Best practice

Normocalcaemic primary hyperparathyroidism: a

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pragmatic approach
Feaz Babwah, Harit N Buch

Wolverhampton Endocrine Abstract considerable interest. It has been given the

and Diabetes Unit, New Cross It is well recognised that over the past three to four label of normocalcaemic primary hyperparathy-
Hospital, Wolverhampton, UK
decades the incidence of asymptomatic primary roidism (NPHPT) and was initially described by
hyperparathyroidism has increased significantly. Wills et al as a variant of primary hyperparathy-
Correspondence to
Dr Harit N Buch; ​harit.​buch@​ However, more recently this pattern has further evolved roidism.3 Patients have normal concentration of
nhs.​net into a presentation with normocalcaemia and raised total and ionised serum calcium with raised level of
parathyroid hormone (PTH) level without the presence of parathyroid hormone (PTH). In most such individ-
Received 21 September 2017 a recognised stimulus for its rise, in the form of vitamin uals, the initial PTH measurement is driven by the
Revised 12 January 2018
Accepted 13 January 2018 D deficiency or renal impairment. A diagnostic label of presence of metabolic bone disease or renal stones,
Published Online First normocalcaemic hyperparathyroidism (NPHPT) has been which allows the identification of what is believed
3 February 2018 given to this phenotype and in most such individuals, to be a previously unrecognised stage of the condi-
the initial PTH measurement is driven by the presence of tion. Since its formal recognition in 2008, during
metabolic bone disease. The reported prevalence, degree the third international workshop on asymptomatic
of end-organ involvement and the rate of progression primary hyperparathyroidism,4 several studies have
vary considerably and are related to patients studied been published although there is a lack of unifor-
and the biochemical cut-offs used in its definition. A mity in patient selection and cut-off values used to
majority of patients are diagnosed during assessment define the condition.
of metabolic bone disease of varying degrees. Once
the diagnosis is confirmed by excluding confounding
Definition
factors, the patient should undergo full assessment of
NPHPT is defined by a raised PTH concentration in
end-organ involvement, which is the main determinant
the presence of consistently normal total and ionised
of further therapeutic decisions. Surgery, with prior
calcium levels, after excluding vitamin D deficiency,
localisation, is considered in patients with significant
renal impairment, primary hypercalciuria, calcium
end-organ involvement in keeping with the guidance for
malabsorption and the use of drugs that can poten-
hypercalcaemic patients. If a patient does not meet these
tially elevate PTH level.5 6 A significant proportion
criteria, annual clinical and biochemical surveillance is
of patients who have high PTH in the presence
recommended to identify progression to hypercalcaemia
of normocalcaemia have vitamin D deficiency or
or worsening end-organ involvement. It is less clear
chronic kidney disease and it is essential to exclude
if patients identified during ’routine’ requests for
these and other confounders to confirm the pres-
evaluation of unrelated symptoms require similar close
ence of NPHPT.6 Common drugs which may cause
monitoring. In conclusion, in this review on NPHPT we
a raised PTH include thiazides, lithium, anticonvul-
focus on its definition, planning of further investigations,
sants, bisphosphonates and denosumab.6–8
selection of patients for intervention and devising an
appropriate follow-up strategy.
Pathophysiology
A commonly held hypothesis is that normocal-
caemic and hypercalcaemic primary hyperpara-
Background thyroidism (NPHPT and HPHPT, respectively)
Over the past four to five decades, since the advent represent a bimodal sequence of onset of the same
of multichannel autoanalysers, in a vast majority disorder.9 During the first phase, PTH concentra-
of patients, primary hyperparathyroidism has been tion is elevated but normocalcaemia is maintained
diagnosed as a serendipitously discovered asymp- representing the ‘subclinical’ phase of the condition
tomatic condition, when serum calcium is measured similar to that recognised for several other endo-
for unrelated reasons. It is now one of the most crine conditions. The second phase is the one that
common endocrine disorders and between 1995 has traditionally been recognised by the detection
and 2010 its prevalence rose from 76 to 233 per of hypercalcaemia. The hypothesis that NPHPT
1 00 000 women.1 Despite its incidental discovery, represents an earlier stage of HPHPT is favoured
bone mass is typically reduced at the distal one-third by the lower PTH secretion (75±19 vs 93±49 pg/
of radius, a site that is enriched in cortical bone.2 mL, P<0.001) and lower mass of adenomatous cells
Diagnostic workup and management strategy of (229 vs 500 mg, P<0.05) in the former cohort of
this asymptomatic cohort has been the subject of patients.10 It is further supported by the observa-
four international workshops and is now better tion that in some patients NPHPT progresses to
To cite: Babwah F, understood. HPHPT6 8 11
Buch HN. J Clin Pathol More recently, a newer clinical presentation Maruani et al explored another explanation
2018;71:291–297. of primary hyperparathyroidism has aroused by comparing patients with NPHPT and HPHPT
Babwah F, Buch HN. J Clin Pathol 2018;71:291–297. doi:10.1136/jclinpath-2017-204455    291
 Best practice

Table 1  Prevalence and natural history of NPHPT

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Vitamin D cut- eGFR cut-off (mL/ NPHPT
Study Patient cohort off (nmol/L) min) prevalence (%) Natural history
Population - based studies on asymptomatic patients
Kontogeorgos et al14 (WHO General population aged 25–64 years >50 Not provided 11.0 One person progressed to hypercalcaemia
MONICA, Sweden) (n=608) None developed end-organ involvement (13-
year follow-up)
Lundgren et al15 16 Postmenopausal women (n=5202) Not excluded Not provided (serum 0.5 When reassessed at 8.9 years there was a
(Sweden) Cr >150 μmol/L) similar prevalence of NPHPT
Serum calcium increased by 0.04±0.10 mmol/L
Cusano et al17 Unselected community-dwelling men >50 >60 0.4 Not followed-up
(MrOS, USA) aged ≥65 years (n=2364)
Cusano et al17 General population aged 18–65 years >50 >60 3.1 one person progressed to hypercalcaemia
(DHS, USA) (n=3450) None developed end-organ involvement
29 patients no longer met the criteria for
NPHPT at follow-up (8 years)
García-Martín et al18 (Spain) Postmenopausal women (n=100) >75 >60 6.0 No progression (1-year follow-up)
Berger et al19 General population aged 31– >50 Not excluded 16.7 Not followed-up
(CaMos, Canada) 97(n=1871)
Rejnmark et al38 (DOPS, Postmenopausal women (n=2016) Not excluded >60 17.0 One person progressed to hypercalcaemia
Denmark) (16-year follow-up)
Referral population of high-risk patients*
Lowe et al6 Referred patients to metabolic bone >50 >40 19% progressed to hypercalcaemia 40%
(USA) unit aged 32–78 years (NPHPT, n=37) developed further end-organ involvement
(mean follow-up of 3.1±0.3 years)
Maruani et al10 (France) Referred patients aged 55±11 years >15 >50 19.1 Data on progression not available
to metabolic unit (n=178)
Šiprová et al11 Referred patients aged 26–85 years >50 Not provided 19% progressed to hypercalcaemia (6-year
(Czech Republic) with suspected PHPT follow-up—most progressed within 2 years)
(NPHPT, n=187)
Tordjman et al13 Referred patients aged >50 Not provided 12 required surgery
(Israel) 60.5±10.5 years with suspected PHPT No progression in the rest
(NPHPT, n=32) (mean follow-up of 4.1±3 years)
Marques et al21 Referred women aged >75 >40 8.9 Data on progression not available
(Brazil) 62.4±10.5 years to exclude
osteoporosis(n=156)
*Patients who are at a higher risk of metabolic bone disease or already have adverse bone and renal outcomes like osteoporosis, fragility fractures or renal calculi.
eGFR, estimated glomerular filtration rate; NPHPT, normocalcaemic hyperparathyroidism; PHPT, primary hyperparathyroidism.

for renal calcium and phosphate handling and bone turnover and renal outcomes like osteoporosis, fragility fractures or renal
makers. Patients with NPHPT had lower fasting urine calcium calculi or are at a higher risk of developing these. As would be
excretion and tubular reabsorption, higher value of renal phos- expected, studies undertaken on such high-risk cohorts report
phate threshold and lower values of markers of bone turnover. higher prevalence figures and rates of progression.6 10 11 13 In
Based on these findings they proposed that in patients with the Columbia cohort of 37 patients with NPHPT referred to a
NPHPT, maintenance of normocalcaemia is a manifestation of tertiary bone unit, 40% individuals developed new features of
resistance of renal tubules and the skeleton to the effects of PTH, primary hyperparathyroidism. During a follow-up of 3.1±0.3
possibly linked to the protective impact of oestrogen.10 However, years (mean ±SD), seven individuals developed hypercalcaemia,
the progression of NPHPT to HPHPT and its diagnosis during one had a new fracture, four had new osteoporosis, one devel-
postmenopausal age group do not support this hypothesis. Their oped renal stones and two patients had significant hypercalci-
findings have not been reproduced and the concept of biphasic uria. Patients who showed progression were older, had higher
onset is now widely accepted. baseline serum calcium level (2.4±0.05 vs 2.3±0.02 mmol/L)
and higher baseline urinary calcium excretion. Seven patients
Epidemiology and natural history underwent successful parathyroidectomy leading to normali-
The data on the epidemiology and natural history of NPHPT is sation of PTH in all patients with operative findings of either
limited and conflicting and this has hindered formal recommen- a solitary adenoma or hyperplasia.6 Tordjman et al reported a
dations to be made on its work-up and management. Although series of 32 patients with NPHPT identified from their cohort
no formal age and gender distribution data is available, NPHPT of patients with primary hyperparathyroidism in the endocrine
is more commonly seen in women of postmenopausal age group, clinic. While 20 patients managed conservatively did not have
as is HPHPT.5 11 12 A wide range of prevalence figures and rates any significant change in serum calcium level after a mean
of progression are reported due to variations in the criteria used follow-up of 4.1±3 years, 12 patients required surgery based
to exclude secondary hyperparathyroidism and in the selection on established metabolic bone disease and positive localisation
of the study population as summarised in table 1. studies.13
Most patients in clinical practice are identified during evalu- However, the true prevalence of NPHPT is best assessed by
ation of high-risk groups, that is, those who have adverse bone studies undertaken on unselected cohorts which report a lower
292 Babwah F, Buch HN. J Clin Pathol 2018;71:291–297. doi:10.1136/jclinpath-2017-204455
 Best practice
prevalence and rate of progression.14–18 A Swedish study on 608

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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 hyper-
calcaemia and none had adverse bone, renal or cardiovascular
outcomes. The authors suggest that the seemingly high preva-
lence 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 popu-
lation 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. Figure 1  Proposed management plan for patients with
NPHPT. DXA, dual-energy x-ray absorptiometry, NPHPT, normocalcaemic
Clinical and laboratory evaluation primary hyperparathyroidism; PTH, parathyroid hormone.
There are no formal recommendations on how to investigate,
manage and follow the patients identified with NPHPT. On the studies,6 8 13 14 serum albumin-adjusted total calcium continues
basis of our greater understanding over the past decade, the to be measured and reported in many UK centres.26 However,
following three-step pragmatic approach is proposed for eval- we would certainly recommend confirmation of normocal-
uation of NPHPT and is depicted diagrammatically in figure 1. caemia with ionised calcium estimation if the albumin-adjusted
value remains close to the upper limit of reference range and in
Biochemical confirmation of NPHPT patients with low albumin.
Persistent normocalcaemia
Biochemical diagnosis of NPHPT consists of demonstration of Raised PTH
persistent normocalcaemia using serial ionised calcium or serum A persistently elevated PTH is a sine qua non of NPHPT and it is
albumin-adjusted total calcium in the presence of an elevated important to be aware of the potential problems in the measure-
PTH.5 6 Persistence of normocalcaemia distinguishes NPHPT ment of PTH. The PTH immunoassay has evolved over the last
from HPHPT where calcium can be intermittently elevated.20 50 years. In an effort to reduce the cross-reactivity with PTH
One could hypothesise that the phase of intermittent hypercal- fragments the first generation single-site antibody immunoassay
caemia may represent a transition stage between patients with has been superseded by two-site immunometric second and
normocalcaemia and hypercalcaemia. third generation assays which measure ‘intact PTH’ and ‘whole
The Proceedings of the Fourth International Workshop or complete PTH’ respectively.7 There is, however, consider-
on the diagnosis of asymptomatic PHPT recommended that able variability between the different commercially available
ionised calcium should be in the normal range.7 It represents assays with no universally agreed cut-off for the upper-limit of
the biologically active free fraction of calcium21 and remains normal.27 PTH may also be influenced by ethnicity and age and
the gold-standard measurement. It has specific benefits in the like all immunoassays is subject to analytical interference from
context of NPHPT where the albumin-adjusted value has been heterophilic antibodies.28 29 In addition, chronic renal failure
found to be misleadingly normal in patients with high-ionised increases the level of circulating PTH fragments of varying sizes
calcium.22 23 Adjusted calcium can also be unreliable in low-al- and can lead to a higher level of PTH especially with the use of
bumin states.23 Maruani et al10 and Wade et al24 demonstrated intact PTH assay.27
significant discordance between ionised and total calcium and The impact of these limitations in PTH measurement is not
recommended the use of the former. However, point-of-care crucial in the diagnosis of HPHPT, as current PTH assays are
(POC) testing with blood gas analyzers used to obtain ionised capable of differentiating between PTH-driven and PTH-inde-
calcium level is not widely available in an outpatient setting and pendent hypercalcaemia.28 They are however of greater concern
its use is hindered by other barriers such as precision, standard- in the diagnosis of NPHPT with a potential for patient misclas-
isation, special sample management and high cost.22 25 In view sification and inappropriate patient management. It is widely
of these constraints and in keeping with its use in multiple other accepted that a traceable reference method for PTH1-84 is
Babwah F, Buch HN. J Clin Pathol 2018;71:291–297. doi:10.1136/jclinpath-2017-204455 293
 Best practice
urgently needed to harmonise PTH methodologies and thereby can also result in this biochemical picture. Hypomagnesaemia

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reduce the interassay variability which currently limits clinical should be excluded.20
and epidemiological applications of this assay particularly in
NPHPT.27
Assessment of end-organ involvement
Once a patient is identified as having NPHPT, the next step is
Retesting to determine if they have end-organ involvement, as is the case
Both calcium and PTH should be measured on at least two occa- with asymptomatic HPHPT. One would expect NPHPT to be a
sions 3–6 months apart to secure the diagnosis of NPHPT.7 20 mild condition but this is not necessarily the case. Several reports
indicate that the prevalence of bone and renal involvement is
either higher or similar to patients with hypercalcaemia.6 11 21 36
Exclusion of confounding factors
In patients with established bone or renal involvement at the
The next crucial step in the diagnostic workup is a meticulous
time of the diagnosis, assessment should focus on the likely
search for the presence of secondary hyperparathyroidism for
impact of NPHPT on disease progression.
which vitamin D deficiency is the the most common cause.30
There are several uncertainties about the relationship between
the vitamin D status and PTH level. Over the past decade, Bone
different PTH assays have been used and the level of 25-hydroxy There has been a greater awareness of bone health during recent
vitamin D at which the reference range of a particular assay has times which has led to an increase in targeted screening for
been derived is not clear.31 Moreover, the lower level of vitamin osteoporosis and assessment of fracture risk. This has led to the
D at which PTH rises has not been established across all popu- increase in PTH measurement in patients who are deemed to
lations5 and several factors like ethnicity, dietary calcium and be at a higher risk of metabolic bone disease on the basis of the
serum magnesium have been shown to have an impact on this known risk factors or a high Fracture Risk Assessment (FRAX)
relationship.32 However, it is generally agreed that the absolute risk score.37 This process of PTH measurement was used when
level of 25-hydroxy vitamin D at which PTH begins to rise lies NPHPT was initially formally diagnosed in 20084 and has also
somewhere between 50 and 75 nmol/L (20 and 30 ng/mL)8 and formed the basis of several subsequent studies. Not surprisingly
a value of >50 nmol/L is widely accepted as being sufficient to a high rate of progressive bone involvement has been reported
meet the demands of the majority of patients and would allow in such studies. Lowe et al reported a 57% prevalence of oste-
the diagnosis of NPHPT to be made. Patients with a lower level oporosis and 11% fragility fracture rate in their cohort of 37
should receive vitamin D replacement for at least 3 months, patients with NPHPT. After a median follow-up of 3 years, 43%
followed by PTH monitoring to exclude or confirm NPHPT,20 of patients had a progressive decline in BMD at all sites and in
although in some cases it can take up to 6–12 months for PTH a fifth of these the decline was >10%. There appeared to be no
level to normalise.7 Less commonly vitamin D replacement correlation between the level of PTH or baseline BMD and dete-
may lead to unmasking of hypercalcaemia, thereby making the rioration of bone health.6 In other studies undertaken on similar
diagnosis of HPHPT.5 7 20 26 An interesting approach has been patient groups, the reported rate of progressive bone involve-
proposed by Harvey et al, who used serum calcium, PTH, ment has ranged between 15% and 36%.13 21 24 36 However, the
vitamin D and age to create a four-dimensional nomogram. With selection bias inherent in these studies makes it difficult to esti-
the use of this nomogram in surgically treated patients, 100% of mate the ‘true’ frequency of bone involvement in patients with
patients with HPHPT, 84% with NPHPT and 54% with HPHPT NPHPT. In the WHO MONICA study on a randomly selected
with normal PTH could be predicted.33 Swedish cohort from the general population, there was no impact
The other major confounding factor to consider is renal on ultrasound attenuation values or fracture rate in patients with
failure, which is a well-known cause of secondary and tertiary NPHPT as compared with those with normal PTH.14 The Danish
hyperparathyroidism. There is an inverse relationship between Osteoporosis Prevention Study (DOPS, 1097 patients), a popu-
PTH and glomerular filtration rate (GFR) as demonstrated by lation-based prospective study, correlated PTH level in normo-
Martínez Diaz-Guerra et al.20 PTH has been shown to rise with a calcaemic postmenopausal women with long-term fracture risk.
fall in estimated GFR to <60 mL/min in large population surveys Patients with higher baseline PTH had lower bone mineral
and a value of >60 mL/min would support the diagnosis of density and an increased fracture risk. However, this impact
NPHPT despite the difficulty in ascertaining the cut-off in indi- was only seen in patients whose vitamin D was <80 nmol/L and
vidual patients.7 20 Some studies have used an exclusion criterion higher level of vitamin D appeared to protect against the adverse
of  <40 mL/min,5 6 21 but this seems too generous. bone outcomes associated with high PTH level.38
Primary or idiopathic hypercalciuria (IH) should be excluded. There is a lack of clarity about the pattern of bone involve-
IH is the the most common metabolic abnormality in patients with ment in patients with NPHPT. Lowe et al reported osteoporosis
calcium kidney stones and is defined as a 24-hour urine calcium in NPHPT to commonly involve the lumbar spine (34%) and hip
excretion >6.2  mmol (250  mg) in women and >7.5  mmol (38%), with no preferential bone loss at the distal one-third of
(300 mg) in men.34 Serum calcium is normal in most patients radius6 unlike in patients with HPHPT.5 Marques et al, however,
with IH but can be low-normal with a rise in PTH level resulting demonstrated similar level (28.5%) of osteoporosis at lumbar
in a biochemical picture similar to NPHPT. However, in NPHPT spine and distal radius.21 Charopoulos et al used high-resolu-
the degree of hypercalciuria is milder and serum calcium is high tion peripheral quantitative CT in 52 postmenopausal women
to normal. Thiazide challenge test can be used to exclude IH with primary hyperparathyroidism. The bone mineral content
although is rarely required.35 and volumetric bone mineral density were reduced at cortical as
Other causes of elevated PTH level to be considered include well as cancellous sites in both NPHPT and HPHPT groups but
the use of medications such as thiazide diuretics, lithium, anti- the latter group demonstrated a greater reduction.39 Although
convulsants and bisphosphonates.5 8 Denosumab, which is catabolic effects on bone are present in all patients with primary
increasingly being used in the management of osteoporosis, has hyperparathyroidism, markers of bone turnover and net bone
also been implicated.7 Malabsorptive gastrointestinal conditions calcium release are lower in the normocalcaemic group.10
294 Babwah F, Buch HN. J Clin Pathol 2018;71:291–297. doi:10.1136/jclinpath-2017-204455
 Best practice
This supports the end-organ tissue PTH resistance hypothesis
Table 2  Indications for surgery in asymptomatic PHPT (2013)47

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proposed by Maruani et al10 but could also be explained by the
relatively lower PTH level in patients with NPHPT. Indications for surgery in asymptomatic PHPT
Serum >0.25 mmol/L above the upper limit of normal
calcium
Renal Bone BMD by DXA: T-score (or Z-score if age<50 years)<−2.5 at lumbar spine,
The impact of NPHPT on the kidneys appears to be similar to total hip, femoral neck or distal 1/3 radius
that of patients with HPHPT, namely nephrolithiasis and neph- Vertebral fracture by x-ray, CT, MRI or VFA*
rocalcinosis, with a wide variance in the reported figures for its Renal Creatinine clearance <60 mL/min†
prevalence. A retrospective analysis reported a similar prevalence 24 hours urine for calcium>400 mg/day and increased stone risk by
of nephrolithiasis in NPHPT (18.2%) and HPHPT (18.9%).36 biochemical analysis†
Presence of nephrolithiasis or nephrocalcinosis by x-ray, ultrasound or CT
Maruani et al10 noted a prevalence as high as 35% and in other
studies it has ranged from 4% to 28.6%.6 11 21 The presence of Age <50 years
hypercalciuria in patients with HPHPT has been reported to be Patients need to meet only one criterion for consideration of surgery.
around 40%.40 A similar but milder increase in 24-hour urinary *A history of fragility fracture at any site would define symptomatic PHPT and the
patient would be automatically considered a surgical candidate.
calcium excretion has been observed in patients with NPHPT
†Chronic kidney disease and hypercalciuria are not relevant as these patients
with the proposed mechanism being a relatively lower calcium strictly speaking do not have NPHPT. BMD, bone mineral density; DXA, dual-energy
reabsorption rate.10 However, there are no reports of its prev- x-ray absorptiometry; NPHPT, normocalcaemic primary hyperparathyroidism; VFA,
alence or its correlation with renal calculi formation. As in vertebral fracture assessment.
patients with HPHPT, it is not known why some patients with
NPHPT form stones and in both these groups of patients the
degree of calcium excretion is not a strong single predictor of In clinical practice, in a vast majority of patients, the diag-
calculi formation. There is also no evidence on the likelihood of nosis of NPHPT is arrived at when calcium and PTH levels are
progression of renal involvement with time or on the impact of requested during the evaluation of patients who have, or are at
parathyroid surgery. a higher risk of having, metabolic bone disease or have neph-
rolithiasis. A suggested management strategy for this cohort
Cardiovascular of patients is depicted in figure 1. Once the investigations for
The link between cardiovascular disease and primary hyperpara- assessment of bone and renal involvement are completed, in the
thyroidism remains contentious. An epidemiological study from absence of hypercalcaemia, a decision can be made on whether
Rochester (USA) reported a lower than expected cardiovascular surgery is indicated on the basis of the degree of end-organ
mortality in these patients.41 However, the Parathyroid Epide- involvement. The criteria used are the same as in patients with
miology and Audit Research Study (PEARS)42 as well as several asymptomatic HPHPT as specified in the fourth international
Scandinavian studies43 have shown an increase in all-cause workshop (table 2).47 48
mortality, fatal and non-fatal cardiovascular events in patients Patients in whom surgery is indicated, its suitability should
with primary hyperparathyroidism. A number of risk factors be confirmed on the basis of factors such as age, frailty, comor-
and surrogate end-points have been proposed as mechanisms bidities and patient preference. Localisation studies including
including hypertension, dyslipidaemia, insulin resistance, endo- ultrasonography and radionuclide scanning should be requested.
thelial dysfunction and left ventricular hypertrophy. In comparison to patients with HPHPT, a higher frequency
Neither of these studies comment on whether NPHPT has of negative localisation studies and surgical failure has been
a similar impact on cardiovascular outcomes. However, one reported.24 49 This is likely to be related to the smaller size of
cross-sectional, case–control study involving 25 patients with the adenoma encountered in patients with NPHPT. Another less
NPHPT, matched against a similar number of patients with likely explanation is the greater frequency of multigland hyper-
HPHPT and healthy subjects demonstrated a higher prevalence plasia, reported in some studies.24 50 However, in these studies,
of metabolic syndrome, glucose intolerance and hypertension conclusions were drawn from a small number of patients and
among the NPHPT and HPHPT groups as compared with the there was a lack of clarity on how secondary hyperparathyroidism
control group.44 Another study on 18 subjects with NPHPT, was excluded. Moreover, several other studies have reported
found no difference in insulin resistance or glucose intolerance the presence of a solitary parathyroid adenoma in a majority of
when assessed by oral glucose tolerance test (OGTT) and homeo- patients studied.11 20 51 Successful removal of an adenoma has
stasis model assessment for insulin resistance (HOMA-IR) when been shown to normalise postoperative PTH level6 13 which is
compared with matched control subjects.45 Two other studies the only biochemical criterion that can be used to indicate cure.
have reported a higher prevalence of hypertension in patients BMD has been shown to improve as early as 1–2 years postpara-
with NPHPT compared with patients with a normal PTH.13 46 thyroidectomy in patients with both symptomatic HPHPT and
However, as there is no prospective data on cardiovascular NPHPT.34 52 53
outcomes in patients with NPHPT,47 further investigations to Patients in whom the degree of bone or renal involvement is
evaluate cardiovascular risk do not form part of the workup not significant enough to consider surgery, a structured observa-
for patients identified with NPHPT and nor is parathyroid tional policy can be adopted. This consists of annual monitoring
surgery recommended with a view to improving cardiovascular of albumin-adjusted or ionised calcium, PTH, vitamin D and
endpoints. renal function.5 47 Reassessment of bone density and nephroli-
thiasis at 3–5 year intervals has been recommended,26 although
it may be more practical to adopt an individualised approach
Management strategy and Follow-up guided by the baseline measurements and overall risk profile for
In the absence of sufficient data on its natural history, it is chal- progressive bone disease. A 3-yearly reassessment to examine the
lenging for a clinician to formulate a management plan for an sequential change in the bone density would certainly be recom-
individual patient with a confirmed diagnosis of NPHPT. mended for patients with osteopaenia (T score between −1.0
Babwah F, Buch HN. J Clin Pathol 2018;71:291–297. doi:10.1136/jclinpath-2017-204455 295
 Best practice
and −2.5), those with multiple risk factors for osteoporosis or reference method for PTH analysis against which other methods

J Clin Pathol: first published as 10.1136/jclinpath-2017-204455 on 3 February 2018. Downloaded from http://jcp.bmj.com/ on 3 August 2018 by guest. Protected by copyright.
those with a high FRAX score at baseline. There is no clear guid- could be harmonised.56
ance on the need for monitoring of urinary calcium in NPHPT It would also be of significant clinical advantage to be able to
and we do not recommend this, as the degree of hypercalciuria precisely recognise the relationship between changes in vitamin
is mild10 and is not likely to help in predicting nephrolithiasis. D and PTH levels. Greater understanding of the impact of rela-
During this period, we suggest maintaining vitamin D level to tive changes in vitamin D level on PTH, rather than its absolute
>50 nmol/L (and ideally >75 nmol/L).7 Occasionally, PTH may value, impact of factors such as age, ethnicity and calcium intake
normalise and the patient would no longer fulfil the criteria for on this relationship and the time to normalisation of PTH after
NPHPT. On the other hand, patients who demonstrate progres- vitamin D level reaches a predefined target would be helpful.
sion to hypercalcaemia or new onset of bone or renal complica- Standardisation of PTH assays and information of vitamin D
tions would merit assessment for surgery as above. dynamics may help us to explain an isolated rise in PTH in a
Patients in whom surgery is indicated but is not undertaken significant number of patients which in turn would allow us to
because of comorbidities or patient preference, bisphosphonates focus on the subgroup of patients with a potentially progressive
can be considered. These agents have been proven to be effec- condition with future adverse impact on patient morbidity.
tive in improving bone mineral density in short-term studies
but there is no robust fracture data.47 53 There is also no litera- Take home messages
ture on the benefit of these or any other agents in patients with
NPHPT. There is no role for cinacalcet therapy in lowering PTH ►► NPHPT is not a new entity and following its formal
levels or improving bone outcomes. While one small prospective recognition almost a decade ago, more experience has
randomised study reported a reduction in the number and size of accumulated on the diagnosis and management of this
renal stones with the use of cinacalcet in patients with NPHPT distinct endocrine condition. In clinical practice, patients are
and HPHPT,40 a 5-year multicentre randomised controlled trial diagnosed with NPHPT either incidentally during investigation
showed that there was no effect on bone mineral density.54 of an unrelated condition or during the assessment of
More recently, clinicians are coming across patients with high patients with bone and renal involvement. There is clear
PTH level without hypercalcaemia or end organ involvement, evidence of significant variability in the likelihood of clinical
in whom the initial biochemical tests were requested to explain and biochemical progression of patients with NPHPT, and this
either unrelated symptoms or serendipitous finding of a para- in turn makes it difficult for clinicians to make decisions on
thyroid adenoma on imaging studies. Although a significant how to investigate and manage this diverse condition.
proportion of these patients have one or more of the recognised ►► In this review we have suggested a simple three-step
confounding factors and do not have NPHPT, a small cohort pragmatic approach to a patient suspected to have NPHPT,
meets the criteria for the diagnosis and pose a management which involves confirmation of the diagnosis, exclusion of
challenge to the clinician. The above-mentioned strategy for confounding factors and finally assessment of end-organ
long-term follow-up may not be necessary for many of these involvement, which is the main determinant of the
patients who are often at a lower risk of end-organ involvement. management plan.
We would recommend regular review only for those patients
who are more likely to progress, that is, those with baseline Handling editor  Tahir S Pillay.
albumin-adjusted calcium  ≥2.4±0.05 mmol/L (P<0.01)6 or
Competing interests  None declared.
adverse risk profile for bone disease as described above. For the
remaining patients, the same frequency of reassessment may not Provenance and peer review  Commissioned; externally peer reviewed.
be required and the decision can be individualised on the basis © Article author(s) (or their employer(s) unless otherwise stated in the text of the
of clinical and logistic factors. This approach is supported by article) 2018. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
several studies that have shown a low progression rate in similar
patient groups (table 1).8 14 18
References
1 Yeh MW, Ituarte PH, Zhou HC, et al. Incidence and prevalence of primary
Future possibilities hyperparathyroidism in a racially mixed population. J Clin Endocrinol Metab
Insufficient data on the natural history of NPHPT has led to 2013;98:1122–9.
a paucity of evidence-based recommendations on its manage- 2 Rubin MR, Bilezikian JP, McMahon DJ, et al. The natural history of primary
hyperparathyroidism with or without parathyroid surgery after 15 years. J Clin
ment. More studies on large cohorts of patients followed up for Endocrinol Metab 2008;93:3462–70.
a longer periods would certainly allow us to further standardise 3 Wills MR, Pak CY, Hammond WG, et al. Normocalcemic primary hyperparathyroidism.
our approach to the management of this condition. On the diag- Am J Med 1969;47:384–91.
nostic side, any future development that focuses the inconsis- 4 Bilezikian JP, Khan AA, Potts JT. Third International Workshop on the Management
of Asymptomatic Primary Hyperthyroidism. Guidelines for the management of
tencies with PTH assays described above would be of significant
asymptomatic primary hyperparathyroidism: summary statement from the third
benefit. Although traceable reference materials (eg, the WHO international workshop. J Clin Endocrinol Metab 2009;94:335–9.
Recombinant PTH1-84 International Standard 95/646)55 are 5 Cusano NE, Silverberg SJ, Bilezikian JP, et al. Normocalcemic primary
available, a validated traceable reference method for PTH1-84 hyperparathyroidism. J Clin Densitom 2013;16:33–9.
is awaited. The development of tandem mass spectrometry 6 Lowe H, McMahon DJ, Rubin MR, et al. Normocalcemic primary hyperparathyroidism:
further characterization of a new clinical phenotype. J Clin Endocrinol Metab
methods for measurement of PTH offer superior specificity 2007;92:3001–5.
with similar sensitivity compared with immunoassay but they 7 Eastell R, Brandi ML, Costa AG, et al. Diagnosis of asymptomatic primary
are also subject to interferences such as oxidised and phosphor- hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin
ylated PTH.27 In the short term, the International Federation Endocrinol Metab 2014;99:3570–9.
8 Silverberg SJ, Bilezikian JP. "Incipient" primary hyperparathyroidism: a "forme fruste"
of Clinical Chemistry and Laboratory Medicine working group
of an old disease. J Clin Endocrinol Metab 2003;88:5348–52.
for PTH is actively working towards developing assay-specific 9 Rao DS, Wilson RJ, Kleerekoper M, et al. Lack of biochemical progression
target values of PTH, with the long-term goal of establishing a or continuation of accelerated bone loss in mild asymptomatic primary

296 Babwah F, Buch HN. J Clin Pathol 2018;71:291–297. doi:10.1136/jclinpath-2017-204455

 Best practice
hyperparathyroidism: evidence for biphasic disease course. J Clin Endocrinol Metab 33 Harvey A, Hu M, Gupta M, et al. A new, vitamin D-based, multidimensional nomogram

J Clin Pathol: first published as 10.1136/jclinpath-2017-204455 on 3 February 2018. Downloaded from http://jcp.bmj.com/ on 3 August 2018 by guest. Protected by copyright.
1988;67:1294–8. for the diagnosis of primary hyperparathyroidism. Endocr Pract 2012;18:124–31.
10 Maruani G, Hertig A, Paillard M, et al. Normocalcemic primary hyperparathyroidism: 34 Coe FL, Canterbury JM, Firpo JJ, et al. Evidence for secondary hyperparathyroidism in
evidence for a generalized target-tissue resistance to parathyroid hormone. J Clin idiopathic hypercalciuria. J Clin Invest 1973;52:134–42.
Endocrinol Metab 2003;88:4641–8. 35 Souberbielle JC, Cavalier E, Cormier C. How to manage an isolated elevated PTH? Ann
11 Šiprová H, Fryšák Z, Souček M. Primary hyperparathyroidism, with a focus on Endocrinol 2015;76:134–41.
management of the normocalcemic form: to treat or not to treat? Endocr Pract 36 Amaral LM, Queiroz DC, Marques TF, et al. Normocalcemic versus Hypercalcemic
2016;22:294–301. Primary Hyperparathyroidism: More stone than bone? J Osteoporos 2012;2012:1–4.
12 Wermers RA, Khosla S, Atkinson EJ, et al. Incidence of primary hyperparathyroidism in 37 Kanis JA. FRAX ® Fracture Risk Assessment Tool, 2016. https://www.​sheffield.​ac.​uk/​
Rochester, Minnesota, 1993-2001: an update on the changing epidemiology of the FRAX/​index.​aspx (accessed 1 Nov 2017).
disease. J Bone Miner Res 2006;21:171–7. 38 Rejnmark L, Vestergaard P, Brot C, et al. Increased fracture risk in normocalcemic
13 Tordjman KM, Greenman Y, Osher E, et al. Characterization of normocalcemic primary postmenopausal women with high parathyroid hormone levels: a 16-year follow-up
hyperparathyroidism. Am J Med 2004;117:861–3. study. Calcif Tissue Int 2011;88:238–45.
14 Kontogeorgos G, Trimpou P, Laine CM, et al. Normocalcaemic, vitamin D-sufficient 39 Charopoulos I, Tournis S, Trovas G, et al. Effect of primary hyperparathyroidism
hyperparathyroidism - high prevalence and low morbidity in the general population: on volumetric bone mineral density and bone geometry assessed by peripheral
A long-term follow-up study, the WHO MONICA project, Gothenburg, Sweden. Clin quantitative computed tomography in postmenopausal women. J Clin Endocrinol
Endocrinol 2015;83:277–84. Metab 2006;91:1748–53.
15 Lundgren E, Rastad J, Thrufjell E, et al. Population-based screening for primary 40 Brardi S, Cevenini G, Verdacchi T, et al. Use of cinacalcet in nephrolithiasis
hyperparathyroidism with serum calcium and parathyroid hormone values in associated with normocalcemic or hypercalcemic primary hyperparathyroidism:
menopausal women. Surgery 1997;121:287–94. results of a prospective randomized pilot study. Arch Ital Urol Androl
16 Lundgren E, Hagström EG, Lundin J, et al. Primary hyperparathyroidism revisited in 2015;87:66–71.
menopausal women with serum calcium in the upper normal range at population- 41 Wermers RA, Khosla S, Atkinson EJ, et al. Survival after the diagnosis of
based screening 8 years ago. World J Surg 2002;26:931–6. hyperparathyroidism: a population-based study. Am J Med 1998;104:115–22.
17 Cusano NE, Maalouf NM, Wang PY, et al. Normocalcemic hyperparathyroidism 42 Yu N, Donnan PT, Leese GP. A record linkage study of outcomes in patients with mild
and hypoparathyroidism in two community-based nonreferral populations. J Clin primary hyperparathyroidism: the Parathyroid Epidemiology and Audit Research Study
Endocrinol Metab 2013;98:2734–41. (PEARS). Clin Endocrinol 2011;75:169–76.
18 García-Martín A, Reyes-García R, Muñoz-Torres M. Normocalcemic primary 43 Macfarlane DP, Yu N, Leese GP. Subclinical and asymptomatic parathyroid disease:
hyperparathyroidism: one-year follow-up in one hundred postmenopausal women. implications of emerging data. Lancet Diabetes Endocrinol 2013;1:329–40.
Endocrine 2012;42:764–6. 44 Yener Ozturk F, Erol S, Canat MM, et al. Patients with normocalcemic primary
19 Berger C, Langsetmo L, Hanley D, et al. Relative prevalence of normocalcemic and hyperparathyroidism may have similar metabolic profile as hypercalcemic patients.
hypercalcemic hyperparathryoidism in a community-dwelling cohort. 33rd annual Endocr J 2016;63:111–8.
meeting of the American society of bone and mineral research. San Diego, CA, 2011. 45 Cakir I, Unluhizarci K, Tanriverdi F, et al. Investigation of insulin resistance in patients
Abstract 0173. with normocalcemic primary hyperparathyroidism. Endocrine 2012;42:419–22.
20 Martínez Díaz-Guerra G, Jódar Gimeno E, Reyes García R, et al. [Normocalcemic 46 Chen G, Xue Y, Zhang Q, et al. Is normocalcemic primary hyperparathyroidism harmful
primary hyperparathyroidism: recommendations for management and follow-up]. or harmless? J Clin Endocrinol Metab 2015;100:2420–4.
Endocrinol Nutr 2013;60:456.e1–456.e6. 47 Bilezikian JP, Brandi ML, Eastell R, et al. Guidelines for the management of
21 Marques TF, Vasconcelos R, Diniz E, et al. Normocalcemic primary hyperparathyroidism asymptomatic primary hyperparathyroidism: summary statement from the fourth
in clinical practice: an indolent condition or a silent threat? Arq Bras Endocrinol international workshop. J Clin Endocrinol Metab 2014;99:3561–9.
Metabol 2011;55:314–7. 48 Udelsman R, Åkerström G, Biagini C, et al. The surgical management of asymptomatic
22 Nordenström E, Katzman P, Bergenfelz A. Biochemical diagnosis of primary primary hyperparathyroidism: proceedings of the Fourth International Workshop. J Clin
hyperparathyroidism: analysis of the sensitivity of total and ionized calcium in Endocrinol Metab 2014;99:3595–606.
combination with PTH. Clin Biochem 2011;44:849–52. 49 Díaz-Soto G, Julián MT, Puig-Domingo M. Normocalcemic primary
23 Calvi LM, Bushinsky DA. When is it appropriate to order an ionized calcium? J Am Soc hyperparathyroidism: A newly emerging disease needing therapeutic intervention.
Nephrol 2008;19:1257–60. Hormones 2012;11:390–6.
24 Wade TJ, Yen TW, Amin AL, et al. Surgical management of normocalcemic primary 50 Grimelius L, Ejerblad S, Johansson H, et al. Parathyroid adenomas and glands
hyperparathyroidism. World J Surg 2012;36:761–6. in normocalcemic hyperparathyroidism - a light microscopic study. Am J Pathol
25 Mirzazadeh M, Morovat A, James T, et al. Point-of-care testing of electrolytes and 1976;83:475–82.
calcium using blood gas analysers: it is time we trusted the results. Emerg Med J 51 Rejnmark L, Amstrup AK, Mollerup CL, et al. Further insights into the pathogenesis
2016;33:181–6. of primary hyperparathyroidism: a nested case-control study. J Clin Endocrinol Metab
26 Crowley RK, Gittoes NJ. Elevated PTH with normal serum calcium level: a structured 2013;98:87–96.
approach. Clin Endocrinol 2016;84:809–13. 52 Koumakis E, Souberbielle JC, Sarfati E, et al. Bone mineral density evolution
27 Couchman L, Taylor DR, Krastins B, et al. LC-MS candidate reference methods for after successful parathyroidectomy in patients with normocalcemic primary
the harmonisation of parathyroid hormone (PTH) measurement: a review of recent hyperparathyroidism. J Clin Endocrinol Metab 2013;98:3213–20.
developments and future considerations. Clin Chem Lab Med 2014;52:1251–63. 53 Sankaran S, Gamble G, Bolland M, et al. Skeletal effects of interventions in
28 Marshall W. Association for clinical biochemistry and laboratory medicine. 2012 http:// mild primary hyperparathyroidism: a meta-analysis. J Clin Endocrinol Metab
www.​acb.​org.​uk/​whatwedo/​science/​AMALC.​aspx (accessed 1 Aug 2017). 2010;95:1653–62.
29 Bilezikian JP, Potts JT, Fuleihan G-H, et al. Summary statement from a workshop on 54 Peacock M, Bolognese MA, Borofsky M, et al. Cinacalcet treatment of primary
asymptomatic primary hyperparathyroidism: a perspective for the 21st century. J Clin hyperparathyroidism: biochemical and bone densitometric outcomes in a five-year
Endocrinol Metab 2002;87:5353–61. study. J Clin Endocrinol Metab 2009;94:4860–7.
30 Saleh F, Jorde R, Sundsfjord J, et al. Causes of secondary hyperparathyroidism in a 55 National Institute for Biological Standards and Control, NIBSC. WHO International
healthy population: the Tromsø study. J Bone Miner Metab 2006;24:58–64. standard parathyroid hormone 1-84, human recombinant, NIBSC code 95/646,
31 Julian M-T, Olaizola I, Diaz-Soto G, et al. Diaz-Soto G, ed. Normocalcemic primary version 9.0. 2010. http://www.​nibsc.​org/​documents/​ifu/​95-​646.​pdf (accessed 1 Aug
hyperparathyroidism, hyperparathyroidism, 2012. ISBN: 978-953-51-0478-0. 2017).
http://www.i​ ntechopen.​com/​books/​hyperparathyroidism/​normocalcemic-​primary-​ 56 Sturgeon CM, Fraser WD, Singh R, et al. Improving the comparability of parathyroid
hyperparathyroidism hormone measurements – a report from the IFCC working group for PTH. Biochimica
32 Fraser WD. Hyperparathyroidism. Lancet 2009;374:145–58. Clinica 2013;37(Suppl):S431.

Babwah F, Buch HN. J Clin Pathol 2018;71:291–297. doi:10.1136/jclinpath-2017-204455 297