Classic Primary Hyperparathyroidism Research Articles

Hyperparathyroidism and Peripheral Arterial Disease.

Primary hyperparathyroidism (PHPT) is presented in various forms, including classic PHPT, characterised by increased parathyroid hormone (PTH) secretion, normohormonal PHPT, and normocalcaemic PHPT. Secondary hyperparathyroidism is characterised by increased PTH secretion triggered by factors such as vitamin D deficiency and kidney failure. This review aims to discuss the involvement of hyperparathyroidism (HPT) in atherosclerosis, including peripheral arterial disease (PAD). The increased level of PTH is involved in developing subclinical and overt vascular diseases, encompassing endothelial dysfunction, vascular stiffness, hypertension, and coronary and peripheral arterial diseases. It has been consistently associated with an augmented risk of cardiovascular morbidity and mortality, independent of classical risk factors for atherosclerosis. Chronic hypercalcemia associated with increased levels of PTH contributes to the development of calcification of vessel walls and atherosclerotic plaques. Vascular calcification can occur in the intima or media of the arterial wall and is associated with stiffness of peripheral arteries, which the formation of atherosclerotic plaques and narrowing of the vessel lumen can follow. For treating hyperparathyroidism, particularly SHPT, calcimimetics, novel phosphorus binders and novel vitamin D receptor activators are used. However, they are ineffective in severe PHPT. Therefore, parathyroidectomy remains the primary therapeutic option of PHPT.

Normocalcemic hyperparathyroidism: Intervention to differentiate primary from secondary hyperparathyroidism

BackgroundNormocalcemic hyperparathyroidism can occur, but surgery should not be considered until common etiologies for secondary hyperparathyroidism are comprehensively excluded. Calcium deficiency is an underrecognized cause of normocalcemic parathyroid hormone elevation, and we aim to determine if the implementation of a preoperative calcium challenge can be used to reduce unnecessary parathyroidectomy. MethodsConsecutive patients referred for parathyroidectomy (1/21–6/22) with normocalcemia (serum calcium <10 mg/dL) and concurrently elevated parathyroid hormone levels were routinely treated with supplemental calcium and vitamin D3, and follow-up laboratory studies were assessed. ResultsA total of 29/314 (9%) patients had normocalcemic parathyroid hormone elevation with mean calcium, parathyroid hormone, and vitamin D 25OH levels of 9.5 ± 0.3 mg/dL, 109.9 ± 34.9 pg/mL, and 42.7 ± 23.8 ng/mL respectively. Confounding factors included estimated glomerular filtration rate <60 in 2, loop diuretic use in 4, and prior gastric bypass or gastric sleeve surgery in 4. Follow-up biochemical evaluation was available in 27 (92%); results were unchanged in 7 patients (26%); normalization of parathyroid hormone levels with persistently normal calcium levels occurred in 15 (55%), thus confirming secondary hyperparathyroidism and hypercalcemia with elevated parathyroid hormone levels (classic primary hyperparathyroidism) was diagnosed in 5 (19%). Parathyroid exploration has been completed for 3 of 5 patients with classic primary hyperparathyroidism to date. ConclusionA preoperative calcium challenge was prospectively initiated in normocalcemic patients with parathyroid hormone elevation, and there was high compliance (92%). Short-interval calcium supplementation revealed ∼50% to have resolved secondary hyperparathyroidism due to insufficient calcium intake, which avoided unnecessary surgery. In contrast, classic patients were unveiled in 20%, allowing for prompt and correct surgical intervention.

Normocalcemic primary hyperparathyroidism is an early stage of primary hyperparathyroidism according to fibroblast growth factor 23 level.

Normocalcemic primary hyperparathyroidism is a variant of primary hyperparathyroidism with consistently normal albumin-adjusted or free-ionized calcium levels. It may be an early stage of classic primary hyperparathyroidism or could represent primary kidney or bone disorder characterized by permanent elevation of PTH level. The study aims to compare the FGF-23 levels in patients with PHPT, NPHPT, and normal calcium and PTH levels. Our study included patients who were referred to the endocrinology clinic with a presumptive diagnosis of primary hyperparathyroidism, an isolated increased level of PTH, or reduced bone densitometry. For each patient, we performed blood analysis of FGF-23, calcium, phosphate, vitamin D [25(OH)D3], estimated glomerular filtration rate (eGFR), bone turnover markers, and urine analysis for calcium/creatinine ratio. Our study included 105 patients. Thirty patients with hypercalcemic hyperparathyroidism (HPHPT group), thirty patients with elevated PTH and normal calcium levels (NPHPT group), and 45 patients with normal calcium and PTH levels in the control group. FGF 23 level was 59.5± 23 pg/ml in the NPHPT group, 77 ± 33 pg/ml in the HPHPT group, and 49.7 ± 21.7 pg/ml in the control group (p=0.012). The phosphate level was lowest in the HPHPT group: 2.9 ± 0.6 vs 3.5 ± 0.44 in the NPHPT and 3.8 ± 0.5 in the control groups (p=0.001). No differences were found in eGFR, 25(OH)D3, C-terminal telopeptide type I collagen (CTX) and procollagen type 1 N-terminal propeptide (P1NP) levels, and bone densitometry scores between the three study groups. Our findings suggest that NPHPT is an early stage of PHPT. Further studies are needed to determine the role of FGF-23 and its usefulness in NPHPT.

Familial hypocalciuric hypercalcaemia type 1 caused by a novel heterozygous missense variant in the CaSR gene, p(His41Arg): two case reports

BackgroundFamilial hypocalciuric hypercalcaemia (FHH) is a rare, inherited disorder of extracellular calcium sensing. It is clinically characterised by mild to moderate parathyroid hormone dependent hypercalcaemia, an autosomal dominant pattern of inheritance, and a normal to reduced urinary calcium excretion in spite of high serum calcium.Case presentationWe report two cases of FHH in a family caused by a novel pathogenic missense variant in the CaSR gene, p. His41Arg. Case 1, describes a 17 year old female with no significant past medical history, admitted with acute appendicitis requiring laparoscopic appendectomy and reporting a six month history of polydipsia. Routine investigations were significant for hypercalcaemia, corrected calcium 3.19 mmol/L (2.21-2.52mmol/L), elevated parathyroid hormone of 84pg/ml (15-65pg/ml) and a low 24-hour urine calcium of 0.75mmol/24 (2.50-7.50mmol/24). She was initially managed with intravenous fluids and Zolendronic acid with temporary normalisation of calcium though ultimately required commencement of Cinacalcet 30 mg daily for persistent symptomatic hypercalcaemia. Genetic analysis was subsequently positive for the above variant. Case 2, a 50-year-old female, was referred to the endocrine outpatient clinic for the management of type 2 diabetes and reported a longstanding history of asymptomatic hypercalcaemia which had not been investigated previously. Investigation revealed hypercalcaemia; corrected calcium of 2.6 mmol/L (reference range: 2.21–2.52 mmol/L); PTH of 53.7ng/L (reference range: 15–65 ng/L) and an elevated 24-hour urine calcium of 10 mmol/24 (2.50–7.50 mmol/24hr) with positive genetic analysis and is managed conservatively. Despite sharing this novel mutation, these cases have different phenotypes and their natural history is yet to be determined. Two further relatives are currently undergoing investigation for hypercalcaemia and the family have been referred for genetic counselling.ConclusionAccurate diagnosis of FHH and differentiation from classic primary hyperparathyroidism can be challenging, however it is essential to avoid unnecessary investigations and parathyroid surgery. Genetic analysis may be helpful in establishing a diagnosis of FHH in light of the biochemical heterogeneity in this population and overlap with other causes of hypercalcaemia.

How low is too low? Intraoperative parathyroid hormone decline in normohormonal primary hyperparathyroidism

BackgroundIn normohormonal primary hyperparathyroidism, parathyroid hormone levels are normal but inappropriately elevated for the degree of hypercalcemia. The study goals were to determine intraoperative parathyroid hormone parameters predictive of (1) cure and (2) hypocalcemia in this subgroup. MethodsWe performed a retrospective cohort study comparing patients who underwent parathyroidectomy (2002–2019) for normohormonal and classic primary hyperparathyroidism. The primary outcomes were cure (calcium <10.3 mg/dL) and hypocalcemia (≤8.4 mg/dL) ≥6 months postoperatively. ResultsIn the study, 127 of 1,087 patients (11.7%) had normohormonal primary hyperparathyroidism. The groups experienced similar rates of cure (91.3% vs 94.1%, P = .23) and hypocalcemia (3.9% vs 2.9%, P = .53). However, intraoperative parathyroid hormone decline in cured patients was lower in those with normohormonal primary hyperparathyroidism (66.4% vs 84.5%, P < .0001). Receiver operating characteristic curves provided Youden’s indices of 52% and 75% (cure) and 75% and 88% (hypocalcemia) for patients with normohormonal and classic primary hyperparathyroidism, respectively. Cure rates with ≥50% intraoperative parathyroid hormone decline were similar (94.1% vs 95.0%, P = .72), but hypocalcemia was more prevalent in patients with normohormonal primary hyperparathyroidism and ≥70% intraoperative parathyroid hormone decline (10.4% vs 3.3%, P = .01). ConclusionIn patients with normohormonal primary hyperparathyroidism, intraoperative parathyroid hormone declines of ≥50% and ≥70% were predictive of postoperative cure and hypocalcemia, respectively. These parameters may inform intraoperative decision making and postoperative management.

Effect of Parathyroidectomy on Metabolic Homeostasis in Primary Hyperparathyroidism.

Background: The benefits of parathyroidectomy on cardiovascular risk in primary hyperparathyroidism (PHPT) are controversial. This monocentric, observational, prospective study aimed to assess the effects of parathyroidectomy on glucose and lipid metabolism in classic or mild PHPT. Methods: Patients who underwent parathyroidectomy for classic (calcemia >2.85 mmol/L) or mild PHPT (calcemia ≤2.85 mmol/L) between 2016 and 2019 were included. A metabolic assessment was performed before and 1 year after parathyroidectomy. Patients with a history of diabetes were excluded. Results: Nineteen patients had classic and 120 had mild PHPT. Ninety-five percent were normocalcemic 6 months after surgery. Fasting plasma glucose and insulin levels decreased after parathyroidectomy in patients with mild PHPT (p < 0.001). HOMA-IR decreased after surgery in the overall population (p < 0.001), while plasma adiponectin concentrations increased in patients with both classic (p = 0.005) and mild PHPT (p < 0.001). Plasma triglyceride levels decreased significantly only in patients with classic PHPT (p = 0.021). Plasma PCSK9 levels decreased in patients with mild PHPT (p < 0.001). Conclusions: Parathyroidectomy for PHPT improves insulin resistance and decreases plasma triglyceride levels in classic PHPT and plasma PCSK9 levels in mild PHPT. Further studies are needed to better characterize the consequences of such metabolic risk factors’ improvements on cardiovascular events.

Comparison of Parathyroid Autofluorescence Signals in Different Types of Hyperparathyroidism.

There are scant data in the literature regarding whether parathyroid autofluorescence (AF) signal patterns vary based on the etiology of hyperparathyroidism. The aim of this study was to compare AF signals of parathyroid glands across different etiologies of hyperparathyroidism. As a prospective institutional review board-approved study between 2016 and 2019, AF intensities and heterogeneity indexes (HIs) of parathyroid glands in patients who underwent parathyroidectomy using AF were calculated and compared using Chi-square, Kruskal Wallis, Mann Whitney U, and logistic regression tests. Of the total of 183 patients, 127 patients had sporadic classic primary hyperparathyroidism, 30 patients had sporadic normohormonal primary hyperparathyroidism, 10 patients had sporadic normocalcemic primary hyperparathyroidism, 12 patients had tertiary hyperparathyroidism, and 4 patients had familial primary hyperparathyroidism related to multiple endocrine neoplasia (MEN) 2A. There were no statistical differences in AF signals of abnormal parathyroid glands in classic, normohormonal or normocalcemic sporadic hyperparathyroidism. Parathyroid glands in patients with tertiary hyperparathyroidism were similar in intensity, but more homogenous compared to those in sporadic primary hyperparathyroidism. The pattern of AF exhibited by abnormal parathyroid glands was similar across different spectrums of primary hyperparathyroidism, in accordance with observations in the literature. However, parathyroid glands in tertiary hyperparathyroidism were more homogeneous, despite exhibiting a similar intensity of AF compared to those in sporadic primary hyperparathyroidism. These differences should be kept in mind when using the AF pattern as an adjunct to visual assessment in parathyroid exploration.

Surgical management of MILD hyperparathyroidism.

There is no consensus for management of Mild primary hyperparathyroidism (MILD-pHP). Specific management has been suggested by some authors. We have compared the surgical management of the patients with MILD-pHP to those with Classic primary hyperparathyroidism (C-pHP) treated by surgery according to The Fourth International Workshop on pHP. Data of 173 patients who underwent a parathyroidectomy were reviewed and retrospectively analysed. Management of 32 patients with MILD-pHPT (18.5%) patients were compared to that of 141 (81.5%) patients with C-pHPT. MILD-pHP group was more often discovered after non-fractured osteoporosis (21.9% vs 7.1%, p = 0.02) and surgery for chondrocalcinosis was more often carried out (6.3% vs 0%, p = 0.03) in the MILD-pHP group. A Mini-Invasive Parathyroidectomy (MIP) was carried out in 81.3% of cases, and 87.5% of patients had a single adenoma. The rate of multiglandular pathology was not different. Same day discharge was significantly higher in MILD-pHP group (37.5% vs 17.7%, p = 0.01). Success was obtained in 87.5% in the MILD-pHP group, there was no significant difference with the C-pHP group (92.9%, p = 0.48). There was no significant difference in the imaging performances. Imaging discordance was observed in 18.8% of cases in MILD-pHP and 33.6% in C-pHP (p = 0.38) without correlation with surgical failure. This study suggests that, by selecting patients on the basis of concordant imaging and international recommendations, there is no difference in outcome between MILD-pHP and C-pHP treated surgically.

MON-123 Underdiagnosis of Primary Hyperparathyroidism in the Outpatient Setting of an Academic Health Care System

Background: Primary hyperparathyroidism (PHPT) is the leading cause of hypercalcemia in the outpatient population and is associated with nephrolithiasis, osteoporosis, and further end-organ effects. When indicated, parathyroidectomy is an effective intervention. The aim of this study was to assess the prevalence of patients with hypercalcemia resulting from undiagnosed PHPT within a large, urban, academic healthcare system. Methods: The study population comprised all patients within UCLA Health. The electronic medical record was queried between 01/01/2016-12/31/2018 to include patients with at least two elevated serum total calcium concentrations (>10.4 mg/dL) within a six-month period in the outpatient setting. Causes of secondary and tertiary PHPT were excluded. In concordance with the PHPT diagnostic criteria outlined by the Fourth International Workshop, we evaluated the proportion of patients with hypercalcemia who were further assessed with a serum intact parathyroid hormone (iPTH) test. The study identified cases of PHPT as defined by confirmed elevated serum total calcium concentrations and elevated or inappropriately normal iPTH concentrations. Results: There were 7102 patients with a single elevated serum total calcium result who never received a repeat assessment within the study period. Although there were 5617 patients with confirmed hypercalcemia, only 2773 (51%) had an iPTH level assessed within six months of the repeated calcium measurement. Of those who underwent iPTH testing, 1931 (69%) were biochemically confirmed to have classic (34.2%) or normohormonal (35.4%) PHPT; the remaining 31% had an appropriately suppressed iPTH concentration relative to the hypercalcemia. Conclusions: In a large, academic, tertiary healthcare center, over half of the ambulatory patients with confirmed hypercalcemia did not receive further work-up to assess for possible PHPT. Efforts to improve diagnosis of PHPT and expand curative treatment have the potential to decrease the prevalence of nephrolithiasis, bone loss, and further end-organ effects associated with the disease.

Clinical Guidelines and PTH Measurement: Does Assay Generation Matter?

PTH is an important regulator of calcium and phosphate homeostasis and bone remodeling. It is metabolized into PTH fragments, which are measured to a different extent by PTH assays of different generations because of differences in fragments recognized and lack of assay standardization. PTH is measured in the workup of several conditions, and clinical guidelines provide recommendations concerning these measurements. This review provides an overview of the impact of differences between PTH assays, applying distinct clinical guidelines for primary and secondary hyperparathyroidism and perioperative use of PTH measurements. Guidelines deal with PTH measurement in different ways, recommending either trend monitoring, the use of a fold increase of the upper reference limit, or an absolute PTH cutoff value. For classic primary hyperparathyroidism (PHPT), the type of PTH assay used will not affect diagnosis or management because the precise concentration of PTH is less relevant. In chronic kidney disease, the guideline recommends treating secondary hyperparathyroidism above a twofold to ninefold PTH increase, which will result in different clinical decisions depending on the assay used. For patients after bariatric surgery, guidelines state absolute cutoff values for PTH, but the impact of different generation assays is unknown because direct comparison of PTH assays has never been performed. During parathyroid surgery, PTH measurements with a third-generation assay reflect treatment success more rapidly than second-generation assays. Increased awareness among clinicians regarding the complexity of PTH measurements is warranted because it can affect clinical decisions.

Biochemical Dynamics of Untreated Primary Hyperparathyroidism: an Observational Study

Objective: The natural biochemical history of untreated primary hyperparathyroidism (PHPT) is poorly understood. The purpose of this study was to determine the extent of biochemical fluctuations in patients with PHPT. Methods: Retrospective cohort study from January 1, 1995, to December 31, 2014. Serum calcium and parathyroid hormone (PTH) levels in patients with classic (Ca >10.5 mg/dL, PTH >65 pg/mL) and nonclassic (Ca >10.5 mg/dL, PTH 40 to 65 pg/mL) PHPT were followed longitudinally at 1, 2, and 5 years. Biochemical profiles in follow-up were ranked in descending biochemical severity as classic PHPT, nonclassic PHPT, normal calcium with elevated PTH (Ca <10.5 mg/dL, PTH >65 pg/mL), possible PHPT (Ca >10.5 mg/dL, PTH 21 to 40 pg/mL), or absent PHPT (Ca >10.5 mg/dL, PTH <21 pg/mL or Ca <10.5 mg/dL, PTH <65 pg/mL). Results: Of 10,598 patients, 1,570 were treated with parathyroidectomy (n = 1,433) or medications (n = 137), and 4,367 were censored due to study closure, disenrollment, or death. In the remaining 4,661 untreated patients with 5 years of follow-up, 235 (5.0%) progressed to a state of increased biochemical severity, whereas 972 (20.8%) remained the same, and 3,454 (74.1%) regressed to milder biochemical states. In 2,522 untreated patients with classic PHPT, patients most frequently transitioned to the normal calcium with elevated PTH group (n = 1,257, 49.8%). In 2,139 untreated patients with nonclassic PHPT, patients most frequently transitioned to the absent PHPT group (n = 1,354, 63.3%). Conclusion: PHPT is a biochemically dynamic disease with significant numbers of patients exhibiting both increases and decreases in biochemical severity. Abbreviations: IQR = interquartile range; KPSC = Kaiser Permanente Southern California; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone; PTx = parathyroidectomy.

End-organ effects of primary hyperparathyroidism: A population-based study

BackgroundPatients with primary hyperparathyroidism are at risk for skeletal and renal end-organ damage. MethodsWe studied patients with biochemically confirmed primary hyperparathyroidism from 1995–2014 and quantified the frequency of osteoporosis, nephrolithiasis, hypercalciuria, and decrease in renal function. ResultsThe cohort comprised 9,485 patients. In total, 3,303 (35%) had preexisting end-organ effects (osteoporosis, 24%; nephrolithiasis, 10%; hypercalciuria, 5%). Of 6,182 remaining patients, 1,769 (29%) exhibited progression to 1 or more end-organ effects over a median 3.7 years. Among patients with classic primary hyperparathyroidism (calcium and parathyroid hormone increased), progression was unrelated to the degree of hypercalcemia (calcium >11.5 mg/dL, hazard ratio 1.03, 95% confidence interval 0.85–1.25; 11.1–11.5 mg/dL, HR 1.07, 95% confidence interval 0.93–1.23; 10.5–11.0 mg/dL = reference). Patients with nonclassic primary hyperparathyroidism (calcium increased, parathyroid hormone 40–65 pg/mL) had a lesser risk of progression (calcium >11.5 mg/dL, hazard ratio 0.68, 95% confidence interval 0.50–0.94; 11.1–11.5 mg/dL, hazard ratio 0.68, 95% confidence interval 0.56–0.82; 10.5–11.0 mg/dL, hazard ratio 0.66, 95% confidence interval 0.59–0.74). End-organ damage developed before or within 5 years of diagnosis for 62% of patients. ConclusionEnd-organ manifestations of primary hyperparathyroidism develop before biochemical diagnosis or within 5 years in most patients. End-organ damage occurred more frequently in patients with classic primary hyperparathyroidism versus nonclassic primary hyperparathyroidism, regardless of severity of hypercalcemia.

Surgery for Primary Hyperparathyroidism with Normal Non-suppressed Parathyroid Hormone can be Both Challenging and Successful.

Criteria for diagnosing primary hyperparathyroidism (PHPT) include hypercalcemia in the presence of parathyroid hormone (PTH) levels that are either elevated (classic PHPT) or normal but non-suppressed. However, there is no standard definition of what constitutes normal non-suppressed levels, and data are lacking regarding the potential for surgical cure in these patients. A retrospective review of patients undergoing parathyroidectomy for sporadic PHPT between 2012 and 2014 was performed. Patients with normal PTH were compared to classic PHPT patients to assess demographics, imaging, operative findings, and outcomes. In total, 332 patients met study criteria, and 60 (18%) had normal PTH levels. Negative sestamibi scans were seen more often with normal PTH levels (18.3 vs. 4.8%, p<0.001). Patients with normal PTH were more likely to have ≥2 glands removed (26.7 vs. 14.3%, p=0.02), and the specimens were more likely to be classified as only mildly hypercellular or normocellular (20 vs. 2.9%, p<0.001). Average follow-up was 24months (range 6-55). Cure rate was 88% in the normal PTH group, compared to 96% in classic PHPT (p=0.02). Among patients with normal PTH, those with PTH≤55pg/mL had an 83% cure rate, whereas those with PTH 56-65 had a 96% cure rate (p=0.12). Parathyroidectomy can have a high cure rate in the context of normal PTH levels despite an increased likelihood of negative imaging and multigland resection. Operative success is equivalent to classic PHPT when PTH levels are >55pg/mL.

Normohormonal primary hyperparathyroidism is a distinct form of primary hyperparathyroidism

Normohormonal primary hyperparathyroidism presents diagnostic and intraoperative challenges, and current literature is conflicting about management. We aim to better define normohormonal primary hyperparathyroidism in order to improve the care for these patients. In the study, 516 consecutive patients undergoing parathyroidectomy for primary hyperparathyroidismwere divided into 2 groups: classic primary hyperparathyroidism (classic primary hyperparathyroidism, increased serum levels of calcium, and parathyroid hormone) and normohormonal primary hyperparathyroidism (hypercalcemia, normal serum levels of parathyroid hormone). We evaluated inter-group differences in presentation, gland weight, pathology, and complications. The normohormonal primary hyperparathyroidism group was comprised of 116 (22.5%) patients. Mean serum levels of parathyroid hormone and calcium were 62.1 pg/mL ± 10.1 and 10.6mg/dL ± 0.63 in normohormonal primary hyperparathyroidism, and 142±89.0pg/mL and 11.0±0.88 (both P<.01) for classic primary hyperparathyroidism. Nephrolithiasis was more common in normohormonal primary hyperparathyroidism. Multigland hyperplasia was more common in normohormonalprimary hyperparathyroidism 23 (19.8%) vs 44 (11%; P=.04). Concordant imaging studies were less likely in normohormonal primary hyperparathyroidism (82 [73.2%] vs 337 [87.1%; P<.01]), had a lesser total gland weight (531.8mg±680.0 vs 1,039.6mg±1,237.3; P<.01), and lesser 2-week parathyroid hormone (32.5 pg/mL±18.95 vs 41.0 pg/mL±27.8; P=.01). There was no difference in hypoparathyroidism (parathyroid hormone <15 pg/mL; P=.93) at 2weeks postoperatively. Normohormonal primary hyperparathyroidism represents 22.5% of our primary hyperparathyroidism population, which is greater than reported previously. It is a distinct disease process from classic primary hyperparathyroidism in presentation, imaging, and operative findings. More hyperplasia and a lesser gland weight make it challenging to resect the ideal amount of tissue. Studies with long-term follow-up are needed to determine optimal operative management.

Characterizing the operative findings and utility of intraoperative parathyroid hormone (IOPTH) monitoring in patients with normal baseline IOPTH and normohormonal primary hyperparathyroidism

During parathyroidectomy with intraoperative parathyroid hormone monitoring, the successful removal of a hypersecreting gland(s) resulting in normocalcemia is indicated by a >50% decrease in intraoperative parathyroid hormone level, typically into the normal range. Some patients, however, will have baseline parathyroid hormone levels within the normal range. We sought to determine the utility of intraoperative parathyroid hormone testing in these patients. We retrospectively studied all patients who underwent parathyroidectomy for primary hyperparathyroidism at our institution over a 10-year period. Overall, 317 (17%) patients had parathyroid hormone within the normal range at the onset of operation (baseline intraoperative parathyroid hormone), and 1,544 (83%) had classic primary hyperparathyroidism. The intraoperative parathyroid hormone degradation was slower in normal baseline intraoperative parathyroid hormone patients than classic primary hyperparathyroidism patients, though this did not reach statistical significance (P < .254). A >50% intraoperative parathyroid hormone decrease predicted cure in 98.7% of normal baseline patients and 98.8% of classic primary hyperparathyroidism patients (P=.810). Normal baseline patients had a lesser cure rate the longer it took to achieve a 50% decrease intraoperatively; however, the cure rate was constant at any time point the 50% decrease occurred in patients with classic primary hyperparathyroidism (P<.05). The 50% rule delineating operative cure can be applied with equal confidence to patients with normal range, baseline intraoperative parathyroid hormone. Moreover, the time at which the 50% drop is achieved impacts operative success rates in these patients.

Differences in single gland and multigland disease are seen in low biochemical profile primary hyperparathyroidism

Primary hyperparathyroidism is characterized by increased levels of serum calcium and parathyroid hormone. Recently, 2 additional mild biochemical profiles have emerged, normocalcemic and normohormonal primary hyperparathyroidism. We reviewed our surgical experience of mild biochemical profile patients and compared them with classic primary hyperparathyroidism patients. This is a single institution, retrospective cohort review of all patients who underwent parathyroidectomy for primary hyperparathyroidism from 2006-2012. Preoperative and intraoperative variables were analyzed. Univariable analysis was performed with analysis of variance and the χ2 test. A logistic regression was performed to identify significantly independent predictor variables for multigland disease. A total of 573 patients underwent parathyroidectomy for primary hyperparathyroidism (classic, n=405; normohormonal, n=96; normocalcemic, n=72). Normocalcemic primary hyperparathyroidism was associated with multigland disease in 43 (45%, P<.001) patients as compared with the normohormonal (7, 10%) and classic (36, 9%) groups. On logistic regression, significant predictors for multigland disease were the normocalcemic subtype and positive family history. Twelve month biochemical normalization rates after operative treatment were >98% in all 3 groups. Our series shows that normocalcemic primary hyperparathyroidism is associated with a high incidence of multigland disease. Normohormonal disease is similar to classic disease patients with >90% presenting with single adenomas. Excellent rates of biochemical normalization can be obtained by operative treatment in all 3 groups.

MECHANISMS IN ENDOCRINOLOGY: Kidney involvement in patients with primary hyperparathyroidism: an update on clinical and molecular aspects.

Primary hyperparathyroidism (PHPT) is the third most common endocrine disease. Kidney is a target of both chronic elevated PTH and calcium in PHPT. The classic PHPT complications of symptomatic kidney stones and nephrocalcinosis have become rare and the PHPT current presentation is asymptomatic with uncertain and long-lasting progression. Nonetheless, the routine use of imaging and of biochemical determinations have revealed the frequent occurrence of asymptomatic kidney stones, hypercalciuria and reduced kidney function in asymptomatic PHPT patients. Though the pathogenesis is far from being elucidated, PHPT is associated with reduced renal function, in terms of estimated glomerular filtration rate, and related increased morbidity and mortality. In the last decade, the effort of the Kidney Disease: Improving Global Outcomes (KDIGO) panel of experts highlighted that even mild reduction of kidney function is associated with increased risk of cardiovascular disease. These considerations provided the basis for the Fourth Workshop recommendations of a more extensive diagnostic workout about kidney features and of wider criteria for parathyroid surgery including asymptomatic kidney disease. Moreover, kidney involvement in PHPT is likely to be affected by variants of genes coding the key molecules regulating the calcium and ions renal handling; these features might have clinical relevance and should be considered both during diagnostic workout and follow-up. Finally, the effects of parathyroid surgery and of medical treatment on kidney involvement of PHPT are reviewed.

Mild primary hyperparathyroidism: a literature review.

The biochemical profile of classic primary hyperparathyroidism (pHPT) consists of both elevated calcium and parathyroid hormone levels. The standard of care is parathyroidectomy unless prohibited by medical comorbidities. Because more patients are undergoing routine bone density evaluation and neck imaging studies for other purposes, there is a subset of people identified with a biochemically mild form of the pHPT that expresses itself as either elevated calcium or parathyroid hormone levels. These patients often do not fall into the criteria for operation based on the National Institutes of Health consensus guidelines, and they can present a challenge of diagnosis and management. The purpose of this paper is to review the available literature on mild pHPT in an effort to better characterize this patient population and to determine whether patients benefit from parathyroidectomy. Evidence suggests that there are patients with mild pHPT who have overt symptoms that are found to improve after parathyroidectomy. There is also a group of patients with biochemically mild pHPT who are found to progress to classic pHPT over time; however, it is not predictable which group of patients this will be. Early intervention for this group with mild pHPT may prevent progression of bone, psychiatric, and renal complications, and parathyroidectomy has proven safe in appropriately selected patients at high volume centers.

Diagnosis, natural history, and treatment of primary hyperparathyroidism.

Primary hyperparathyroidism, one of the most common endocrine disorders, is characterized by hypercalcemia in the presence of elevated parathyroid hormone levels. The disease today bears little resemblance to the severe disorder of ‘stones, bones and groans’ described by Fuller Albright and others in the 1930s [1–6]. Osteitis fibrosa cystica was the hallmark of classic primary hyperparathyroidism. This skeletal condition was characterized by brown tumors of the long bones, subperiosteal bone resorption, distal tapering of the clavicles and phalanges, and a‘salt and pepper’ appearance of the skull on radiograph [7]. Nephrocalcinosis was present in 80% of patients, and neuromuscular dysfunction with muscle weakness was common. With the advent of the automated serum chemistry autoanalyzer in the 1970s, diagnosis of primary hyperparathyroidism became commonplace in the complete absence of symptoms [8–10].