Key words
primary hyperparathyroidism - normocalcemic - secondary hyperparathyroidism - diagnosis
- prevalence
Introduction
Classical and “symptomatic” primary hyperparathyroidism (PHPT) manifests with nephrolithiasis,
fractures, or symptoms of hypercalcemia. Nowadays, most patients are “asymptomatic”
at the time of diagnosis despite elevated serum calcium. Finally, some patients have
normal calcium concentrations, which do not rule out bone or renal complications.
The prevalence and even the diagnostic criterion of “normocalcemic” PHPT (NPHPT) are
still uncertain and there is no consensual definition. In general, the diagnosis of
NPHPT is made based on the finding of (i) normocalcemia, including ionized calcium,
(ii) associated with elevated parathyroid hormone (PTH), and both should be confirmed
(iii) after the exclusion of known causes of secondary HPT (SHPT) [1]
[2]
[3]
[4]
[5]. Surgery is not readily indicated in patients with NPHPT [6]. Thus, imaging methods for the detection of altered parathyroid glands initially
are also not recommended [1]
[3]
[4]
[7]. The underlying parathyroid pathology (hyperplasia or adenoma) is therefore unknown
at the time of diagnosis of NPHPT. Curiously, many patients first diagnosed with NPHPT
do not progress to hypercalcemia or PTH elevation and spontaneous normalization of
this hormone is even observed [8]
[9]
[10]. It is possible that some patients with a laboratory diagnosis of NPHPT actually
do not have the condition and may correspond to the small percentage of normal individuals
whose PTH is outside the reference range or to patients with inapparent or subclinical
causes of SHPT. Finally, controversy exists regarding the exclusion of the 2 main
causes of SHPT (chronic kidney disease and vitamin D insufficiency). Some authors
consider an estimated glomerular filtration rate (eGFR)>40 ml/min/1.73 m2 [11]
[12] for the diagnosis of NPHPT and others an eGFR>60 ml/min/1.73 m2 [1]
[2]
[3]
[4]
[8]
[9]
[13]
[14], as well as concentrations of 25-hydroxyvitamin D>20 ng/dl [4]
[9]
[10]
[11]
[13] or>30 ng/dl [2]
[8]
[12]
[14].
In clinical practice, PTH is only requested in patients with altered calcemia or in
the case of a strong suspicion of HPT (primary or secondary), that is, patients with
osteoporosis, fractures, nephrolithiasis, or chronic kidney disease. NPHPT is therefore
expected to be underdiagnosed in individuals without a known diagnosis of these conditions.
The prevalence of NPHPT was investigated in some studies [8]
[9]
[10]
[12]
[14]
[15]. First, many of these studies evaluated postmenopausal women [8]
[12]
[15]. Second, considering the diagnostic criterion above [1]
[2]
[3]
[4]
[5], limitations are identified in these studies: ionized calcium was not measured [8]
[9]
[10]
[12]
[14], normocalcemia and PTH elevation were not confirmed [9]
[10]
[12]
[14], hypercalciuria was not excluded as a cause of elevated PTH [8]
[9]
[10]
[12]
[14], and the diagnosis was only considered when initial calcium ≥10.2 mg/dl [15]. In addition, diagnostic definition was not uniform, considering eGFR>40 ml/min/1.73 m2
[12] or>60 ml/min/1.73 m2 [8]
[9]
[14] and 25-hydroxyvitamin D>20 ng/dl [9]
[10] or>30 ng/dl [8]
[12]
[14] for the exclusion of SHPT. Third, these studies did not investigate the underlying
parathyroid pathology by imaging methods or surgery in most of the patients diagnosed
with NPHPT [8]
[9]
[10]
[12]
[14]
[15].
The objective of this prospective study was to evaluate the prevalence of NPHPT (whose
definition included the measurement of ionized calcium, confirmation of normocalcemia
and elevated PTH) in an adult population (including men and premenopausal women) without
a history of fractures or nephrolithiasis. The study also analyzed the impact of this
prevalence on the adoption of 2 different cut-offs for 25-hydroxyvitamin D and eGFR,
and agreement of the laboratory diagnosis of NPHPT with the surgical finding of altered
parathyroid glands.
Patients and Methods
Study design
The study was prospective. The selection criteria and study protocol were predefined,
and the details are described below. The study was approved by the local Research
Ethics Committee [16].
Patients
Adults (age ≥18 years) with nodular thyroid disease consecutively seen by the authors
between 2009 and 2014 and who would be submitted to thyroidectomy were evaluated.
Patients whose thyroid nodules were detected by neck US because of a diagnosis of
PHPT were not included. The following patients were also not included: patients with
a history of nephrolithiasis, nephrocalcinosis and pathological fracture; andf patients
with a personal or family history of multiple endocrine neoplasia or diagnosis of
medullary thyroid cancer. We initially selected 676 patients [16].
The patients were submitted to the measurement of calcium (total and ionized), phosphorus,
25-hydroxyvitamin D, TSH, PTH, and urinary calcium, and creatinine. Six patients had
a diagnosis of hypercalcemic PHPT and these cases have been published previously [16]. None of the patients had PTH-independent hypercalcemia. The following subjects
were excluded from the group of normocalcemic patients: patients using diuretics,
lithium, bisphosphonates, denosuamb, recombinant PTH, and corticosteroids; patients
with primary aldosteronism (investigated in the recommended situations [17]), a suspicion or known diagnosis of malabsorption syndrome; hyperphosphatemia, 25-hydroxyvitamin
D<20 ng/dl, eGFR<40 ml/min/1.73 m2, calcium/urinary creatine ratio ≥0.25, or thyroid dysfunction. The remaining patients
also underwent measurement of tissue anti-transglutaminase IgA antibodies and those
with a positive result were excluded. Finally, calcium and PTH measurements were repeated
in normocalcemic patients with elevated PTH and without a known cause of SHPT for
confirmation of the initial result.
Parathyroidectomy
Trained surgeons performed the surgery of all patients included in the study. The
surgeon was aware of the screening results and the team of surgeons was the same throughout
the study. The 4 parathyroid glands were fully explored in patients with elevated
PTH. The exploration was considered complete when either the 4 glands had been seen
or when at least one enlarged and one normal parathyroid gland had been identified
[16]
[18]. Parathyroid glands were examined based on their macroscopic appearance. We removed
only the grossly abnormal parathyroid glands, that is, enlarged. Histology of the
removed parathyroid glands was always obtained.
Methods
Total calcium [corrected for low albumin (<4 mg/dl) using the formula: (4 – albumin)×0.8+Ca]
(reference range: 8.4–10.4 mg/dl) and urinary calcium were measured by a colorimetric
method. Ionized calcium (reference range: 1.12–1.32 mmol/l) was measured with a selective
electrode and automatic correction for pH variation. Serum PTH was measured with a
chemiluminescent assay (Immulite 2000, Diagnostic Products Corporation, Los Angeles,
CA, USA), with reference values of 12–65 pg/ml. Chemiluminescence assay was used to
measure 25-hydroxyvitamin D. Creatinine was measured by a kinetic colorimetric method.
The eGFR was calculated using the Modification of Diet in Renal Disease Study equation.
Tissue anti-transglutaminase IgA antibodies were measured by enzyme immunoassay. All
measurements were obtained in the morning after fasting for approximately 10 h, and
the samples were processed and analyzed immediately after collection. Of note, there
was no change in laboratory methods during the study.
Results
After the exclusion of 6 patients with hypercalcemic PHPT [16] and 176 with known causes of SHPT, 46 patients (6.8%) had normal total and ionized
calcium and elevated PTH in 2 measurements, in the absence of conditions associated
with SHPT (see Methods). Hence, these patients could have a laboratory diagnosis of
NPHPT.
During surgical exploration, altered parathyroid glands were only detected in 4 patients,
corresponding to 0.6% of all patients and to 8.7% of those with a laboratory diagnosis
of NPHPT. In these patients, the histological diagnosis was adenoma of the parathyroid
gland. PTH was persistently normal after surgery in these 4 patients. Sex, age, calcium
and PTH levels of these patients with confirmed NPHPT are shown in [Table 1]. NPHPT was confirmed in 0/174 men, in 1/252 premenopausal women (0.4%), and in 3/250
postmenopausal women (1.2%).
Table 1 Sex, age, calcium, and PTH levels of the patients with NPHPT.
|
Patient
|
Sex
|
Age (years)
|
Ca (mg/dl)
|
Ca ionized (mmol/l)
|
PTH (pg/ml)
|
Histology (parathyroid)
|
|
1
|
F
|
44
|
10.3
|
1.3
|
76
|
Adenoma (400 mg)
|
|
2
|
F
|
52
|
9.2
|
1.22
|
112
|
Adenoma (850 mg)
|
|
3
|
F
|
58
|
9.5
|
1.28
|
108
|
Adenoma (600 mg)
|
|
4
|
F
|
62
|
10.2
|
1.3
|
85
|
Adenoma (800 mg)
|
|
5
|
M
|
50
|
9.8
|
1.28
|
78
|
–
|
NPHPT: Normocalcemic primary hyperparathyroidism; Ca: Calcium; PTH: Parathyroid hormone;
F: Female; M: Male.
We evaluated 42 normocalcemic patients with elevated PTH but without altered parathyroid
glands during surgery, with emphasis on eGFR and 25-hydroxyvitamin D. Estimated GFR
between 40 and 60 ml/min/1.73 m2 and/or 25-hydroxyvitamin D between 20 and 30 ng/dl were found in 41 patients (25
patients had vitamin D insufficiency, 7 had stage 3 chronic kidney disease, and 9
had both). One patient exhibited elevated PTH without a known cause of SHPT (see Methods)
and without altered parathyroid glands during surgical exploration ([Table 1]). This patient had a urinary calcium/creatinine clearance ratio>0.02 and was submitted
to 99mTcMIBI SPECT/CT and neck MRI after surgery, but both were negative. The patient currently
continues normocalcemic with elevated PTH. [Table 2] shows the impact of the 25-hydroxyvitamina D and eGFR cut-offs on the prevalence
of NPHPT.
Table 2 Frequency of NPHPT in patients without a history of nephrolithiasis or fractures
using different 25-hydroxyvitamin D and eGFR cut-offs.
|
Criterion for definition of NPHPT
|
Frequency of laboratory NPHPT
|
Percentage of patients with laboratory NPHPT and confirmed parathyroid pathology
|
|
eGFR>40 ml/min/1.73 m2 and
25-hydroxyvitamin D>20 ng/dl
|
6.8% (n=46)
|
8.7%
|
|
eGFR>60 ml/min/1.73 m2 and
25-hydroxyvitamin D>20 ng/dl
|
4.4% (n=30)
|
13.3%
|
|
eGFR>40 ml/min/1.73 m2 and
25-hydroxyvitamin D>30 ng/dl
|
1.8% (n=12)
|
33.3%
|
|
eGFR>60 ml/min/1.73 m2 and
25-hydroxyvitamin D>30 ng/dl
|
0.74% (n=5)
|
80%
|
NPHPT: Normocalcemic primary hyperparathyroidism; eGFR: Estimated glomerular filtration
rate.
The 5 patients with NPHTP were compared with the 41 patients with elevated PTH without
altered parathyroid glands during surgery and who had vitamin D insufficiency (between
20 and 30 ng/dl) and/or stage 3 chronic kidney disease (estimated GFR between 40 and
60 ml/min/1.73 m2). There was no difference in sex, age, and serum PTH; but calcium concentrations
were higher in patients with NPHTP ([Table 3]).
Table 3 Sex, age, calcium, and PTH levels of the patients with NPHPT (group A) and patients
with elevated PTH without altered parathyroid glands and who had vitamin D insufficiency
and/or stage 3 CKD (group B).
|
Group A (n=5)
|
Group B (n=41)
|
|
Sex
|
4 F, 1 M
|
30 F, 11 M
|
|
Age (years)
|
44–62 (mean: 53)
|
32–76 (mean: 55)
|
|
Ca (mg/dl)
|
9.2–10.3 (mean: 9.8)
|
8.5–9.6 (mean: 9.2)
|
|
Ca ionized (mmol/l)
|
1.22–1.3 (mean: 1.28)
|
1.14–1.25 (mean: 1.2)
|
|
PTH (pg/ml)
|
76–112 (mean: 92)
|
78–130 (mean: 98)
|
NPHPT: Normocalcemic primary hyperparathyroidism; CKD: Chronic kidney disease; Ca:
Calcium; PTH: Parathyroid hormone; F: Female; M: Male.
The 25 patients with vitamin D insufficiency received supplements and were followed
up every 8 weeks for dose adjustment to achieve concentrations>30 ng/dl. After 6 months,
the 20 patients who achieved these concentrations in all 3 measurements had normal
PTH without hypercalcemia.
Discussion
This was a prospective study that used predefined and uniformly followed selection
criteria of the patients, laboratory assessment, and surgical approach [16]. In the present series, the prevalence of NPHPT was also evaluated in men and in
premenopausal women, who were not included in some of the previous studies [8]
[12]
[15]. Regarding laboratory assessment, we emphasize that total and ionized calcium was
measured and that normocalcemia and elevated PTH were confirmed for the diagnosis
of NPHPT. Ionized calcium was not obtained [8]
[9]
[10]
[12]
[14] and PTH elevation was not confirmed [9]
[10]
[12]
[14] at diagnosis in many previous series that analyzed the prevalence of NPHPT. In those
population studies, hypercalciuria was not excluded as a cause of elevated PTH [8]
[9]
[10]
[12]
[14]. With respect to the eGFR and vitamin D cut-offs for the exclusion of SHPT, each
study adopted a different criterion. In contrast, hypercalciuria and the 4 possible
combinations of eGFR and vitamin D concentration were evaluated in the present study.
We also point out that, in contrast to the previous studies [8]
[9]
[10]
[12]
[14], all participants in our series were submitted to surgical exploration of the parathyroid
glands, which permitted to correlate the laboratory diagnosis of NPHPT with the confirmation
of altered glands.
Using the more rigorous diagnostic criterion (eGFR>60 ml/min/1.73 m2 and 25-hydroxivitamin D>30 ng/dl), we found NPHPT (confirmed during surgery) in 1.2%
of 250 postmenopausal women without a history of nephrolithiasis or fractures. Also
in Brazil, another study found NPHPT in 8% of 179 postmenopausal women, but all of
them had been referred to a specialty center for the investigation of osteoporosis
[12]. In Spain, NPHPT was diagnosed in 6/100 postmenopausal women but this diagnosis
was confirmed in only 4 (4%) when reevaluated after 1 year [8]. As mentioned earlier, NPHPT might be overestimated in these series since ionized
calcium was not obtained [8]
[12], elevated PTH was not confirmed at diagnosis [12], hypercalciuria was not excluded as a cause of this finding [8]
[12], SHPT was only considered in the presence of eGFR<40 ml/min/1.73 m2
[12], and there was no confirmation of the underlying parathyroid pathology [8]
[12]. With opposite results, the frequency of NPHPT was only 1.5% in a large Swedish
study, but only patients with calcium ≥ 10.2 mg/dl were investigated [15], and no case of NPHPT was detected among 157 postmenopausal women in an Italian
series [14].
To the best of our knowledge, only 3 previous studies have evaluated the prevalence
of NPHPT in men and in women before menopause [9]
[10]
[14]. In the first, the prevalence was only 0.4% in men>65 years, 0.67% in men between
18 and 65 years, and 0.35% in women between 18 and 65 years. Nevertheless, these prevalence
rates might be overestimated since elevated PTH was not confirmed, hypercalciuria
was not investigated for the exclusion of SHPT, and only individuals with 25-hydroxivitamin
D<20 ng/ml were excluded [9]. Corroborating the possibility of an initial misdiagnosis of NPHPT, during long-term
follow-up, the criterion of PHPT persisted in only 22% of the patients and spontaneous
normalization of PTH was observed in 45% [9]. In the second study, no case was diagnosed in adult women and the prevalence was
1% in men, but again elevated PTH was not confirmed and hypercalciuria was not excluded
[14]. In the present study in which elevated PTH was confirmed, hypercalciuria was excluded
and 25-hydroxivitamin D>30 ng/ml was considered for diagnosis, NPHPT was found in
only 0.57% of 174 men (patient without altered parathyroid gland during surgery) and
in 0.4% of 252 premenopausal women.
Another result of the present study was the implication of different eGFR and 25-hydroxyvitamin
D cut-offs for the diagnosis of NPHPT. The prevalence of NPHPT was 6.8% considering
eGFR>40 ml/min/1.73 m2 and 25-hydroxyvitamin D>20 ng/dl and only 0.74% using eGFR>60 ml/min/1.73 m2 and 25-hydroxyvitamin D>30 ng/dl. Whereas altered parathyroid glands were confirmed
during surgery in only 8.7% of the patients with a diagnosis of NPHPT using the first
criterion, the same was observed in 80% of patients diagnosed using the second criterion.
Thus, the criterion of eGFR>60 ml/min/1.73 m2 and 25-hydroxyvitamin D>30 ng/dl seems to be more appropriate to avoid an excessive
number of false-positive results. Since patients with NPHPT can have eGFR<60 ml/min/1.73 m2 and 25-hydroxyvitamin D<30 ng/dl, to ensure that these cases will also be diagnosed,
replacement therapy would be useful when vitamin D is between 20–30 ng/dl, maintaining
persistent levels>30 ng/dl and observing if there is normalization of PTH (SHPT) or
even the development of hypercalcemia (PHPT). In the case of eGFR<60 ml/min/1.73 m2, considering the irreversibility of this situation, follow-up verifying the evolution
of calcium, PTH and correlation of eGFR with PTH may be helpful in the differential
diagnosis.
Our study has limitations. Imaging methods directed at the parathyroid glands were
not performed before surgery. However, these methods were found to be limited in patients
with NPHPT [19], and surgical exploration by an experienced surgeon is known to be more sensitive
for the identification of altered parathyroid glands. Another limitation was the lack
of information about the follow-up of patients with elevated PTH and eGFR 40–60 ml/min/1.73 m2 in the absence of altered parathyroid glands during surgery. However, with this negative
finding, we believe that they in fact had SHPT.
In conclusion, the prevalence of NPHPT was 0.74% in an adult population without history
of nephrolithiasis or fractures. The diagnostic criterion using eGFR>60 ml/min/1.73 m2 and 25-hydroxyvitamin D>30 ng/dl was more appropriate considering the agreement with
the surgical finding of altered parathyroid glands.
Funding
This work was supported by the National Council for Scientific and Technological Development
(CNPq).
