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Normocalcemic primary hyperparathyroidism

ABSTRACT

Normocalcemic primary hyperparathyroidism (PHPT) is a newer phenotype of PHPT defined by elevated PTH concentrations in the setting of normal serum calcium levels. It is increasingly being diagnosed in the setting of evaluation for nephrolithiasis or metabolic bone diseases. It is important to demonstrate that PTH values remain consistently elevated and to measure ionized calcium levels to make the diagnosis. A diagnosis of normocalcemic disease is one of exclusion of secondary forms of hyperparathyroidism, including vitamin D deficiency, renal failure, medications, malabsorption, and hypercalciuria. Lack of rigorous diagnostic criteria and selection bias of the studied populations may explain the different rates of bone and renal complications. The natural history still remains unknown. Caution should be used in recommending surgery, unless clearly indicated. Here we will review the diagnostic features, epidemiology, clinical presentation, natural history, medical and surgical management of normocalcemic PHPT.

Keywords
Hyperparathyroidism; osteoporosis; nephrolithiasis; parathyroid surgery; calcium; parathyroid hormone

INTRODUCTION

Primary hyperparathyroidism (PHPT) is a common endocrine disorder. In the developed world is now usually an incidental diagnosis made when asymptomatic hypercalcemia is detected on routine blood tests. Symptomatic disease, defined by kidney stones and fractures and remembered by the mnemonic “bones, stones, abdominal groans, and psychiatric overtones,” is still prevalent in some areas of the world, including South America, the Middle East, and Asia (11 Silverberg SJ, Clarke BL, Peacock M, Bandeira F, Boutroy S, Cusano NE, et al. Current issues in the presentation of asymptomatic primary hyperparathyroidism: Proceedings of the fourth International Workshop. J Clin Endocrinol Metab. 2014;99(10):3580-94.).

A newer phenotype of the disease is being described, primarily in patients presenting with nephrolithiasis or osteoporosis. Normocalcemic PHPT can be diagnosed in patients with elevated parathyroid hormone (PTH) concentrations in the setting of persistently normal serum total and ionized calcium levels. Normocalcemic PHPT was first formally recognized at the time of the Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism in 2008 (22 Silverberg SJ, Lewiecki EM, Mosekilde L, Peacock M, Rubin MR. Presentation of asymptomatic primary hyperparathyroidism: Proceedings of the Third International Workshop. J Clin Endocrinol Metab. 2009;94(2):351-65.). Recommendations for diagnosis and management were made at the time of the Fourth International Workshop in 2013, however, there remain limited data on which to base recommendations for this phenotype (33 Eastell R, Brandi ML, Costa AG, D’Amour P, Shoback DM, Thakker R V. Diagnosis of asymptomatic primary hyperparathyroidism: Proceedings of the fourth international workshop. J Clin Endocrinol Metab. 2014;99(10):3570-9.,44 Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: Summary statement from the fourth international workshop. J Clin Endocrinol Metab. 2014;99(10):3561-9.). In this manuscript we will review the available literature regarding diagnostic features, epidemiology, clinical presentation, natural history, medical and surgical management of normocalcemic PHPT.

Diagnosis

A review of the available literature regarding normocalcemic PHPT is complicated due to a lack of consistency in diagnostic criteria. Diagnostic recommendations were made at the time of the Fourth International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism in 2013 (33 Eastell R, Brandi ML, Costa AG, D’Amour P, Shoback DM, Thakker R V. Diagnosis of asymptomatic primary hyperparathyroidism: Proceedings of the fourth international workshop. J Clin Endocrinol Metab. 2014;99(10):3570-9.,44 Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: Summary statement from the fourth international workshop. J Clin Endocrinol Metab. 2014;99(10):3561-9.) and the European Society of Endocrinology Educational Program of Parathyroid Disorders in 2021 (55 Bollerslev J, Rejnmark L, Zahn A, Heck A, Appelman-Dijkstra NM, Cardoso L, et al. European expert consensus on practical management of specific aspects of parathyroid disorders in adults and in pregnancy: recommendations of the ESE Educational Program of Parathyroid Disorders (PARAT 2021). Eur J Endocrinol. 2022;186(2):R33-63.). A consistent diagnosis is needed moving forward for research investigations to better guide physicians regarding management decisions.

The guidelines generally recommend that a diagnosis of normocalcemic PHPT be made in individuals with an elevated PTH concentration on multiple occasions at least three months apart, in the setting of consistently normal serum calcium (both total and ionized serum calcium). The importance of repeated measurements has been demonstrated by a lack of persistence of hyperparathyroidism in some patients diagnosed with normocalcemic disease and concern for misclassification of individuals with secondary hyperparathyroidism. In a population-based study of disease prevalence, 108 of 3450 (3.1%) men and women were noted to have an elevated PTH concentration with normal serum calcium, after exclusion of secondary causes of hyperparathyroidism. Of the 64 individuals with follow-up data eight years later, only 13 (0.6%) had persistent hyperparathyroidism (66 Cusano NE, Maalouf NM, Wang PY, Zhang C, Cremers SC, Haney EM, et al. Normocalcemic hyperparathyroidism and hypoparathyroidism in two community-based nonreferral populations. J Clin Endocrinol Metab. 2013;98(7):2734-41.). Patients with typical hypercalcemic PHPT can occasionally have normal serum calcium levels and should not be classified as having normocalcemic disease. Ionized calcium should be measured as part of the evaluation of a patient suspected of having normocalcemic disease, since 4-64% of patients with a diagnosis of normocalcemic PHPT can be reclassified as having traditional hypercalcemic disease with measurement of ionized calcium levels (77 Nordenström E, Katzman P, Bergenfelz A. Biochemical diagnosis of primary hyperparathyroidism: Analysis of the sensitivity of total and ionized calcium in combination with PTH. Clin Biochem. 2011;44(10–11):849-52.99 Ross AC, Manson JAE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53-8.).

Normocalcemic PHPT is a diagnosis of exclusion. Secondary causes of hyperparathyroidism are common, and a rigorous exclusion of secondary causes is needed.

  1. Vitamin D deficiency. Vitamin D is a common secondary cause of hyperparathyroidism, and it may take months for secondary hyperparathyroidism to resolve after treatment of vitamin D deficiency. The National Academy of Medicine (formally the Institute of Medicine) acknowledged that the literature provides no widespread agreement regarding a 25-hydroxyvitamin D level by which there is a plateau in PTH concentrations, suggesting that a range of values may be needed for different individuals (99 Ross AC, Manson JAE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: What clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53-8.). The 25-hydroxyvitamin D level should be at minimum 20 ng/mL as per the Fourth International Workshop guidelines (33 Eastell R, Brandi ML, Costa AG, D’Amour P, Shoback DM, Thakker R V. Diagnosis of asymptomatic primary hyperparathyroidism: Proceedings of the fourth international workshop. J Clin Endocrinol Metab. 2014;99(10):3570-9.), and at least 30 ng/mL as per the European Society of Endocrinology Expert Consensus to make a diagnosis of normocalcemic disease (55 Bollerslev J, Rejnmark L, Zahn A, Heck A, Appelman-Dijkstra NM, Cardoso L, et al. European expert consensus on practical management of specific aspects of parathyroid disorders in adults and in pregnancy: recommendations of the ESE Educational Program of Parathyroid Disorders (PARAT 2021). Eur J Endocrinol. 2022;186(2):R33-63.). In addition, patients with the traditional phenotype may become hypercalcemic with resolution of vitamin D deficiency.

  2. Renal failure. PTH levels rise as eGFR falls. To make a diagnosis of normocalcemic PHPT, eGFR should be at least 60 mL/min to exclude stage 3-5 chronic kidney disease as a cause of hyperparathyroidism (1010 Martinez I, Saracho R, Montenegro J, Llach F. The importance of dietary calcium and phosphorous in the secondary hyperparathyroidism of patients with early renal failure. Am J Kidney Dis. 1997;29(4):496-502.,1111 Group KDIGO (KDIGO) C-MW. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2009;113:S1-130.).

  3. Medications. Antiresorptive medications, including bisphosphonates and denosumab, are a known cause of hyperparathyroidism by blocking calcium release from the skeleton (1212 Chesnut CH, McClung MR, Ensrud KE, Bell NH, Genant HK, Harris ST, et al. Alendronate treatment of the postmenopausal osteoporotic woman: Effect of multiple dosages on bone mass and bone remodeling. Am J Med. 1995;99(2):144-52.1414 McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354(8):821-31.). With zoledronic acid infusion, elevated PTH concentrations can persist for up to a year after the dose. Denosumab results in an exuberant increase in PTH concentrations peaking at around 3 months after the dose, with subsequently decline until the next dose. By shifting calcium sensing, lithium can result in hyperparathyroidism (1515 Haden ST, Stoll AL, Mccormick S, Scott J, Fuleihan GEH. Alterations in parathyroid dynamics in lithium-treated subjects. J Clin Endocrinol Metab. 1997;82(9):2844-8.). The relationship between the diuretics hydrochlorothiazide and furosemide and PTH concentrations is less clear (1616 Rejnmark L, Vestergaard P, Heickendorff L, Andreasen F, Mosekilde L. Effects of thiazide- and loop-diuretics, alone or in combination, on calcitropic hormones and biochemical bone markers: A randomized controlled study. J Intern Med. 2001;250(2):144-53.,1717 Yacobi-Bach M, Serebro M, Greenman Y, Tordjman K, Stern N. Letter to the Editor: Thiazides Are Not Inducers of PTH Secretion: A Comment on Normocalcemic Hyperparathyroidism. J Clin Endocrinol Metab. 2015;100(2):L27.). It is recommended to exclude diuretics as a cause of hyperparathyroidism. Newer data also indicate that proton pump inhibitors (1818 Hinson AM, Wilkerson BM, Rothman-Fitts I, Riggs AT, Stack BC, Bodenner DL. Hyperparathyroidism associated with long-term proton pump inhibitors independent of concurrent bisphosphonate therapy in elderly adults. J Am Geriatr Soc. 2015;63(10):2070-3.) and SGLT-2 inhibitors (1919 Ye Y, Zhao C, Liang J, Yang Y, Yu M, Qu X. Effect of sodium-glucose co-transporter 2 inhibitors on bone metabolism and fracture risk. Front Pharmacol. 2019;9:1-9.) may also result in elevated PTH concentrations.

  4. Insufficient calcium intake or malabsorption. Low calcium intake, celiac disease, and gastric bypass procedures can result in hyperparathyroidism (2020 Ciacci C, Bilancio G, Russo I, Iovino P, Cavallo P, Santonicola A, et al. 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and peripheral bone densitometry in adults with celiac disease. Nutrients. 2020;12(4):1-11.,2121 Balsa JA, Botella-Carretero JI, Peromingo R, Zamarrón I, Arrieta F, Muñoz-Malo T, et al. Role of calcium malabsorption in the development of secondary hyperparathyroidism after biliopancreatic diversion. J Endocrinol Invest. 2008;31(10):845-50.). Patients should be advised to have sufficient calcium intake through diet and/or supplements.

  5. Hypercalciuria. It has been recommended to exclude hypercalciuria, defined as a 24-hour urine calcium excretion >250 mg for women or >300 mg for men (2222 Coe FL, Canterbury JM, Firpo JJ, Reiss E. Evidence for secondary hyperparathyroidism in idiopathic hypercalciuria. J Clin Invest. 1973;52(1):134-42.). The European Society of Endocrinology Expert Consensus recommends a trial of hydrochlorothiazide to determine if improving the hypercalciuria can resolve the elevation in PTH concentrations (55 Bollerslev J, Rejnmark L, Zahn A, Heck A, Appelman-Dijkstra NM, Cardoso L, et al. European expert consensus on practical management of specific aspects of parathyroid disorders in adults and in pregnancy: recommendations of the ESE Educational Program of Parathyroid Disorders (PARAT 2021). Eur J Endocrinol. 2022;186(2):R33-63.).

  6. Disorders of phosphate metabolism. Since extracellular phosphate regulation involves change in PTH concentrations, both hypo- and hyperphosphatemia can cause hyperparathyroidism (2323 Centeno PP, Herberger A, Mun HC, Tu C, Nemeth EF, Chang W, et al. Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion. Nat Commun. 2019;10(1):1-12.). The European Society of Endocrinology Expert Consensus recommends exclusion of disorders of phosphate metabolism for a diagnosis of normocalcemic PHPT.

Epidemiology

There are few population-based studies investigating the prevalence of normocalcemic PHPT in healthy individuals since PTH concentrations are not often ordered in the absence of hypercalcemia or symptoms. As such, it is difficult to describe the epidemiology in a general healthy population. In addition, few studies have measured ionized calcium levels and there are significant differences in the literature in the exclusion of secondary causes of hyperparathyroidism, especially in the cutoffs for 25-hydroxyvitamin D and eGFR. Of note, few studies have monitored biochemical parameters over time, which can overestimate the disease prevalence. The disease appears to be relatively rare, with most studies using established criteria demonstrating a prevalence of 0.1%-0.7% (66 Cusano NE, Maalouf NM, Wang PY, Zhang C, Cremers SC, Haney EM, et al. Normocalcemic hyperparathyroidism and hypoparathyroidism in two community-based nonreferral populations. J Clin Endocrinol Metab. 2013;98(7):2734-41.,2424 Palermo A, Jacques R, Gossiel F, Reid DM, Roux C, Felsenberg D, et al. Normocalcaemic hypoparathyroidism: Prevalence and effect on bone status in older women. The OPUS study. Clin Endocrinol (Oxf). 2015;82(6):816-23.3333 García-Martín A, Reyes-García R, Muñoz-Torres M. Normocalcemic primary hyperparathyroidism: One-year follow-up in one hundred postmenopausal women. Endocrine. 2012;42(3):764-6.). The epidemiologic data are summarized in Table 1.

Table 1
Epidemiology of normocalcemic primary hyperparathyroidism

Clinical presentation

Traditional hypercalcemic PHPT has now become a disease that presents primarily asymptomatically, although kidney stones or vertebral fractures are more common if screening procedures are performed to evaluate for these complications as recommended per the guidelines. Cohorts of patients with normocalcemic disease, however, typically present symptomatically. This is most likely due to selection bias, where patients with normal serum calcium are only screened for parathyroid disease in the setting of fracture or nephrolithiasis. Few population-based, unselected cohorts have been described. In these individuals identified through biochemical testing, there do not appear to be significant differences in clinical indices, bone turnover markers, or bone mass as compared to euparathyroid patients or patients with secondary hyperparathyroidism. The clinical features are summarized in Table 2 (66 Cusano NE, Maalouf NM, Wang PY, Zhang C, Cremers SC, Haney EM, et al. Normocalcemic hyperparathyroidism and hypoparathyroidism in two community-based nonreferral populations. J Clin Endocrinol Metab. 2013;98(7):2734-41.,2525 Marques TF, Vasconcelos R, Diniz E, Rêgo D, Griz L, Bandeira F. Normocalcemic primary hyperparathyroidism in clinical practice: an indolent condition or a silent threat? Arq Bras Endocrinol Metabol. 2011;55(5):314-7.,2727 Wu K, Anpalahan M. Normocalcaemic Primary Hyperparathyroidism: Is nephrolithiasis more common than osteoporosis? Intern Med J. 2021.,3030 Rosário PW, Calsolari MR. Normocalcemic Primary Hyperparathyroidism in Adults Without a History of Nephrolithiasis or Fractures: A Prospective Study. Horm Metab Res. 2019;51(4):243-7.,3333 García-Martín A, Reyes-García R, Muñoz-Torres M. Normocalcemic primary hyperparathyroidism: One-year follow-up in one hundred postmenopausal women. Endocrine. 2012;42(3):764-6.4141 Cakir I, Unluhizarci K, Tanriverdi F, Elbuken G, Karaca Z, Kelestimur F. Investigation of insulin resistance in patients with normocalcemic primary hyperparathyroidism. Endocrine. 2012;42(2):419-22.).

Table 2
Clinical summary of skeletal and renal complications in cohorts of patients with normocalcemic primary hyperparathyroidism

While severe traditional PHPT with significant elevations in serum calcium can result in manifestations involving multiple organ systems, studies investigating nonclassical manifestations of the mild, asymptomatic form of hypercalcemic PHPT have been mixed regarding possible complications such as hypertension, left ventricular hypertrophy, glucose intolerance, and quality of life. Nonclassical manifestations have also been studied in patients with the normocalcemic phenotype. Studies of glucose metabolism have not demonstrated any differences in hemoglobin A1c or insulin sensitivity in men and women with normocalcemic PHPT versus controls, however a few studies have shown a small but statistically significant increase in mean fasting glucose values (4242 Hagström E, Lundgren E, Rastad J, Hellman P. Metabolic abnormalities in patients with normocalcemic hyperparathyroidism detected at a population-based screening. Eur J Endocrinol. 2006;155(1):33-9.4646 Karras SN, Koufakis T, Tsekmekidou X, Antonopoulou V, Zebekakis P, Kotsa K. Increased parathyroid hormone is associated with higher fasting glucose in individuals with normocalcemic primary hyperparathyroidism and prediabetes: A pilot study. Diabetes Res Clin Pract. 2020;160:107985.). Studies using echocardiography or various noninvasive measures of arterial compliance as surrogate markers for vascular risk found no differences in individuals with normocalcemic disease (4747 Tordjman KM, Yaron M, Izkhakov E, Osher E, Shenkerman G, Marcus-Perlman Y, et al. Cardiovascular risk factors and arterial rigidity are similar in asymptomatic normocalcemic and hypercalcemic primary hyperparathyroidism. Eur J Endocrinol. 2010;162(5):925-33.,4848 Pepe J, Colangelo L, Sonato C, Occhiuto M, Ferrara C, Del Fattore A, et al. Echocardiographic Findings in Patients With Normocalcemic Primary Hyperparathyroidism Compared With Findings in Hypercalcemic Primary Hyperparathyroid Patients and Control Subjects. Endocr Pract. 2021;27(1):21-6.). While one study showed an increase in coronary artery calcium score in patients with normocalcemic PHPT (4949 Koubaity O, Mandry D, Nguyen-Thi PL, Bihain F, Nomine-Criqui C, Demarquet L, et al. Coronary artery disease is more severe in patients with primary hyperparathyroidism. Surg (United States). 2020;167(1):149-54.), another found no difference (5050 Mesquita PN, Leite APDL, Crisóstomo S das C, Filho EV, Da Cunha Xavier L, Bandeira F. Evaluation of coronary calcium score in patients with normocalcemic primary hyperparathyroidism. Vasc Health Risk Manag. 2017;13:225-9.). One study demonstrated small but significant reductions in quality of life in individuals with normocalcemic disease (5151 Voss L, Nóbrega M, Bandeira L, Griz L, Rocha-Filho PAS, Bandeira F. Impaired physical function and evaluation of quality of life in normocalcemic and hypercalcemic primary hyperparathyroidism. Bone. 2020;141:115583.).

Natural history

There are few investigations into the natural history of normocalcemic PHPT, with most data from small cohorts showing that many patients may never develop hypercalcemia (3131 Kontogeorgos G, Trimpou P, Laine CM, Oleröd G, Lindahl A, Landin-Wilhelmsen K. Normocalcaemic, vitamin D-sufficient hyperparathyroidism - High prevalence and low morbidity in the general population: A long-term follow-up study, the WHO MONICA project, Gothenburg, Sweden. Clin Endocrinol (Oxf). 2015;83(2):277-84.,3333 García-Martín A, Reyes-García R, Muñoz-Torres M. Normocalcemic primary hyperparathyroidism: One-year follow-up in one hundred postmenopausal women. Endocrine. 2012;42(3):764-6.,3535 Šiprová H, Fryšák Z, Souček M. Primary Hyperparathyroidism, With a Focus on Management of the Normocalcemic Form: To Treat or Not To Treat? Endocr Pract. 2016;22(3):294-301.,3737 Lowe H, McMahon DJ, Rubin MR, Bilezikian JP, Silverberg SJ. Normocalcemic primary hyperparathyroidism: Further characterization of a new clinical phenotype. J Clin Endocrinol Metab. 2007;92(8):3001-5.,3939 Tordjman KM, Greenman Y, Osher E, Shenkerman G, Stern N. Characterization of normocalcemic primary hyperparathyroidism. Am J Med. 2004;117(11):861-3.). In one study of individuals with normocalcemic PHPT, none of the 20 patients developed hypercalcemia over a median of four years of monitoring (3939 Tordjman KM, Greenman Y, Osher E, Shenkerman G, Stern N. Characterization of normocalcemic primary hyperparathyroidism. Am J Med. 2004;117(11):861-3.). Another study demonstrated that 7 of 37 (19%) of patients developed hypercalcemia over a median of three years (3737 Lowe H, McMahon DJ, Rubin MR, Bilezikian JP, Silverberg SJ. Normocalcemic primary hyperparathyroidism: Further characterization of a new clinical phenotype. J Clin Endocrinol Metab. 2007;92(8):3001-5.). During this monitoring period, 41% of patients showed evidence of progressive disease, including hypercalcemia, new hypercalciuria, kidney stone, and/or fracture. In a symptomatic cohort of 187 patients with normocalcemic PHPT, 36 patients (19%) became hypercalcemic (3535 Šiprová H, Fryšák Z, Souček M. Primary Hyperparathyroidism, With a Focus on Management of the Normocalcemic Form: To Treat or Not To Treat? Endocr Pract. 2016;22(3):294-301.). The majority (67%) of these patients transitioned to hypercalcemia within the first two years of follow-up, however, a small cohort (6%) became hypercalcemic after four years. In the Dallas Heart Study cohort, only one of the initial 64 patients with a diagnosis of normocalcemic PHPT as defined developed hypercalcemia on subsequent measurement eight years later (66 Cusano NE, Maalouf NM, Wang PY, Zhang C, Cremers SC, Haney EM, et al. Normocalcemic hyperparathyroidism and hypoparathyroidism in two community-based nonreferral populations. J Clin Endocrinol Metab. 2013;98(7):2734-41.). In a small cohort of 6 asymptomatic postmenopausal women with normocalcemic disease, none developed evidence of hypercalcemia, nephrolithiasis, or fracture after one year (3333 García-Martín A, Reyes-García R, Muñoz-Torres M. Normocalcemic primary hyperparathyroidism: One-year follow-up in one hundred postmenopausal women. Endocrine. 2012;42(3):764-6.).

Management

Medical therapy

Two studies have evaluated the impact of pharmacologic treatment on bone and renal complications associated with normocalcemic PHPT (5252 Cesareo R, Di Stasio E, Vescini F, Campagna G, Cianni R, Pasqualini V, et al. Effects of alendronate and vitamin D in patients with normocalcemic primary hyperparathyroidism. Osteoporos Int. 2015;26(4):1295-302.,5353 Brardi S, Cevenini G, Verdacchi T, Romano G, Ponchietti R. Use of cinacalcet in nephrolithiasis associated with normocalcemic or hypercalcemic primary hyperparathyroidism: results of a prospective randomized pilot study. Arch Ital Urol Androl. 2015;87(1):66-71.). Of note, neither study met the recommended diagnostic criteria for normocalcemic PHPT.

Bisphosphonate therapy is presumed to be as effective in patients with normocalcemic PHPT as in postmenopausal women or older men. One prospective open-label study evaluated the effects of oral alendronate in 30 postmenopausal women with normocalcemic PHPT (5252 Cesareo R, Di Stasio E, Vescini F, Campagna G, Cianni R, Pasqualini V, et al. Effects of alendronate and vitamin D in patients with normocalcemic primary hyperparathyroidism. Osteoporos Int. 2015;26(4):1295-302.). Patients were randomized to receive alendronate and cholecalciferol or cholecalciferol alone for 12 months. Lumbar spine, femoral neck and total hip bone mineral density (BMD) improved in the alendronate and cholecalciferol cohort by 4.7%, 2.6% and 4.0%, respectively, while BMD decreased significantly in the cholecalciferol-only group by –1.6%, –1.7% and –1.4%, respectively. Bisphosphonates therefore seem to be safe and effective for the treatment of osteoporosis in normocalcemic, as in hypercalcemic, PHPT. We would consider antiresorptive agents in patients with osteoporosis or with osteopenia and elevated fracture risk as calculated by the country-specific FRAX score. Of note, while densitometric changes in patients with PHPT treated with antiresorptive therapy appear similar to those in euparathyroid patients, there are no data to evaluate fracture risk reduction using antiresorptive therapy in patients with PHPT.

Another study evaluated the efficacy of cinacalcet in improving nephrolithiasis (5353 Brardi S, Cevenini G, Verdacchi T, Romano G, Ponchietti R. Use of cinacalcet in nephrolithiasis associated with normocalcemic or hypercalcemic primary hyperparathyroidism: results of a prospective randomized pilot study. Arch Ital Urol Androl. 2015;87(1):66-71.). Although the study consisted of only 6 patients with normocalcemic PHPT, cinacalcet reduced the number and size of urinary stones over a follow-up period of 10 months. Given the small sample size of this study, larger studies are needed to evaluate the impact of cinacalcet on patients with normocalcemic PHPT. Cinacalcet has been approved by the US Food and Drug administration (FDA) for the treatment of severe hypercalcemia in patients with PHPT who are unable to undergo parathyroidectomy (PTX), and by the European Medicines Agency (EMA) for the reduction of hypercalcemia in patients with PHPT, for whom PTX would be indicated on the basis of serum calcium levels (as defined by the relevant guidelines), but in whom surgery is not clinically appropriate or is contraindicated. Thus, in our opinion the use of cinacalcet in patients with normocalcemic PHPT patients is unreasonable.

Surgery

The Fourth International Workshop for the Management of Asymptomatic PHPT recommended PTX for normocalcemic PHPT if the patient developed a progression of the disease (such as worsening BMD) or new symptoms (i.e., fractures, kidney stones) in a very similar way to hypercalcemic patients (44 Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: Summary statement from the fourth international workshop. J Clin Endocrinol Metab. 2014;99(10):3561-9.). Similarly, the guidelines of the American Association of Endocrine Surgeons recommended surgery in symptomatic patients, without differentiating between hypercalcemic PHPT and normocalcemic PHPT (5454 Welsh P, Doolin O, Mcconnachie A, Boulton E, Mcneil G, Macdonald H, et al. Calcium Associations with Incident Cardiovascular Disease and Mortality: The MIDSPAN Family Study. J Clin Endocrinol Metab. 2012;97(12):4578-87.,5555 Wilhelm SM, Wang TS, Ruan DT, Lee JA, Asa SL, Duh QY, et al. The American association of endocrine surgeons guidelines for definitive management of primary hyperparathyroidism. JAMA Surg. 2016;151(10):959-68.). A recent expert consensus of the European Society of Endocrinology stated that surgical intervention should be considered only after experienced endocrine review; in this case, only if there are compelling indications and a surgical target (55 Bollerslev J, Rejnmark L, Zahn A, Heck A, Appelman-Dijkstra NM, Cardoso L, et al. European expert consensus on practical management of specific aspects of parathyroid disorders in adults and in pregnancy: recommendations of the ESE Educational Program of Parathyroid Disorders (PARAT 2021). Eur J Endocrinol. 2022;186(2):R33-63.). In our opinion, it is also important that discussion regarding surgery be individualized, and patient expectations also be comprehensively explored prior to surgery. We would consider surgery in patients with normocalcemic PHPT if the diagnosis has been clearly established with a long-standing history of elevated PTH values, symptoms, and a clear target on localization studies and/or referral to an experienced surgeon.

Preoperative localization studies are critical to the surgical management of PHPT. Precise preoperative localization may allow for a minimally invasive surgery with shorter operative time and decreased postoperative morbidity. Neck ultrasonography and 99mTc-sestamibi scintigraphy are generally the first-line imaging tests to localize the hyperfunctioning gland(s) (5656 Mariani G, Mazzeo S, Rubello B. Preoperative localization of abnormal parathyroid glands. In: Bilezikian J, Marcus R, Levine M, Marcocci C, Silverberg S, Potts JJ, editors. The Parathyroids: Basic and Clinical Concepts. 3rd ed. San Diego: Elsevier; 2015. p. 499-515.).

There are few investigations into imaging studies in patients with normocalcemic PHPT, and the data are unclear because most series do not fulfill the strict diagnostic criteria for normocalcemic PHPT (3434 Wade TJ, Yen TWF, Amin AL, Wang TS. Surgical management of normocalcemic primary hyperparathyroidism. World J Surg. 2012;36(4):761-6.,3535 Šiprová H, Fryšák Z, Souček M. Primary Hyperparathyroidism, With a Focus on Management of the Normocalcemic Form: To Treat or Not To Treat? Endocr Pract. 2016;22(3):294-301.,5757 Musumeci M, Pereira LV, San Miguel L, Cianciarelli C, Vazquez EC, Mollerach AM, et al. Normocalcemic primary hyperparathyroidism: 99mTc SestaMibi SPECT/CT results compare with hypercalcemic hyperparathyroidism. Clin Endocrinol (Oxf). 2022;96(6):831-6.6060 Cunha-Bezerra P, Vieira R, Amaral F, Cartaxo H, Lima T, Montarroyos U, et al. Better performance of four-dimension computed tomography as a localization procedure in normocalcemic primary hyperparathyroidism. J Med Imaging Radiat Oncol. 2018;62(4):493-8.). Moreover, most studies have selection bias given that they are mostly surgical case series. These studies are summarized in Table 3.

Table 3
Summary of imaging studies in cohorts of patients with normocalcemic primary hyperparathyroidism

Patients with normocalcemic PHPT generally have less positive localization studies compared to patients with classic hypercalcemic disease (3535 Šiprová H, Fryšák Z, Souček M. Primary Hyperparathyroidism, With a Focus on Management of the Normocalcemic Form: To Treat or Not To Treat? Endocr Pract. 2016;22(3):294-301.,6060 Cunha-Bezerra P, Vieira R, Amaral F, Cartaxo H, Lima T, Montarroyos U, et al. Better performance of four-dimension computed tomography as a localization procedure in normocalcemic primary hyperparathyroidism. J Med Imaging Radiat Oncol. 2018;62(4):493-8.). The lower efficacy of localization studies is based on the higher prevalence of multiglandular disease and presence of smaller adenomas, a finding shared by most series (Table 3). The positivity rate of neck ultrasound ranges from 2 to 75% whereas that of scintigraphy from 0 to 56% depending on the population studied and the criteria used for exclusion of secondary causes of hyperparathyroidism. Of note, the positivity rate of single-photon emission computerized tomography (SPECT-CT) reported in a single study was 75% (5757 Musumeci M, Pereira LV, San Miguel L, Cianciarelli C, Vazquez EC, Mollerach AM, et al. Normocalcemic primary hyperparathyroidism: 99mTc SestaMibi SPECT/CT results compare with hypercalcemic hyperparathyroidism. Clin Endocrinol (Oxf). 2022;96(6):831-6.). Indeed, SPECT-CT, a combination of SPECT and CT acquisitions, is superior to each technique alone, particularly true in patients with ectopic glands, prior PTX, and coexistence of thyroid disease (5656 Mariani G, Mazzeo S, Rubello B. Preoperative localization of abnormal parathyroid glands. In: Bilezikian J, Marcus R, Levine M, Marcocci C, Silverberg S, Potts JJ, editors. The Parathyroids: Basic and Clinical Concepts. 3rd ed. San Diego: Elsevier; 2015. p. 499-515.). Four-dimensional CT (4D-CT) has recently emerged as a promising technique for preoperative localization of parathyroid lesions in patients with PHPT (6161 Yeh R, Tay YKD, Tabacco G, Dercle L, Kuo JH, Bandeira L, et al. Diagnostic performance of 4D CT and sestamibi SPECT/CT in localizing parathyroid adenomas in primary hyperparathyroidism. Radiology. 2019;291(2):469-76.6363 Rodgers SE, Hunter GJ, Hamberg LM, Schellingerhout D, Doherty DB, Ayers GD, et al. Improved preoperative planning for directed parathyroidectomy with 4-dimensional computed tomography. Surgery. 2006;140(6):932-41.). In one study, the sensitivity for identifying the parathyroid lesion, according to presentation of PHPT (hypercalcemic or normocalcemic), was found to be best with 4D-CT (56% positivity in normocalcemic vs. 75% in hypercalcemic) followed by ultrasound (22% vs. 58%), and scintigraphy (11% vs. 75%) (6060 Cunha-Bezerra P, Vieira R, Amaral F, Cartaxo H, Lima T, Montarroyos U, et al. Better performance of four-dimension computed tomography as a localization procedure in normocalcemic primary hyperparathyroidism. J Med Imaging Radiat Oncol. 2018;62(4):493-8.). PET/CT with 18F-Fluorocholine (18F-FCH) has been shown to improve the detection of pathologic parathyroid glands in hypercalcemic PHPT. The diagnostic performance of 18F-FCH-PET/CT was evaluated in a small series of patients with normocalcemic PHPT (5858 Bossert I, Chytiris S, Hodolic M, Croce L, Mansi L, Chiovato L, et al. PETC/CT with 18 F-Choline localizes hyperfunctioning parathyroid adenomas equally well in normocalcemic hyperparathyroidism as in overt hyperparathyroidism. J Endocrinol Invest. 2019;42(4):419-26.). The detection rate 18F-FCH-PET/CT was of 69% vs. 61% for neck ultrasound, and a complete failure of scintigraphy to detect any hyperfunctioning parathyroid gland (5858 Bossert I, Chytiris S, Hodolic M, Croce L, Mansi L, Chiovato L, et al. PETC/CT with 18 F-Choline localizes hyperfunctioning parathyroid adenomas equally well in normocalcemic hyperparathyroidism as in overt hyperparathyroidism. J Endocrinol Invest. 2019;42(4):419-26.).

Normocalcemic PHPT has been reported to have a higher prevalence of multiglandular disease, ranging from 0 to 43% (Table 4) (3535 Šiprová H, Fryšák Z, Souček M. Primary Hyperparathyroidism, With a Focus on Management of the Normocalcemic Form: To Treat or Not To Treat? Endocr Pract. 2016;22(3):294-301.,5959 Gómez-Ramírez J, Gómez-Valdazo A, Luengo P, Porrero B, Osorio I, Rivas S. Comparative prospective study on the presentation of normocalcemic primary hyperparathyroidism. Is it more aggressive than the hypercalcemic form? Am J Surg. 2020;219(1):150-3.,6464 Sho S, Kuo EJ, Chen AC, Li N, Yeh MW, Livhits MJ. Biochemical and Skeletal Outcomes of Parathyroidectomy for Normocalcemic (Incipient) Primary Hyperparathyroidism. Ann Surg Oncol. 2019;26(2):539-46.7070 Koumakis E, Souberbielle JC, Sarfati E, Meunier M, Maury E, Gallimard E, et al. Bone mineral density evolution after successful parathyroidectomy in patients with normocalcemic primary hyperparathyroidism. J Clin Endocrinol Metab. 2013;98(8):3213-20.). Of note, multiglandular disease may decrease the success of preoperative localization and has implications for the technical difficulty of the operation by requiring bilateral cervical exploration (3434 Wade TJ, Yen TWF, Amin AL, Wang TS. Surgical management of normocalcemic primary hyperparathyroidism. World J Surg. 2012;36(4):761-6.,6565 Pandian TK, Lubitz CC, Bird SH, Kuo LE, Stephen AE. Normocalcemic hyperparathyroidism: A Collaborative Endocrine Surgery Quality Improvement Program analysis. Surgery. 2020;167(1):168-72.,6868 Trinh G, Rettig E, Noureldine SI, Russell JO, Agrawal N, Mathur A, et al. Surgical Management of Normocalcemic Primary Hyperparathyroidism and the Impact of Intraoperative Parathyroid Hormone Testing on Outcome. Otolaryngol Head Neck Surg. 2018;159(4):630-7.,7171 Schneider DF, Burke JF, Ojomo KA, Clark N, Mazeh H, Sippel RS, et al. Multigland disease and slower decline in intraoperative PTH characterize mild primary hyperparathyroidism. Ann Surg Oncol. 2013;20(13):4205-11.). Several authors have recommended using intraoperative PTH (ioPTH) in this context to guide appropriate resection considering that its decline might take longer than that observed during PTX for classic PHPT (7272 Graves CE, McManus CM, Chabot JA, Lee JA, Kuo JH. Biochemical Profile Affects IOPTH Kinetics and Cure Rate in Primary Hyperparathyroidism. World J Surg. 2020;44(2):488-95.). If more than one preoperative imaging technique provides concordant evidence for single-gland disease, then a focused exploration with ioPTH can be utilized. However, if ioPTH values indicate that single gland excision is not consistent with biochemical cure the surgeon should convert from a focused approach to four-gland exploration. An increased risk of conversion from a targeted approach to bilateral neck exploration has been reported in patients with normocalcemic compared to hypercalcemic PHPT (13% vs. 4%; p < 0.001, respectively) (6868 Trinh G, Rettig E, Noureldine SI, Russell JO, Agrawal N, Mathur A, et al. Surgical Management of Normocalcemic Primary Hyperparathyroidism and the Impact of Intraoperative Parathyroid Hormone Testing on Outcome. Otolaryngol Head Neck Surg. 2018;159(4):630-7.).

Table 4
Summary of the studies investigating the rate of multiglandular disease at surgery and the effect of parathyroidectomy on bone mineral density, nephrolithiasis and quality of life

Few data are available on outcomes of parathyroid surgery in normocalcemic PHPT (Table 4). These studies have shown an improvement in bone mineral density, nephrolithiasis, cardiovascular risk factors and quality of life. Of note, few studies fulfill the diagnostic criteria of normocalcemic PHPT.

Successful PTX has been reported to be followed at 1 year by a significant individual BMD gain in nearly half of normocalcemic PHPT patients with osteoporosis (Table 4) (5959 Gómez-Ramírez J, Gómez-Valdazo A, Luengo P, Porrero B, Osorio I, Rivas S. Comparative prospective study on the presentation of normocalcemic primary hyperparathyroidism. Is it more aggressive than the hypercalcemic form? Am J Surg. 2020;219(1):150-3.,6464 Sho S, Kuo EJ, Chen AC, Li N, Yeh MW, Livhits MJ. Biochemical and Skeletal Outcomes of Parathyroidectomy for Normocalcemic (Incipient) Primary Hyperparathyroidism. Ann Surg Oncol. 2019;26(2):539-46.,6767 Traini E, Bellantone R, Tempera SE, Russo S, De Crea C, Lombardi CP, et al. Is parathyroidectomy safe and effective in patients with normocalcemic primary hyperparathyroidism? Langenbeck's Arch Surg. 2018;403(3):317-23.,7070 Koumakis E, Souberbielle JC, Sarfati E, Meunier M, Maury E, Gallimard E, et al. Bone mineral density evolution after successful parathyroidectomy in patients with normocalcemic primary hyperparathyroidism. J Clin Endocrinol Metab. 2013;98(8):3213-20.).

Only one study evaluated the effect of PTX on nephrolithiasis. The study included only 10 patients, with no further evidence of kidney stones present in 4/10 patients, persistence in one and stability in five (Table 4) (6767 Traini E, Bellantone R, Tempera SE, Russo S, De Crea C, Lombardi CP, et al. Is parathyroidectomy safe and effective in patients with normocalcemic primary hyperparathyroidism? Langenbeck's Arch Surg. 2018;403(3):317-23.).

One study showed that blood pressure, serum total cholesterol, and homeostatic model assessment-insulin resistance (HOMA-IR) improved after PTX (7373 Beysel S, Caliskan M, Kizilgul M, Apaydin M, Kan S, Ozbek M, et al. Parathyroidectomy improves cardiovascular risk factors in normocalcemic and hypercalcemic primary hyperparathyroidism. BMC Cardiovasc Disord. 2019;19(1):1-8.). Conversely, neither glycated hemoglobin levels nor the homeostatic model assessment-beta cell function (HOMA-B) index changed in patients with normocalcemic PHPT and prediabetes undergoing parathyroid surgery or conservative follow-up for up to 8 months, indicating a minor impact of parathyroid surgery on these outcomes (7474 Karras S, Kotsa K, Annweiler C, Kiortsis D, Koutelidakis I. Improving glucose homeostasis after parathyroidectomy for normocalcemic primary hyperparathyroidism with co-existing prediabetes. Nutrients. 2020;12(11):1-9.). Of note, the latest guidelines on the management of asymptomatic PHPT (44 Bilezikian JP, Brandi ML, Eastell R, Silverberg SJ, Udelsman R, Marcocci C, et al. Guidelines for the management of asymptomatic primary hyperparathyroidism: Summary statement from the fourth international workshop. J Clin Endocrinol Metab. 2014;99(10):3561-9.) did not recommend parathyroid surgery to improve overall cardiovascular risk either for mild traditional hypercalcemic or normocalcemic PHPT because of the lack of evidence and contradictory findings.

The question of whether PTX can improve quality of life (QoL) is still uncertain in patients with classic PHPT and only one study evaluated this question in patients with normocalcemic PHPT (Table 4) (6969 Bannani S, Christou N, Guérin C, Hamy A, Sebag F, Mathonnet M, et al. Effect of parathyroidectomy on quality of life and non-specific symptoms in normocalcaemic primary hyperparathyroidism. Br J Surg. 2018;105(3):223-9.). QoL was assessed by self-administered Short Form-36 v.2 Questionnaire. Patients with normocalcemic PHPT had improvement in some QoL domains after PTX. There was an improvement in anxiety at 3 months, while only thirst was still improved at 6 months, and thirst and fatigue at 12 months.

In conclusion, the literature on normocalcemic PHPT is based mostly on larger studies of population-based cohorts and smaller studies from referral centers. Few studies have rigorously followed the definition of normocalcemic PHPT given by the latest guidelines, which require that serum total or ionized calcium should be normal on repeated measurements over time. The lack of rigorous diagnostic criteria and selection bias may explain the heterogeneity of reported rates of bone and renal complications in relation to consistently mild laboratory alterations. Moreover, there are questions regarding the significance of normocalcemic PHPT when it is just a biochemical signature in a patient without bone or kidney complications. Finally, its natural history remains still to be elucidated because a proportion of patients diagnosed with normocalcemic PHPT may spontaneously revert to having normal PTH levels. With all these concerns, caution should be used in recommending surgery for normocalcemic PHPT. Surgery should be considered only in the setting of an expert multidisciplinary approach and only if there are compelling indications and a surgical target.

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Publication Dates

  • Publication in this collection
    05 Dec 2022
  • Date of issue
    Sep-Oct 2022

History

  • Received
    20 July 2022
  • Accepted
    29 Aug 2022
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