariate and multivariate analysis was made to evaluate the clinical and biological factors associated with negative 99mTc-MIBI scanning. RESULT: 50 patients (26%) with negative 99mTc-MIBI scanning had lower PTH levels (146 ±â€¯98 vs. 244 ±â€¯334; p < 0,001), adenomas with smaller sonographic dimensions (maximum diameter: 1,2 ±â€¯0,4 vs. 1,7 ±â€¯0,9 cm; p = 0,001 and volume: 0,36 ±â€¯0,43 vs. 1,7 ±â€¯4,1 cm3; p < 0,001), localized more frequently in upper parathyroid glands (37% vs 14%; p = 0,005) and associated more frequently to thyroid nodules (72% vs 57%; p = 0,045) than patients with positive scanning. 116 patients were operated and parathyroid adenomas were smaller (maximum diameter: 1,3 ±â€¯0,5 vs. 1,9 ±â€¯1,1 cm; p = 0,008 and volume: 0,30 ±â€¯0,20 vs. 1,2 ±â€¯1,1 cm3; p < 0,001), less heavy (567 ±â€¯282 vs. 1470 ±â€¯1374 mgr.; p = 0,030) and were localized more frequently in upper situation (65% vs 16%; p < 0,001) than patients with positive scanning. In the multivariate analysis an independent association between negative 99mTc-MIBI scanning and size of removed adenoma ≤1 cm (OR: 5,77; IC 95: 1,46-22,71) and upper adenoma localization were observed (OR: 8,05; IC 95%: 2,22-29,16). CONCLUSIONS: One in four patients studied for PHPT had a negative 99mTc-MIBI scanning and were independent associated with size of adenoma ≤1 cm and upper adenoma localization.

Systems-Level Opportunities in the Management of Primary Hyperparathyroidism: An Informatics-based Assessment.

CONTEXT: Primary hyperparathyroidism (PHPT), a leading cause of hypercalcemia and secondary osteoporosis, is underdiagnosed. OBJECTIVE: This work aims to establish a foundation for an electronic medical record-based intervention that would prompt serum parathyroid hormone (PTH) assessment in patients with persistent hypercalcemia and identify care gaps in their management. METHODS: A retrospective cohort study was conducted in a tertiary academic health system of outpatients with persistent hypercalcemia, who were categorized as having classic or normohormonal PHPT. Main outcome measures included the frequencies of serum PTH measurement in patients with persistent hypercalcemia, and their subsequent workup with bone mineral density (BMD) assessment, and ultimately, medical therapy or parathyroidectomy. RESULTS: Among 3151 patients with persistent hypercalcemia, 1526 (48%) had PTH measured, of whom 1377 (90%) were confirmed to have classic (49%) or normohormonal (41%) PHPT. PTH was measured in 65% of hypercalcemic patients with osteopenia or osteoporosis (P < .001). At median 2-year follow-up, bone density was assessed in 275 (20%) patients with either variant of PHPT (P = .003). Of women aged 50 years or older with classic PHPT, 95 (19%) underwent BMD assessment. Of patients with classic or normohormonal PHPT, 919 patients (67%) met consensus criteria for surgical intervention, though only 143 (15%) underwent parathyroidectomy. CONCLUSION: Within a large academic health system, more than half of patients with confirmed hypercalcemia were not assessed for PHPT, including many patients with preexisting bone disease. Care gaps in BMD assessment and medical or surgical therapy represent missed opportunities to avoid skeletal and other complications of PHPT.

Is extensive surgery really necessary in patients with parathyroid carcinoma? Single-centre experience and a brief review of the literature.

AIM: Parathyroid carcinoma (PC) represents a rare cause of primary hyperparathyroidism (PHPT). In this paper, among patients who underwent surgery for PHPT, we compared those with benign parathyroid disease with those affected by PC in terms of demographic and preoperative biochemical features. Moreover, we singularly described all 10 cases of PC treated at our Institution (including a case that occurred in a patient with tertiary hyperparathyroidism) and a brief review of the literature. MATERIAL AND METHODS: Patients undergoing surgery for PHPT in our Unit between 2003 and 2018 were retrospectively analysed. They were divided into two groups: Group A (benign parathyroid disease), Group B (PC). The case of PC that occurred in the patient with tertiary hyperparathyroidism was not included into the two groups. RESULTS: Three hundred and eight patients were included: 299 in Group A and 9 in Group B. The mean preoperative serum PTH value and mean preoperative serum calcium level were significantly higher in Group B than in Group A (P = 0.018, P = 0.027; respectively). Including the case of PC that occurred in the patient with tertiary hyperparathyroidism, 10 patients with PC were treated at our Institution. Among these, 3 underwent a re-exploration. Disease recurrence occurred in 1 (10%) patient, who developed a local recurrence and distant metastases. CONCLUSIONS: In the presence of PHPT characterized by particularly high preoperative levels of serum PTH and calcium this malignancy should be suspected. On the basis of our experience, we believe that extensive surgery is not always necessary. KEY WORDS: Hyperparathyroidism, Parathyroid carcinoma, Parathyroid surgery.

Focused parathyroidectomy without intraoperative parathyroid hormone measurement in primary hyperparathyroidism: Still a valid approach?

BACKGROUND: Concern regarding suboptimal cure rates has led to some endocrine surgery units abandoning focused parathyroidectomy for primary hyperparathyroidism in favor of open bilateral neck exploration or making intraoperative parathyroid hormone estimation mandatory in focused parathyroidectomy. This study explores whether focused parathyroidectomy for radiologically localized primary hyperparathyroidism without intraoperative parathyroid hormone is still a valid approach. METHODS: Retrospective review of a tertiary referral endocrine surgery unit database. All parathyroidectomies for primary hyperparathyroidism over 6 years (2013-2019) were included. Lithium-induced hyperparathyroidism, reoperations, familial disease, and concurrent thyroid surgery were excluded. Characteristics and outcomes for focused parathyroidectomy and open bilateral neck exploration were compared by intention-to-treat and treatment delivered. Persistence and recurrence, conversions and complications were analyzed as endpoints. RESULTS: A total of 2,828 parathyroidectomies were performed and 2,421 analyzed. By intention to treat there were 1,409 focused parathyroidectomies and 1,012 open bilateral neck explorations. Focused parathyroidectomy patients were younger: 63 vs 66 years (P < .01); however, gender (77%, 79% female), preoperative peak serum calcium (2.72, 2.70 mmol/L [P = .23]), and serum parathyroid hormone (11.5, 11.0 pmol/L [P = .52]) did not differ. In total, 229 (16.3%) focused parathyroidectomies were converted to open bilateral neck exploration. Multiple gland disease was confirmed in 54.5% of converted patients. Median follow-up was 41 months (3-60 months). Persistence or recurrence requiring reoperation totaled 2.2% and did not differ between focused parathyroidectomy and open bilateral neck exploration in either intention to treat or final treatment analyses. Complications occurred in 1.2% of focused parathyroidectomy and 3.2% open bilateral neck exploration (P < .01). CONCLUSIONS: In experienced hands and with a ready-selective approach to conversion, focused parathyroidectomy based on concordant imaging and without intraoperative parathyroid hormone may deliver equivalent cure rates to open bilateral neck exploration with significantly fewer complications. Focused parathyroidectomy without intraoperative parathyroid hormone should therefore be maintained in the endocrine surgeon's armamentarium.

Primary hyperparathyroidism presenting as a brown tumor with hypercalcemia crisis in a second-trimester pregnant woman: A case report.

INTRODUCTION: Primary hyperparathyroidism (PHPT) in pregnancy is rare and unrecognized because the maternal physiological adaptations blurs the symptoms. There is no standard treatment strategy for maternal PHPT. Early diagnosis and interventions can prevent catastrophic consequences to the mother and fetus. PATIENT CONCERNS: A 31-year-old Chinese woman was admitted, due to a lump on the left lower leg for 4 months. The patient complained of mild pain in the left lower leg following exercise that could be relieved after a short rest. The patient was at 18 weeks of gestation, and the growth of the fetus was normal. The patient has a 3-year history of hypercalcemia and a 2-year history of nephrolithiasis. No family history of hypercalcemia and endocrine tumors were present. DIAGNOSIS: Laboratory tests demonstrated high serum calcium level of 3.84 mmol/L, parathyroid hormone 1393 pg/mL, alkaline phosphatase 488 µ/L. Ultrasound showed a 22.4 mm × 7.8 mm solid nodule in the left lower lobe of the thyroid gland. Based on these findings, the patient was diagnosed with PHPT. INTERVENTIONS: The patient accepted continuous renal replacement to reduce ironized calcium level. Parathyroidectomy was performed at the 19th week of gestation. Threatened abortion occurred 2 days after the surgery, and magnesium sulfate was used to prevent the abortion. Calcium gluconate, calcium carbonate and vitamin D3 were used to treat the hypocalcemia that occurred 5 days after the surgery. OUTCOMES: Pathology examination demonstrated the parathyroid adenoma. Abortion was prevented using magnesium sulfate and hypocalcemia was cured with calcium gluconate, calcium carbonate and vitamin D3. At 38-week of gestation, the patient (ionized calcium level: 2.16 mmol/L) delivered a healthy female baby weighing 2700 g with 10/10 Apgar. Till now, both the mother and infant showed no complications. CONCLUSION: Maternal PHPT is rare and challenging to diagnose, causing life-threatening complications to mother and fetus. Any decision regarding surgery for a pregnant woman with primary hyperparathyroidism is more complex than in men or nonpregnant women. The decision should be made based on the severity of hypercalcemia and symptoms.

Higher prevalence of Concomitant Hyperparathyroidism in African American Patients Undergoing Thyroid Surgery.

BACKGROUND: Hyperparathyroidism (HPT) occurs in about 1% of the general population. Previous studies have suggested that the incidence is higher in those patients with thyroid disease who are undergoing thyroid surgery. The study purpose was to examine the incidence of concomitant HPT in patients already undergoing a thyroid procedure and to identify risk factors. MATERIALS AND METHODS: A prospective database of all patients who had thyroidectomy by the endocrine surgery team was reviewed between August 2012 and April 2020. Per institutional protocol, all patients having thyroid surgery were screened for concomitant hyperparathyroidism. ANOVA/T-Test and Chi-square were conducted to compare those with and without hyperparathyroidism. RESULTS: The median age was 43 and 79% were female. Of the 481 patients undergoing thyroidectomy, 31 (6%) had HPT. The mean preoperative calcium and parathyroid hormone levels were 10 ± 0 mg/dL and 67 ± 5 pg/mL, respectively. When comparing the groups, patients with concomitant HPT were older (53 ± 4 versus 42 ± 1 y, P = 0.005). African American race was a significant risk factor for concomitant HPT. While African Americans represented only 29% of those undergoing surgery, 58% of those with concomitant HPT were African American (P = 0.007). CONCLUSION: In patients having thyroid surgery, concomitant HPT was present in 6% of the population, higher than estimated general population prevalence. While we understand that primary HPT incidence increases with age, to our knowledge, this is the first report to document that African Americans are at a higher risk for concomitant HPT with thyroid disease. Thus, routine screening for hyperparathyroidism in patients undergoing thyroid surgery, especially in vulnerable populations, such as the older and African American population, is beneficial.

Mortality after surgery for primary hyperparathyroidism: results from a nationwide cohort.

BACKGROUND: Contemporary patients with primary hyperparathyroidism are often diagnosed with mildly raised serum calcium levels. Previous studies have reported increased mortality in patients with primary hyperparathyroidism. This retrospective cohort study aimed to examine whether contemporary patients operated for primary hyperparathyroidism have higher mortality than the general population, and whether mortality in these patients is associated with serum calcium concentration, adenoma weight or multiglandular disease. METHODS: Patients from a Swedish national cohort consisting of patients registered in the Scandinavian Quality Register for Thyroid, Parathyroid, and Adrenal Surgery 2003-2013, were matched with population controls. The National Patient Register, the Swedish Cause of Death Register, and socioeconomic data were cross-linked. End of follow-up was 10 years after surgery, 31 December 2015, or emigration. Mortality was analysed by standardized mortality ratio, Kaplan-Meier survival estimates, and univariable and multivariable Cox regression. Multiple imputation by chained equations was performed on missing data. RESULTS: After exclusions, there were 5009 patients with primary hyperparathyroidism and 14 983 controls. Multivariable Cox regression analysis adjusted for age, sex, Charlson Co-morbidity Index, marital status, level of education, disposable income, and period of surgery showed lower mortality in patients than controls (hazard ratio (HR) 0.83, 95 per cent c.i. 0.75 to 0.92). In univariable Cox regression of mortality in patients, serum calcium concentration (mmoles per litre) was associated with mortality (HR 2.20, 1.53 to 3.16). This association remained in multivariable Cox regression after multiple imputation (HR 1.79, 1.19 to 2.70). CONCLUSION: Mortality was not increased in patients operated for primary hyperparathyroidism compared with controls in a contemporary setting. Preoperative serum calcium concentration might, however, influence survival.

Role of LncRNA score and PVT1 in primary hyperparathyroidism-- a preliminary study.

BACKGROUND: Dysregulated lncRNA score and PVT1 expression may be involved in cancer. However, relationships of lncRNAs with hyperparathyroidism and parathyroid cancer (PC) diagnosis remain mysterious. METHODS: Using quantitative real-time polymerase chain reaction (RT-qPCR), expression profile of PVT1 was evaluated in 57 patients with primary hyperparathyroidism, including 11 with parathyroid cancer (PC) and 46 with parathyroid adenoma (PA). RESULTS: Higher levels of lncRNA score and PVT1 expression were associated with increased serum calcium level after water ingestion and PC risk (P < 0.05). Accordingly, lncRNA score and PVT1 expression were increased with varying degrees of hypercalcemia in PC. A higher level of lncRNA score (but not PVT1) was an independent risk factor of PC, with an AUC up to 0.872 (95% CI: 0.756-0.945, P < 0.001). Moreover, lncRNA score was more valuable (with AUC 0.974, sensitivity of 85.71% and specificity of 100%, respectively) than intact parathyroid hormone (iPTH) in predicting risk of PC among patients with hypercalcemia (especially based on greater AUC, P = 0.010). CONCLUSION: Increased lncRNA score is correlated with an elevated level of serum calcium, which may serve as a potential biomarker for PC diagnosis, especially with hypercalcemia.