C H A P T E R

22
Normocalcemic PHPT
Natalie E. Cusano, Shonni J. Silverberg, John P. Bilezikian
Metabolic Bone Diseases Unit, Division of Endocrinology, Department of Medicine, Columbia University College of
Physicians and Surgeons, New York, NY, USA

INTRODUCTION a concept that describes a biphasic chronology of the

Over the past 40 years, the clinical presentation of pri-
mary hyperparathyroidism (PHPT) has changed from a
disorder that was most often diagnosed with overt skel-
etal and kidney stone manifestations to one that pres-
ents most commonly asymptomatically (see Chapter 21,
“Asymptomatic Primary Hyperparathyroidism”). With
routine laboratory monitoring made possible by the
multichannel autoanalyzer in the 1970s, hypercalce-
mia is usually discovered incidentally in the absence
of any symptoms attributable to the disease.1,2 Despite
its asymptomatic presentation, bone mineral density
is characteristically reduced when measured by dual
energy X-ray absorptiometry (DXA), preferentially at
the distal 1/3 radius, a site comprised primarily of cor-
tical bone.3 Although relatively preserved by DXA and
by histomorphometric analysis of bone biopsy speci-
mens, high resolution imaging has demonstrated that
both cortical and trabecular bone are affected in PHPT
(see Chapter 30, “Skeletal Imaging in Primary Hyper-
parathyroidism”).4–6 The characteristic densitometric
effects of PHPT are usually noted at the time of diag-
nosis. While this may indicate a delay in diagnosis,
more frequent blood chemistry monitoring makes this
explanation less likely. These findings more likely dem-
onstrate that changes to bone structure and microarchi-
tecture occur prior to the development of hypercalcemia.
Over the past decade, a newer clinical description of
PHPT has emerged, characterized by normal total and
ionized serum calcium concentrations with consistently
elevated PTH levels, in the absence of obvious causes for
secondary hyperparathyroidism.7–10 Individuals with
this new phenotype, normocalcemic PHPT, are increas-
ingly being discovered as many physicians are now
requesting PTH levels in patients with or suspected of
having a metabolic bone disease despite a normal serum
calcium. Recognition of normocalcemic PHPT supports
development of PHPT first proposed by Rao et al.9.
The first phase, where PTH levels are elevated but the
serum calcium is normal, until recently remained unrec-
ognized. The second phase has traditionally been recog-
nized because of the development of hypercalcemia.
The term “normocalcemic” deserves specific atten-
tion. By definition, the normal range includes 95% of the
normal population. The normal range does not define an
individual’s normal range but rather that of the popula-
tion. Serum calcium levels within a given individual are
remarkably constant over time and vary within a much
more limited range than the population levels.11 Thus,
an individual with normocalcemic PHPT may represent
someone whose mean serum calcium has increased from
their usual level of 9.3 mg/dL to 9.9 mg/dL. The higher
value is still within normal limits, but for that patient,
it is elevated. One cannot know what a given subject’s
normal range is unless there are sufficient data for serum
calcium that predate the recognition of the hyperpara-
thyroid state.
Normocalcemic PHPT was first formally recognized
at the time of the Third International Workshop on the
Management of Asymptomatic PHPT in 2008,12 although
much remains unknown about the disorder, particularly
regarding its epidemiology, natural history, and man-
agement. This chapter reviews the literature surround-
ing this new phenotypic variant.
PATHOPHYSIOLOGY
The pathophysiology of normocalcemic PHPT remains
incompletely understood. Maruani et al.7 suggested that
normocalcemic PHPT may be due to target organ resistance
to the actions of PTH. They studied normocalcemic and
hypercalcemic PHPT subjects matched on the basis of age,
gender, and PTH concentration. Bone turnover markers,

The Parathyroids, Third Edition 331

http://dx.doi.org/10.1016/B978-0-12-397166-1.00022-9 2015 Published by Elsevier Inc.
332 22.  NORMOCALCEMIC PHPT
fasting calcium to creatinine ratio as a measure of net skel-
etal calcium release, and renal tubular calcium reabsorp-
tion were lower in the normocalcemic group, as was the
ability of PTH to reduce tubular phosphate reabsorption
and to stimulate 1,25-dihydroxyvitamin D synthesis. When
administered an oral calcium load, the normocalcemic
group exhibited a 25% decrease in PTH, which was consid-
ered to be an inadequate suppression of PTH. The authors
cited studies in which estrogen was noted to protect against
the bone-resorbing effects of PTH,13 and estrogen replace-
ment in postmenopausal women with PHPT significantly
decreased serum and urine calcium.14,15 They proposed
that the development of estrogen deficiency in postmeno-
pausal women plays a role in the unmasking of hypercal-
cemia in these subjects. While this is consistent with the
demographics of hypercalcemic PHPT, demonstrating a
peak incidence in the first decade after the menopause,1,2
it does not explain why normocalcemic PHPT occurs most
commonly in postmenopausal, estrogen-deficient women.
If PTH resistance is a valid pathophysiologic factor in the
development of normocalcemic PHPT, it would not be
explained by the masking effect of estrogen on hypercalce-
mia in the majority of individuals.
A subsequent study by Invernizzi et al.16 compared
subjects with normocalcemic PHPT to subjects with
hypercalcemic PHPT as well as healthy controls. They
found that the normocalcemic subjects responded more
like the healthy controls to an oral peptone load from
meat extract rich in phosphorus. They also showed a
greater suppression of PTH to an oral calcium load than
did Maruani et al.7 However, as PTH was suppressed
in both normocalcemic and normal subjects after an
oral calcium load, they suggested a preserved feedback
mechanism in the normocalcemic subjects. All of their
normocalcemic subjects were asymptomatic, suggesting
that they may have represented a very early period in
the disease process.
DIAGNOSIS
While patients with traditional PHPT demonstrate
hypercalcemia most of the time, they may occasionally
have normal serum calcium values. It is important to
distinguish patients who have hypercalcemic PHPT with
occasionally normal serum calcium from those with nor-
mocalcemic PHPT, in whom the serum calcium is always
normal. Some cohorts previously reported with normo-
calcemic PHPT may have had hypercalcemic disease
with occasionally normal serum calcium.17 In addition
to normal total serum calcium concentration corrected
for albumin, normocalcemic PHPT is also characterized
by normal ionized calcium concentrations. Reports that
described normocalcemic individuals with elevated ion-
ized calcium levels would thus not qualify as having
II.   CLINICAL ASPECTS OF PRIMARY HYPERPARATHYROIDISM
normocalcemic PHPT.18,19 The diagnostic criteria for
normocalcemic PHPT should include consistently nor-
mal albumin-adjusted total serum calcium and normal
ionized calcium.20 The constancy of the normal serum
calcium value over a period of time does not conflict
with the fact that individuals with normocalcemic PHPT
may go on to develop hypercalcemia as part of their dis-
ease course (see “Natural history,” below).
In addition, causes of secondary hyperparathyroidism
must be excluded in order to make a diagnosis of normo-
calcemic PHPT. The following are consensus diagnostic
guidelines from the Fourth International Workshop on
the Management of Asymptomatic PHPT:20
1. V  itamin D deficiency/insufficiency. PTH and
25-hydroxyvitamin D are inversely related to
each other. The parathyroid glands are signaled to
increase PTH secretion when 25-hydroxyvitamin D
is below a threshold value, although the exact value
of 25-hydroxyvitamin that leads to an increase in
PTH is controversial, and, in fact, probably varies
across the population. The Institute of Medicine
report21 found no conclusive evidence that levels of
25-hydroxyvitamin D ≥20 ng/ml (50 nmol/L) were
regularly associated with increases in PTH levels in
population studies. These studies are confounded
by the lack of individual-level prospective data,
however. Further data are necessary to establish
a normal range for PTH in vitamin D sufficient
individuals, given that the normal range is more
narrow than the general assay range (10–65 pg/mL)
in these subjects.20,22,23 It should also be noted
that there are no data regarding levels of
25-hydroxyvitamin D that lead to secondary
increases in PTH concentration specifically in
PHPT patients, and it is possible that the data
that have been collected in non-hyperparathyroid
individuals may not be directly applicable. The
25-hydroxyvitamin D level should be at least
20 ng/mL, and preferably >30 ng/mL (75 nmol/L),
in order to rule out any realistic possibility of a
secondary hyperparathyroidism due to vitamin D
deficiency. In addition, normocalcemic patients with
high PTH levels may become hypercalcemic when
25-hydroxyvitamin D levels are raised to over 30 ng/
mL, making a diagnosis of traditional hypercalcemic
PHPT that was masked by vitamin D deficiency.
2. Reduced creatinine clearance. Martinez et al.24–26 have
shown that PTH begins to rise when the estimated
glomerular filtration rate (GFR) falls to below 60 cc/
min. These determinations are based upon large
population surveys such as National Health and
Nutrition Examination Survey (NHANES) III, and
therefore it cannot be known in a given situation
whether a mild reduction in creatinine clearance
 Epidemiology
is the explanation for the increased PTH level. It
seems reasonable to require that GFR be greater than
60 cc/min to support a diagnosis of normocalcemic
PHPT. Of note, Walker et al.27 demonstrated that
in hypercalcemic PHPT, reduction in creatinine
clearance to <60 cc/min was associated with increased
parameters of bone resorption as determined by
dynamic histomorphometric analysis of bone biopsies.
3. Medications. Thiazide diuretics28 and lithium29 have
been associated with a rise in PTH and should be
considered as a cause of increased PTH levels in
subjects on these medications. Lithium decreases
sensitivity to calcium within the parathyroid gland
and may also reduce urinary calcium excretion.29,30
The mechanism by which thiazide diuretics can raise
PTH levels is poorly understood. Discontinuation
or substitution of the thiazide diuretic can be
considered if there are no contraindications, with
subsequent retesting of calcium and PTH in 3–6
months. It is not as easy to discontinue lithium or
to employ an equivalently effective medication for
those whose psychiatric disease requires lithium.
Other medications that are associated with increased
PTH levels include the bisphosphonates and
denosumab. The increased PTH levels in these
patients most likely represent a compensatory,
and often transient, effect in the setting of small
declines in the serum calcium concentration. While
bisphosphonate medications can raise PTH levels,
the effect appears to be attenuated or reversed with
chronic use.31–34 Clinical studies of denosumab have
shown a dose-dependent increase in PTH levels that
commonly persists for half of the 6-month treatment
interval35 for at least 7 years.36 A recent study
demonstrated that use of higher than normal doses
of calcium and vitamin D supplementation (2 g and
1600 IU daily, respectively) prevented the increase
in PTH following therapy with denosumab.37
These higher doses of supplementation may not be
appropriate for all patients, however.
Based upon this information, the diagnosis of
normocalcemic PHPT cannot be made confidently in
subjects who are taking thiazide diuretics, lithium,
bisphosphonates, or denosumab.
4 . Hypercalciuria. When hypercalciuria occurs as a
primary renal abnormality, it can be associated with a
secondary elevation in PTH.38 Thiazide diuretics can
be used as a therapy for hypercalciuria,39,40 and some
authors support a diagnosis of normocalcemic PHPT
in patients with persistent hyperparathyroidism that
does not improve after treatment of hypercalciuria
with a thiazide diuretic.19,41 This suggestion is
confounded, however, by whatever effect treatment
of the hypercalciuria with thiazides may have on
parathyroid gland function.
II.   CLINICAL ASPECTS OF PRIMARY HYPERPARATHYROIDISM
333
 astrointestinal disorders associated with calcium
5. G
malabsorption.42,43 A malabsorption syndrome
is usually obvious as a clinical problem, but
gluten enteropathy, for example, can be present
in asymptomatic individuals without obvious
symptoms of gastrointestinal tract disease. A low
normal serum calcium concentration in the presence
of vitamin D deficiency and low urinary calcium
excretion can be clues to such a diagnosis.44
In addition, patients with other metabolic bone dis-
eases, such as Paget’s disease, can demonstrate elevated
PTH levels along with normal serum calcium. In this
case, the Paget’s disease is usually very active, involv-
ing many areas of the skeleton with very high alkaline
phosphatase levels.45 However, rarely, PHPT can be con-
currently present in patients with Paget’s disease. These
patients typically have hypercalcemia.46
EPIDEMIOLOGY
The epidemiology of normocalcemic PHPT has been
investigated in various populations, but interpretation of
the data is confounded by differing criteria used among
the studies to make the diagnosis (Table 22.1). Data
from the population-based Osteoporosis in Men (MrOS)
study47 of men ≥65 years of age showed a prevalence of
0.5% after excluding those with kidney disease (eGFR
<60 cc/min), vitamin D deficiency (25-hydroxyvitamin
D <20 ng/dL), or thiazide diuretic use. Lundgren et al.48
found elevated PTH levels with normal serum and ion-
ized calcium in 0.5% of Swedish postmenopausal women
aged 55–75 years, although secondary etiologies of hyper-
parathyroidism, such as vitamin D deficiency, were not
excluded. Data from the population-based NHANES
cohort49 of men and women >45 years of age demon-
strated a prevalence estimate of 1% after excluding those
with kidney disease (GFR <60 cc/min) and vitamin D defi-
ciency (25-hydroxyvitamin D <30 ng/dL). Data from the
Dallas Heart Study,47 a convenience sample of men and
women 18–65 years of age, demonstrated a prevalence
of 3.1% after excluding those with kidney disease (eGFR
<60 cc/min), vitamin D deficiency (25-hydroxyvitamin D
<20 ng/dL), and thiazide diuretic and lithium use. When
many of these subjects were reinvestigated 8 years later,
the prevalence dropped to 0.6%. The population-based
study by Garcia-Martin et al.50 described in further detail
below, found a prevalence of 6% in 100 healthy Spanish
postmenopausal women. Data from the population-based
Canadian Multicentre Osteoporosis Study (CaMos)51
of men and women 19–97 years of age identified 312 of
1871 individuals (prevalence 16.7%) using a cutoff of
25-hydroxyvitamin D <20 ng/dL but not excluding other
causes of secondary hyperparathyroidism. Except for the
334
TABLE 22.1  Prevalence of Normocalcemic PHPT in Various Populations
Study Population
Cusano et al.47 Men ≥65 years, US (MrOS)
Lundgren et al.48 Women 55–75 years, Sweden
Misra et al.49 Men and women >45 years, US
(NHANES)
Cusano et al.47 Men and women 18–65 years, US
(DHS)
Garcia-Martin et al.50 Postmenopausal women, Spain
Berger et al.51 Men and women 19–97 years,
Canada (CaMos)
National Health and Nutrition Examination Survey, NHANES; The Osteoporotic Fractures in Men Study, MrOS; Dallas Heart Study, DHS; Canadian Multicentre
Osteoporosis Study, CaMos.
data from Garcia-Martin et al.50 and Berger et al.,51 preva-
lence estimates approach those expected for hypercalce-
mic PHPT.52 It is of note that none of these studies other
than that of Lundgren et al.48 measured ionized calcium
levels, and thus they would not meet current more strin-
gent diagnostic standards for normocalcemic PHPT.
CLINICAL PRESENTATION
Reports of normocalcemic PHPT have largely come
from referral centers since patients are usually identi-
fied in the evaluation of a metabolic bone disease. The
cohort described by Lowe et al.53 consisted of 29 post-
menopausal women, six premenopausal women, and
two men, aged 58 ± 12 years (mean ± SD; range 32–78)
referred to the Columbia University Metabolic Bone
Diseases Unit. All 37 subjects had eGFR >40 cc/min and
25-hydroxyvitamin D levels >20 ng/mL, with 65% hav-
ing levels >30 ng/mL. None used thiazide diuretics or
lithium or demonstrated significant hypercalciuria. The
reasons for referral included hyperparathyroidism dis-
covered during the evaluation of low bone mass (n = 27),
recent fragility fracture (n = 4), nephrolithiasis (n = 2), or
other (n = 4). At the time of diagnosis, 57% had osteoporo-
sis, 11% had documented fragility fractures, and 14% had
nephrolithiasis. Laboratory evaluation showed elevated
PTH, while albumin-corrected serum calcium, serum
phosphorus, alkaline phosphatase activity, urinary cal-
cium, and N-telopeptide were in the mid-normal range.
Other normocalcemic PHPT cohorts have been des
cribed8,19,41,50,54–56,67 (Table 22.2). These reports also
describe patients from referral populations and the
II.   CLINICAL ASPECTS OF PRIMARY HYPERPARATHYROIDISM
22.  NORMOCALCEMIC PHPT
Prevalence Comments
0.4% Excluding renal failure (GFR <60 cc/min), vitamin D
deficiency (25-hydroxyvitamin D <20 ng/dL), thiazide
diuretic use
0.5% Secondary etiologies of hyperparathyroidism not
excluded, although pathologic evidence of parathyroid
disease noted in some subjects
1.0% Excluding renal failure (GFR <60 cc/min) and vitamin
D deficiency (25-hydroxyvitamin D <30 ng/dL)
3.1% (Baseline) Excluding renal failure (GFR <60 cc/min), vitamin D
0.6% (Follow-up) deficiency (25-hydroxyvitamin D <20 ng/dL), thiazide
diuretic and lithium use
6% Excluding renal disease, vitamin D deficiency
(25-hydroxyvitamin D <30 ng/dL), and malnutrition
16.7% Excluding vitamin D deficiency (25-hydroxyvitamin D
<20 ng/dL)
observation that many subjects are symptomatic is,
therefore, not surprising. Of particular interest is a report
from Charopoulos et al.57 in which peripheral quantita-
tive computed tomography was used to assess the skele-
ton in subjects with normocalcemic PHPT in comparison
to those with hypercalcemic PHPT. Of the 52 postmeno-
pausal women studied, 24 had normocalcemic PHPT,
with a mean age of 60 years. Imaging found catabolic
effects in both groups that were more pronounced in
hypercalcemic subjects. While cortical geometric proper-
ties were also adversely affected in subjects with normo-
calcemic PHPT, trabecular properties were preserved.
In addition to the symptomatic patients described
above, the two-phase hypothesis of the evolution of
PHPT suggests that there is another cohort of asymp-
tomatic normocalcemic subjects that could be discovered
through screening of large unselected community-
dwelling populations. Garcia-Martin et al.50 are the
first to have conducted community-based screening
to identify patients. They found six out of 100 healthy
postmenopausal women (prevalence 6%) with high
PTH and normal albumin-adjusted serum calcium after
excluding renal disease (no cutoff value given), vitamin D
deficiency (25-hydroxyvitamin D <30 ng/dL), and mal-
nutrition. Ionized calcium values were not obtained or
reported. The subjects identified with normocalcemic
PHPT were compared to women with secondary hyper-
parathyroidism. There were no differences in biochemi-
cal or clinical indices between these two groups except
that the 25-hydroxyvitamin D level was lower in those
with secondary hyperparathyroidism. In addition, both
groups had normal bone turnover markers and bone
mass as measured by quantitative ultrasound.
 Clinical Presentation 335
TABLE 22.2 Summary of Cohorts with Normocalcemic PHPT Described in the Literature
Cohort Age Female Osteoporosis/ Nephrolithiasis
Study Size (Years) (%) Fracture (%) (%) Comments Regarding Diagnosis

SYMPTOMATIC REFERRAL-BASED COHORTS

Silverberg 22 57 ± 10 91 45 14 All had normal total serum calcium corrected for albumin;
et al.8 5 ionized calcium was normal in eight subjects in whom data
were available
Secondary hyperparathyroidism exclusions:
25-hydroxyvitamin D >20 ng/mL; renal disease;
hypercalciuria (>350 mg/d); thiazide diuretic, lithium,
bisphosphonate, anticonvulsant use; malabsorption; other
metabolic bone diseases

Tordjman 32 61 ± 11 84 36 9 All had normal total serum calcium corrected for albumin;
et al.41 Not given ionized calcium not measured in all and not reported
Secondary hyperparathyroidism exclusions:
25-hydroxyvitamin D >15 ng/mL; hypercalciuria
(>300 mg/d) not responding to hydrochlorothiazide

Lowe et al.53 * 37 58 ± 12 95 57 14 All had normal total serum calcium corrected for albumin;
11 ionized calcium was normal in 20 subjects in whom data
were available
Secondary hyperparathyroidism exclusions:
25-hydroxyvitamin D >20 ng/mL (65% >30 ng/mL); renal
insufficiency (GFR >40 cc/min); hypercalciuria (>350
mg/d); thiazide diuretic or lithium use; other metabolic
bone diseases

Marques 14 61 ± 15 100** 36 29 All had normal total serum calcium corrected for albumin;
et al.67 21 ionized calcium not measured
Secondary hyperparathyroidism exclusions:
25-hydroxyvitamin D >30 ng/mL; renal insufficiency (GFR
>40 cc/min); thiazide diuretic, lithium, bisphosphonate,
anticonvulsant use; malabsorption; other metabolic bone
diseases

Amaral et al.54 33 64 ± 14 79 Not given 18 All had normal total serum calcium; ionized calcium not
15 measured
Secondary hyperparathyroidism exclusions:
25-hydroxyvitamin D >30 ng/mL; renal insufficiency (GFR
>60 cc/min); hypercalciuria (urinary Ca/Cr <240 mg/g Cr);
thiazide diuretic, lithium, bisphosphonate, anticonvulsant
use; malabsorption; other metabolic bone diseases

Cakir et al.55 18 50 ± 8 89 47 11 All had normal total serum calcium corrected for albumin;
Not given ionized calcium not measured
Secondary hyperparathyroidism exclusions:
25-hydroxyvitamin D >20 ng/mL
Aim of investigating glucose and lipid metabolism; no
differences between patients and age-, sex-, and BMI-
matched controls with respect to indicators of insulin
resistance

Wade et al.56 8 60 63 25 25 All had normal total serum and ionized calcium
(range 13 No documented exclusions of secondary
38–78) hyperparathyroidism, although almost all had preoperative
localization studies
Surgical cohort

Continued

II.   CLINICAL ASPECTS OF PRIMARY HYPERPARATHYROIDISM

336
TABLE 22.2 Summary of Cohorts with Normocalcemic PHPT Described in the Literature—cont’d
Cohort Age Female Osteoporosis/
Study Size (Years) (%) Fracture (%)
Koumakis 39 64 ± 10 92 92
et al.19 40
ASYMPTOMATIC COHORT DISCOVERED FROM POPULATION-BASED SAMPLING
Garcia-Martin 6 56 ± 3 100** 0 0
et al.50 0 ionized calcium not measured
Mean ± SD; body mass index, BMI; glomerular filtration rate, GFR.
*Included patients from Silverberg et al.8
**Study design.
Another source of identification may come from indi-
viduals noted to have a parathyroid incidentaloma on
neck ultrasonography or during surgery for thyroid
pathology. Of interest, an autopsy series studying para-
thyroid incidentalomas found adenomas in 2.4% of sub-
jects while hyperplasia was noted in 7%.58 Incidentally
enlarged parathyroid glands are noted during thyroid-
ectomy in approximately 0.2–4.5% of operations.59,60
Recently, there are reports of parathyroid incidentalo-
mas recognized in subjects undergoing neck ultrasonog-
raphy of the thyroid, with a prevalence of 0.4–1.2% for
parathyroid lesions.61–63 Of these, 12.5–37.5% were noted
to be hyperfunctioning. This rather recent appreciation
of the parathyroid incidentaloma brings the parathyroid
glands in line with other endocrine tissues, in which non-
functioning but enlarged glands can be demonstrated.60
NATURAL HISTORY
There are very limited data on the clinical course of
normocalcemic PHPT with or without surgery, and even
more limited data on whether current surgical criteria
are appropriate in this phenotypic variant. Since most of
the longitudinal data are from observational studies of
small convenience samples, they provide a window into
the natural history issue while highlighting the need for
more data.
Without Surgery
In the Columbia cohort,53 a symptomatic popula-
tion at diagnosis, 40% of the 37 individuals developed
II.   CLINICAL ASPECTS OF PRIMARY HYPERPARATHYROIDISM
22.  NORMOCALCEMIC PHPT
Nephrolithiasis
(%) Comments Regarding Diagnosis
18 All had normal total serum calcium levels; 16 subjects
had normal ionized calcium, the remaining had elevated
ionized calcium
Secondary hyperparathyroidism exclusions:
25-hydroxyvitamin D levels >20 ng/mL; renal
insufficiency (GFR >40 cc/min); thiazide test in patients
with hypercalciuria; absence of thiazide diuretic,
lithium, bisphosphonate, anticonvulsant use; absence of
gastrointestinal disorder
Surgical cohort
All had normal total serum calcium corrected for albumin;
Secondary hyperparathyroidism exclusions: vitamin D
deficiency (25-hydroxyvitamin D <30 ng/dL), renal disease,
malnutrition
further signs of PHPT during the mean follow-up period
of 3.1 years. Hypercalcemia developed in 19% of these
subjects, who tended to be older, have higher baseline
serum calcium levels within the normal range, and
higher baseline urinary calcium excretion. In another
symptomatic cohort described by Tordjman et al.,41 20
patients were followed for a mean of 4.1 years, without
significant change in serum calcium or development of
hypercalcemia. In the cohort described by Garcia-Martin
et al.50 after 1 year of follow-up, hyperparathyroidism
persisted in all six women defined as having normocal-
cemic PHPT. None of these asymptomatic women devel-
oped hypercalcemia, nephrolithiasis, or fracture in their
very short follow-up period.
Rejnmark et al.64 studied approximately 50,000 sub-
jects who provided blood samples to three large Danish
population-based studies. One hundred and seventeen
subjects with a later diagnosis of PHPT were identi-
fied using a national medical register. The majority of
them had normal kidney function. Of these subjects, 44
were normocalcemic at the time of initial blood sam-
pling, with 13 having high PTH levels. While they were
given a putative diagnosis of normocalcemic PHPT by
the authors, almost all had 25-hydroxyvitamin D values
<20 ng/mL.
With Surgery
There are no specific data on the indications for
surgery in normocalcemic PHPT, and limited data on
surgical outcomes. Most describe pathologic findings
similar to that in hypercalcemic disease. The majority of
patients in the cohort of Rejnmark et al.64 who underwent
 References
surgery had a single adenoma. In the cohort described
by ­Tordjman et al.41 12 patients had positive localiza-
tion studies and subsequently underwent successful
parathyroidectomy, with operative findings of a single
adenoma or hyperplasia. In the Columbia cohort,53 three
of the patients who developed hypercalcemia and four
additional patients with persistently normal serum cal-
cium levels underwent successful parathyroidectomy,
with similar operative findings of a single adenoma or
hyperplastic disease. PTH levels normalized postopera-
tively. Data are even more limited on BMD response to
parathyroidectomy. In the surgical cohort described by
Koumakis et al.19 the 16 subjects with normal total and
ionized calcium levels preoperatively demonstrated a
BMD gain of 4.1% at the femoral neck at 1 year after para-
thyroid surgery (p = 0.044), without significant change at
the spine or radius.
MANAGEMENT
Normocalcemic PHPT was first formally recognized
at the Third International Workshop on the Management
of Asymptomatic PHPT in 2008.12 At that time, how-
ever, the expert panel stated it was premature to suggest
guidelines for the normocalcemic variant. The available-
data suggest that there is no single natural history of nor-
mocalcemic PHPT. Instead this diagnosis includes some
patients who are symptomatic and others who are not;
some patients who will develop hypercalcemic disease
as originally proposed in the biphasic disease theory,
and others who may never become hypercalcemic. As a
result of the recognition of this complexity, the Fourth
International Workshop in 2013 proposed an algorithm
for the management of normocalcemic primary hyper-
parathyroidism65,66 (Figure 22.1).
The general approach is to monitor subjects with
normocalcemic PHPT in the same manner in which we
monitor those with asymptomatic hypercalcemic PHPT.
Annual serum calcium and PTH and every 1–2 year
bone mineral density determinations seem reasonable.
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FIGURE 22.1  Management guidelines for normocalcemic PHPT
proposed by the Fourth International Workshop on the Management
of Asymptomatic PHPT.65,66 DXA, dual-energy X-ray absorptiometry;
BMD, bone mineral density.
II.   CLINICAL ASPECTS OF PRIMARY HYPERPARATHYROIDISM
337
If the disease evolves into the hypercalcemic form, the
published guidelines for hypercalcemic PHPT from the
Fourth International Workshop would be reasonable to
follow. Progression of the disease in other ways, such as
worsening bone density, a fracture, or a kidney stone,
may signal that a more proactive surgical approach
to the disease should be considered, even if patients
continue to be normocalcemic. While this approach is
based upon the limited available data, there is clear rec-
ognition that these guidelines are likely to be refined
in response to the collection of evidence over the next
decade(s).
SUMMARY AND CONCLUSIONS
PHPT was previously described as two distinct enti-
ties marked by two eras. Prior to the advent of the multi-
channel autoanalyzer in the 1970s, classical PHPT often
presented with marked hypercalcemia and symptom-
atic bone and stone disease. The presentation shifted in
the 1970s to an asymptomatic disorder characterized by
mild hypercalcemia. The emergence of normocalcemic
PHPT appears to mark a third era in the history of this
disease. Individuals are being discovered with normal
total and ionized serum calcium concentrations but with
PTH levels that are consistently elevated, usually in the
evaluation for an underlying metabolic bone disease.
Even the limited data available today suggest that there
are several subsets of patients: those who will remain
persistently normocalcemic and those who are at risk for
the development of hypercalcemia. At this time, there
are no data that predict whether an individual patient
will fall in one category or another. There is yet another
subset being discovered incidentally by neck imaging
and at the time of thyroid surgery in whom the para-
thyroid adenoma is a non-functioning incidentaloma.
Population-based studies have the potential to identify
asymptomatic individuals with normocalcemic PHPT
and therefore study the possible evolution of the disease.
Acknowledgments
This work was supported in part by National Institutes of Health
grants DK32333, DK074457, and DK095944.
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