Background

Over the past four to five decades, since the advent of multichannel autoanalysers, in a vast majority of patients, primary hyperparathyroidism has been diagnosed as a serendipitously discovered asymptomatic condition, when serum calcium is measured for unrelated reasons. It is now one of the most common endocrine disorders and between 1995 and 2010 its prevalence rose from 76 to 233 per 1 00 000 women.1 Despite its incidental discovery, bone mass is typically reduced at the distal one-third of radius, a site that is enriched in cortical bone.2 Diagnostic workup and management strategy of this asymptomatic cohort has been the subject of four international workshops and is now better understood.

More recently, a newer clinical presentation of primary hyperparathyroidism has aroused considerable interest. It has been given the label of normocalcaemic primary hyperparathyroidism (NPHPT) and was initially described by Wills et al as a variant of primary hyperparathyroidism.3 Patients have normal concentration of total and ionised serum calcium with raised level of parathyroid hormone (PTH). In most such individuals, the initial PTH measurement is driven by the presence of metabolic bone disease or renal stones, which allows the identification of what is believed to be a previously unrecognised stage of the condition. Since its formal recognition in 2008, during the third international workshop on asymptomatic primary hyperparathyroidism,4 several studies have been published although there is a lack of uniformity in patient selection and cut-off values used to define the condition.

Definition

NPHPT is defined by a raised PTH concentration in the presence of consistently normal total and ionised calcium levels, after excluding vitamin D deficiency, renal impairment, primary hypercalciuria, calcium malabsorption and the use of drugs that can potentially elevate PTH level.5 6 A significant proportion of patients who have high PTH in the presence of normocalcaemia have vitamin D deficiency or chronic kidney disease and it is essential to exclude these and other confounders to confirm the presence of NPHPT.6 Common drugs which may cause a raised PTH include thiazides, lithium, anticonvulsants, bisphosphonates and denosumab.6–8

Pathophysiology

A commonly held hypothesis is that normocalcaemic and hypercalcaemic primary hyperparathyroidism (NPHPT and HPHPT, respectively) represent a bimodal sequence of onset of the same disorder.9 During the first phase, PTH concentration is elevated but normocalcaemia is maintained representing the ‘subclinical’ phase of the condition similar to that recognised for several other endocrine conditions. The second phase is the one that has traditionally been recognised by the detection of hypercalcaemia. The hypothesis that NPHPT represents an earlier stage of HPHPT is favoured by the lower PTH secretion (75±19 vs 93±49 pg/mL, P<0.001) and lower mass of adenomatous cells (229 vs 500 mg, P<0.05) in the former cohort of patients.10 It is further supported by the observation that in some patients NPHPT progresses to HPHPT6 8 11

Maruani et al explored another explanation by comparing patients with NPHPT and HPHPT for renal calcium and phosphate handling and bone turnover makers. Patients with NPHPT had lower fasting urine calcium excretion and tubular reabsorption, higher value of renal phosphate threshold and lower values of markers of bone turnover. Based on these findings they proposed that in patients with NPHPT, maintenance of normocalcaemia is a manifestation of resistance of renal tubules and the skeleton to the effects of PTH, possibly linked to the protective impact of oestrogen.10 However, the progression of NPHPT to HPHPT and its diagnosis during postmenopausal age group do not support this hypothesis. Their findings have not been reproduced and the concept of biphasic onset is now widely accepted.

Epidemiology and natural history

The data on the epidemiology and natural history of NPHPT is limited and conflicting and this has hindered formal recommendations to be made on its work-up and management. Although no formal age and gender distribution data is available, NPHPT is more commonly seen in women of postmenopausal age group, as is HPHPT.5 11 12 A wide range of prevalence figures and rates of progression are reported due to variations in the criteria used to exclude secondary hyperparathyroidism and in the selection of the study population as summarised in table 1.

Most patients in clinical practice are identified during evaluation of high-risk groups, that is, those who have adverse bone and renal outcomes like osteoporosis, fragility fractures or renal calculi or are at a higher risk of developing these. As would be expected, studies undertaken on such high-risk cohorts report higher prevalence figures and rates of progression.6 10 11 13 In the Columbia cohort of 37 patients with NPHPT referred to a tertiary bone unit, 40% individuals developed new features of primary hyperparathyroidism. During a follow-up of 3.1±0.3 years (mean ±SD), seven individuals developed hypercalcaemia, one had a new fracture, four had new osteoporosis, one developed renal stones and two patients had significant hypercalciuria. Patients who showed progression were older, had higher baseline serum calcium level (2.4±0.05 vs 2.3±0.02 mmol/L) and higher baseline urinary calcium excretion. Seven patients underwent successful parathyroidectomy leading to normalisation of PTH in all patients with operative findings of either a solitary adenoma or hyperplasia.6 Tordjman et al reported a series of 32 patients with NPHPT identified from their cohort of patients with primary hyperparathyroidism in the endocrine clinic. While 20 patients managed conservatively did not have any significant change in serum calcium level after a mean follow-up of 4.1±3 years, 12 patients required surgery based on established metabolic bone disease and positive localisation studies.13

However, the true prevalence of NPHPT is best assessed by studies undertaken on unselected cohorts which report a lower prevalence and rate of progression.14–18 A Swedish study on 608 individuals from a non-referral population reported a prevalence of 2% in 1995 which increased to 11% in 2007, with vitamin D deficiency and renal impairment appropriately excluded. After 13 years of follow-up only one patient progressed to hypercalcaemia and none had adverse bone, renal or cardiovascular outcomes. The authors suggest that the seemingly high prevalence at the time of the follow-up assessment may be secondary to confounding factors like increasing age, body mass index or changing vitamin D level irrespective of its absolute value.14 A recent review of two unselected community-dwelling cohorts from the USA by Cusano et al (The Osteoporotic Fractures in Men, MrOS and Dallas Heart Study, DHS) reported an even lower prevalence figures of 0.4% and 3.1%, respectively.17 A prevalence of 16.7% was reported in a Canadian-based study of 1871 subjects from general population (CaMos), although vitamin D deficiency was not excluded.19 The above studies also highlight a disparity in the reported prevalence of NPHPT from Canada, USA and Europe.

On the basis of these studies on such varied patient groups, we can conclude that the prevalence of NPHPT in general population is low when strict criteria are used to exclude secondary hyperparathyroidism and other confounding influences. By contrast, when NPHPT is identified during assessment of patients with metabolic bone disease or renal stones, the rate of progression is high in untreated patients, indicating the need to assess such individuals for progressive rise in serum calcium and/or end-organ involvement during the initial evaluation and follow-up.

Clinical and laboratory evaluation

There are no formal recommendations on how to investigate, manage and follow the patients identified with NPHPT. On the basis of our greater understanding over the past decade, the following three-step pragmatic approach is proposed for evaluation of NPHPT and is depicted diagrammatically in figure 1.

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Figure 1

Proposed management plan for patients with NPHPT. DXA, dual-energy x-ray absorptiometry, NPHPT, normocalcaemic primary hyperparathyroidism; PTH, parathyroid hormone.

Management strategy and Follow-up

In the absence of sufficient data on its natural history, it is challenging for a clinician to formulate a management plan for an individual patient with a confirmed diagnosis of NPHPT.

In clinical practice, in a vast majority of patients, the diagnosis of NPHPT is arrived at when calcium and PTH levels are requested during the evaluation of patients who have, or are at a higher risk of having, metabolic bone disease or have nephrolithiasis. A suggested management strategy for this cohort of patients is depicted in figure 1. Once the investigations for assessment of bone and renal involvement are completed, in the absence of hypercalcaemia, a decision can be made on whether surgery is indicated on the basis of the degree of end-organ involvement. The criteria used are the same as in patients with asymptomatic HPHPT as specified in the fourth international workshop (table 2).47 48

Patients in whom surgery is indicated, its suitability should be confirmed on the basis of factors such as age, frailty, comorbidities and patient preference. Localisation studies including ultrasonography and radionuclide scanning should be requested. In comparison to patients with HPHPT, a higher frequency of negative localisation studies and surgical failure has been reported.24 49 This is likely to be related to the smaller size of the adenoma encountered in patients with NPHPT. Another less likely explanation is the greater frequency of multigland hyperplasia, reported in some studies.24 50 However, in these studies, conclusions were drawn from a small number of patients and there was a lack of clarity on how secondary hyperparathyroidism was excluded. Moreover, several other studies have reported the presence of a solitary parathyroid adenoma in a majority of patients studied.11 20 51 Successful removal of an adenoma has been shown to normalise postoperative PTH level6 13 which is the only biochemical criterion that can be used to indicate cure. BMD has been shown to improve as early as 1–2 years postparathyroidectomy in patients with both symptomatic HPHPT and NPHPT.34 52 53

Patients in whom the degree of bone or renal involvement is not significant enough to consider surgery, a structured observational policy can be adopted. This consists of annual monitoring of albumin-adjusted or ionised calcium, PTH, vitamin D and renal function.5 47 Reassessment of bone density and nephrolithiasis at 3–5 year intervals has been recommended,26 although it may be more practical to adopt an individualised approach guided by the baseline measurements and overall risk profile for progressive bone disease. A 3-yearly reassessment to examine the sequential change in the bone density would certainly be recommended for patients with osteopaenia (T score between −1.0 and −2.5), those with multiple risk factors for osteoporosis or those with a high FRAX score at baseline. There is no clear guidance on the need for monitoring of urinary calcium in NPHPT and we do not recommend this, as the degree of hypercalciuria is mild10 and is not likely to help in predicting nephrolithiasis. During this period, we suggest maintaining vitamin D level to >50 nmol/L (and ideally >75 nmol/L).7 Occasionally, PTH may normalise and the patient would no longer fulfil the criteria for NPHPT. On the other hand, patients who demonstrate progression to hypercalcaemia or new onset of bone or renal complications would merit assessment for surgery as above.

Patients in whom surgery is indicated but is not undertaken because of comorbidities or patient preference, bisphosphonates can be considered. These agents have been proven to be effective in improving bone mineral density in short-term studies but there is no robust fracture data.47 53 There is also no literature on the benefit of these or any other agents in patients with NPHPT. There is no role for cinacalcet therapy in lowering PTH levels or improving bone outcomes. While one small prospective randomised study reported a reduction in the number and size of renal stones with the use of cinacalcet in patients with NPHPT and HPHPT,40 a 5-year multicentre randomised controlled trial showed that there was no effect on bone mineral density. 54

More recently, clinicians are coming across patients with high PTH level without hypercalcaemia or end organ involvement, in whom the initial biochemical tests were requested to explain either unrelated symptoms or serendipitous finding of a parathyroid adenoma on imaging studies. Although a significant proportion of these patients have one or more of the recognised confounding factors and do not have NPHPT, a small cohort meets the criteria for the diagnosis and pose a management challenge to the clinician. The above-mentioned strategy for long-term follow-up may not be necessary for many of these patients who are often at a lower risk of end-organ involvement. We would recommend regular review only for those patients who are more likely to progress, that is, those with baseline albumin-adjusted calcium ≥2.4±0.05 mmol/L (P<0.01)6 or adverse risk profile for bone disease as described above. For the remaining patients, the same frequency of reassessment may not be required and the decision can be individualised on the basis of clinical and logistic factors. This approach is supported by several studies that have shown a low progression rate in similar patient groups (table 1).8 14 18

Future possibilities

Insufficient data on the natural history of NPHPT has led to a paucity of evidence-based recommendations on its management. More studies on large cohorts of patients followed up for a longer periods would certainly allow us to further standardise our approach to the management of this condition. On the diagnostic side, any future development that focuses the inconsistencies with PTH assays described above would be of significant benefit. Although traceable reference materials (eg, the WHO Recombinant PTH1-84 International Standard 95/646)55 are available, a validated traceable reference method for PTH1-84 is awaited. The development of tandem mass spectrometry methods for measurement of PTH offer superior specificity with similar sensitivity compared with immunoassay but they are also subject to interferences such as oxidised and phosphorylated PTH.27 In the short term, the International Federation of Clinical Chemistry and Laboratory Medicine working group for PTH is actively working towards developing assay-specific target values of PTH, with the long-term goal of establishing a reference method for PTH analysis against which other methods could be harmonised.56

It would also be of significant clinical advantage to be able to precisely recognise the relationship between changes in vitamin D and PTH levels. Greater understanding of the impact of relative changes in vitamin D level on PTH, rather than its absolute value, impact of factors such as age, ethnicity and calcium intake on this relationship and the time to normalisation of PTH after vitamin D level reaches a predefined target would be helpful.

Standardisation of PTH assays and information of vitamin D dynamics may help us to explain an isolated rise in PTH in a significant number of patients which in turn would allow us to focus on the subgroup of patients with a potentially progressive condition with future adverse impact on patient morbidity.