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.


INTRODUCTION
P rimary 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 (1).
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 (2). 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 (3,4). 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 (3,4) and the European Society of Endocrinology Educational Program of Parathyroid Disorders in 2021 (5). 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 PHPT Arch Endocrinol Metab. 2022;66/5 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 (6). 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 (7)(8)(9).
Normocalcemic PHPT is a diagnosis of exclusion. Secondary causes of hyperparathyroidism are common, and a rigorous exclusion of secondary causes is needed. 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 (10,11). 3. Medications. Antiresorptive medications, including bisphosphonates and denosumab, are a known cause of hyperparathyroidism by blocking calcium release from the skeleton (12)(13)(14).
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 (15). The relationship between the diuretics hydrochlorothiazide and furosemide and PTH concentrations is less clear (16,17). It is recommended to exclude diuretics as a cause of hyperparathyroidism. Newer data also indicate that proton pump inhibitors (18) and SGLT-2 inhibitors (19) may also result in elevated PTH concentrations. 4. Insufficient calcium intake or malabsorption.
The epidemiologic data are summarized in Table 1.

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 (6,25,27,30,(33)(34)(35)(36)(37)(38)(39)(40)(41). 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 (42)(43)(44)(45)(46). Studies using echocardiography or various noninvasive measures of arterial compliance as surrogate markers for vascular risk found no differences in individuals with normocalcemic disease (47,48). While one study showed an increase in coronary artery calcium score in patients with normocalcemic PHPT (49), another found no difference (50). One study demonstrated small but significant reductions in quality of life in individuals with normocalcemic disease (51).

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 (31,33,35,37,39). In one study of individuals with normocalcemic PHPT, none of the 20 patients developed hypercalcemia over a median of four years of monitoring (39). Another study demonstrated that 7 of 37 (19%) of patients developed hypercalcemia over a median of three years (37). 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 (35). The majority (67%) of these patients transitioned to hypercalcemia within the first two years of follow-up, however, a small

Medical therapy
Two studies have evaluated the impact of pharmacologic treatment on bone and renal complications associated with normocalcemic PHPT (52,53). 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 post menopausal women or older men. One prospective open-label study evaluated the effects of oral alendronate in 30 postmenopausal women with normocalcemic PHPT (52). Patients were randomized to receive alendronate and cholecalciferol or cho lecalciferol 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%, re spectively. Bisphosphonates therefore seem to be safe and ef fective 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 Normocalcemic PHPT Arch Endocrinol Metab. 2022;66/5 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 (53). 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 (4). Similarly, the guidelines of the American Association of Endocrine Surgeons recommended surgery in symptomatic patients, without differentiating between hypercalcemic PHPT and normocalcemic PHPT (54,55). 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 (5). 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 99m Tc-sestamibi scintigraphy are generally the first-line imaging tests to localize the hyperfunctioning gland(s) (56).
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 (34,35,(57)(58)(59)(60). Moreover, most studies have selection bias given that they are mostly surgical case series. These studies are summarized in Table 3.
Patients with normocalcemic PHPT generally have less positive localization studies compared to patients with classic hypercalcemic disease (35,60). 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% (57). 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 (56). Fourdimensional CT (4D-CT) has recently emerged as a promising technique for preoperative localization of parathyroid lesions in patients with PHPT (61)(62)(63). 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%) (60). 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 (58). 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 (58).   Only those patients in whom serum PTH remain increased after vitamin D substitution were included in the study. 3 The entire cohort of NPHPT was 89 but only in 58 was available ionized serum calcium.
Normocalcemic PHPT has been reported to have a higher prevalence of multiglandular disease, ranging from 0 to 43% (Table 4) (35,59,(64)(65)(66)(67)(68)(69)(70). 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 (34,65,68,71). 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 (72). 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) (68).
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) (59,64,67,70).
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) (67).
One study showed that blood pressure, serum total cholesterol, and homeostatic model as sessment-insulin resistance (HOMA-IR) improved after PTX (73). Post-operative bone mineral density was only available in 12 patients (not specified the site) and kidney ultrasound in 10 patients.
c Surgery was performed in 5 persistently normocalcemic patients who also had nodular goiter, and they were indicated for thyroidectomy.
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 con servative follow-up for up to 8 months, indicating a minor impact of parathyroid surgery on these outcomes (74). Of note, the latest guidelines on the management of asymptomatic PHPT (4) did not rec ommend 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) (69). QoL was assessed by self-administered Short Form-36 v.2 Questionnaire. Patients with normocalcemic PHPT had im provement in some QoL domains after PTX. There was an im provement in anxi ety 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 populationbased 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.