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DOI:10.4158/EP161206.OR
2016 AACE.
Original Article
EP161206.OR
DOI:10.4158/EP161206.OR
2016 AACE.
Abstract:
Objectives:
To determine the utility of bone health screening panel in identifying disorders of
parathyroid gland secretions.
Methods:
A retrospective analysis of biochemical parameters in bone health screening panel (BHSP)
was conducted. The low and high cut offs were applied to determine hypo functioning and
hyper functioning conditions related to parathyroid hormone. Clinical phenotypes of
parathyroid gland abnormalities were made by using combination of levels of calcium,
vitamin D and iPTH. PTH nomogram defined by Harvey et al was applied to calculate max
expected PTH for existing level of 25OHD. Medical records of patients were reviewed for
clinical validation of biochemical findings.
Results:
Sixty eight percent subjects showed abnormal PTH secretion. Primary hyper and hypo
parathyroidism was detected in 1% (n=5) and 0.4% (n=2) respectively. Normocalcemic
hyperparathyroidism and hypercalcemia with inappropriately high normal PTH was
identified in 8.5% (n=37) and 2% (n=10) respectively. All subjects with primary and
normocalcemic hyperparathyroidism had higher measured PTH than calculated maxPTH
using PTH nomogram. Secondary hyperparathyroidism and functional hypoparathyroidism
was present in 18% (n=88) and 39% (n=194) subjects respectively. High prevalence of bone
pains, renal stones and low BMD were identified in patients with abnormal PTH secretion.
Conclusions:
Panel testing is useful in early diagnosis of metabolic bone disorders related to PTH. BHSP
helps identify normocalcemic hyperparathyroidism and hypercalcemia with inappropriately
high PTH.
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2016 AACE.
ABBREVIATIONS:
MBD = Metabolic bone diseases, VDD = vitamin D deficiency, sHPTH = secondary
hyperparathyroidism, 25OHD = Vitamin D, PTH = plasma parathyroid hormone, AKUH =
Aga Khan University Hospital, BHSP = bone health screening panel; PHP = primary
hyperparathyroidism, NCHP = normocalcemic hyperparathyroidism, SPSS = Statistical
Package of Social Sciences, SD = standard deviation.
BACKGROUND:
Parathyroid glands are instrumental in bone and mineral homeostasis. Disorders of secretion
are primary, in which parathyroid glandular activity is intrinsically abnormal (e.g. primary
hyperparathyroidism (PHP), hypoparathyroidism) and secondary, in which increased or
decreased parathyroid glandular activity is an adjustment to another pathophysiological
process (e.g. vitamin D deficiency (VDD), chronic renal failure (CRF)); or a physiologic
adjustment to another pathophysiological events that lead either to hypercalcemia or
hypocalcaemia.
Recently, newer phenotypes of PHP have evolved. This includes normocalcemic
hyperparathyroidism (NCHP); which is characterized by normal serum calcium and high
intact parathyroid hormone (iPTH) levels in the absence of VDD and CRF. Another
phenotype is of inappropriately normal iPTH in the setting of hypercalcemia (hypercalcemia
with inappropriately normal iPTH). In addition, a significant proportion of subjects do not
demonstrate secondary hyperparathyroidism (sHPT) despite VDD; this has been labelled as
functional hypoparathyroidism.
Disorders of PTH secretion are an important cause of metabolic bone diseases (MBD), which
are frequent in general population (1-3) and contribute to morbidity and decrease quality of
life (4-7). Biochemical assessment of bone health is important for diagnosis. There is wide
variability in clinical presentation; and non-specific in symptoms are a diagnostic challenge.
Most subjects are identified only while investigated for another disorder.
Measurement of serum calcium, 25 hydroxy vitamin D (25OHD) and plasma iPTH
concentrations, although readily available; when used individually are of limited value in
assessing MBD. Simultaneous testing with markers relevant to MBD improves diagnostic
yield as interpretation can be made together with clinical history and examination. They are
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also economical both in terms of time and money for the patients and physician. Bone Health
Screening Panel (BHSP); variably utilizing combination of blood tests to screen, diagnose
and monitor MBD in clinical practice has been developed in laboratories. These panels
facilitate in answering the potential clinical questions that a physician seeks when
investigating MBD.
For this reason we introduced a biochemical testing panel (comprising of serum 25OHD,
calcium, phosphorus, magnesium, alkaline phosphatase, creatinine, albumin and iPTH) to
screen for bone and mineral disorders at the Clinical Laboratories, Aga Khan University
Hospital in January 2011. So this audit was conducted to determine the utility of BHSP in
identifying disorders of parathyroid gland secretion. There are not many studies on
simultaneous testing with multiple biochemical tests for correctly assessing bone minerals
status, which can be missed on routine health screening.
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2016 AACE.
II.
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2016 AACE.
III.
IV.
Ethical Consideration:
Study was done in accordance with Helsinkis ethical code. To maintain confidentiality
coding was given to patients and their original identifications were removed. Exemption was
sought from Institutions Ethical Review committee (ERC number: 2894-Pat-ERC-14)
Data Analysis:
The statistical analysis was performed using the Statistical Package of Social Sciences
(SPSS) version 19. Frequency was generated for gender and means with standard deviation
(SD) for continuous variables. Analysis of variance was done and mean and SD of all
analytes for five clinical groups were generated.
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2016 AACE.
RESULTS:
General Characteristics of the Study Subjects:
Five hundred and forty eight subjects were tested with BHSP from January 2011 till
December 2013 at the Section of Clinical Chemistry Pathology, Department of Pathology &
Laboratory Medicine, Aga Khan University Hospital (AKUH) in Karachi, Pakistan. Fourteen
subjects with incomplete information were excluded and analysis to determine biochemical
phenotype was performed on 534 subjects. Among them, clinical details of 111 subjects,
registered at AKUH were reviewed for clinical validation (figure 1).
Table 1 shows the mean biochemical parameters of 534 subjects grouped into hyper- and
hypo-functioning states on the basis of reference interval used by the laboratory. Sixty five
percent subjects were females with mean age of 44.517 years. Mean iPTH was high and
mean 25OHD was in insufficient range. High creatinine was found in 7% of subjects (n=37);
suggestive of renal pathology. Mean levels of other analytes were in normal range, however
subjects with low and high levels were identified for each of analyte.
VDD and insufficiency were the predominant abnormalities identified in 60% (n=318) and
20% (n=109) of the subjects respectively; with only 19.8% of the subjects having optimal
25OHD levels. One subject had 25OHD levels greater than 150ng/ml with normal iPTH,
calcium, alkaline phosphatase and phosphorus. Mean iPTH levels were suggestive of sHPTH
in VDD group only (mean iPTH 87 127pg/ml) while mean iPTH in the insufficient
(6536ng/ml) and sufficient group (7451ng/ml) was within the reference interval. Mean
levels of calcium, phosphorus and alkaline phosphatase were within the reference interval
and were not reflective of VDD, insufficiency and sufficiency (data not shown).
Distribution of Subjects into Phenotypes of Parathyroid Hormone Dysfunction:
PTH disorders were classified on 497 subjects after excluding those with high creatinine.
Abnormalities of secretion were identified in 340 subjects. Figures 1 & 2 shows distribution
of subjects into various phenotypes of parathyroid hormone dysfunction based on calcium,
25OHD and iPTH cutoffs, defined in methodology section. Table 2 depicts the frequency
and mean blood levels in different phenotypes of parathyroid gland disorders from figure 1.
Among the twenty subjects with hypercalcemia (mean calcium 10.60.59mg/dl); 5 had high
iPTH levels suggestive of PHP, while 10 subjects had hypercalcemia with inappropriately
normal iPTH. Secondary hyperparathyroidism to VDD was present in 17.7% (n=88) while
39% (n=194) had functional hypoparathyroidism. Magnesium deficiency was not related to
functional hypoparathyroidism. Overall mean iPTH in VDD was high. Thirty seven subjects
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were identified with NCHP and primary hypoparathyroidism was observed in 2 subjects
only.
Statistically significant differences were seen in calcium, phosphorous, 25OHD and iPTH
levels among the different phenotypes while significant difference was not found in alkaline
phosphatase and magnesium levels (table 2).
Identification of Primary Hyperparathyroidism using maxPTH Nomogram:
The maxPTH nomogram was applied in subjects grouped in PHP, NCHP and hypercalcemia
with inappropriately normal PTH to identify subject specific upper limit of PTH on the basis
of age, calcium and 25OHD, as shown in table 3. All subjects with PHP and NCHP had
higher PTH levels than calculated maxPTH. In subjects of hypercalcemia with
inappropriately normal PTH, 6 had PTH < maxPTH showing normal PTH response to
hypercalcemia and 2 had PTH = maxPTH, while in only 2 subjects PTH > maxPTH but the
mean difference in PTH and maxPTH was 16.754.75 only.
Clinical Validation of Biochemical Phenotypes Tested for BHSP:
Clinical charts of 111 subjects were reviewed. Bone pain and myalgias present in 66%
(n=73) of subjects; were the major indications for screening with BHSP. Thirty two per cent
(n=35) subjects did not show any abnormality in the biochemical parameters.
NCHP, PHP and hypercalcemia with inappropriately normal iPTH levels was identified in 7,
2 and 3 subjects respectively. Symptoms of generalized myalgias and bone pains were
predictive of underlying PHP/NCHP. Four subjects; one each in PHP and hypercalcemia
with inappropriately normal PTH and two in NCHP; were identified with parathyroid
adenoma, 3 on Sestamibi scan of parathyroid glands and 1 on ultrasound neck; distribution is
shown in table 3. Three subjects with NCHP reviewed, were diagnosed with osteopenia
based on low bone density on DXA scan. A subject each of NCHP and hypercalcemia with
inappropriately normal PTH had renal stones.
VDD with sHPTH and functional hypoparathyroidism were identified in 22 and 42 subjects,
respectively. More than half of these subjects (n=42) had pain either in joints or generalized,
6 subjects had fractures, 6 had osteoporosis and 6 subjects had osteopenia identified on DXA
scanning. Proximal myopathy was present in 7 subjects. History of having renal stone was
identified in one subject.
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2016 AACE.
DISCUSSION:
Our data demonstrates that BHSP helps identify parathyroid gland dysfunction. Phenotypes
of PHP classified on biochemical cutoffs were validated by maxPTH nomogram and further
correlated with clinical presentation. According to guidelines by Endocrine Society on PHP;
repeat measurement of iPTH and calcium is required for confirmation of PHP (9). Since ours
was a retrospective analysis, we used a multidimensional nomogram to estimate maxPTH for
differentiating between normal and disease phenotypes. This approach enhanced the
diagnostic accuracy in subjects with atypical biochemical findings.
Awareness of biochemical phenotypes of PHP may facilitate earlier diagnosis. With
increased recognition of these phenotypes, we anticipate the prevalence of
hyperparathyroidism to increase beyond what is currently reported in literature in our
population, where every symptom of bone pain is currently linked to vitamin D deficiency.
This also has implication for management of VDD.
The most common MBD in our subjects is VDD either with sHPTH or functional
hypoparathyroidism. The first recognition of functional hypoparathroidism as a distinct
entity was described by RK Rude in 1976 (10). This was later used by Sahota et al and
Amouzougan et al to describe subjects presenting with hypovitaminosis D but with normal
PTH levels (11, 12). However, there is debate to recognize it as a distinct entity as vitamin D
is not directly regulating PTH secretion rather it is affected by calcium and phosphorus levels
(13).
While understanding this entity one should bear in mind that functional hypoparathyroidism
is not a type of primary hypoparathyroidism at all (which presents with hypocalcemia and
hypoparathyroidism), rather just vitamin D deficiency without secondarily increased PTH
secretion but with robust calcium absorption (12). In this dataset only 15 subjects with
functional hypothyroidism had hypocalcemia while the rest had normal calcium levels.
This pattern of PTH response has been frequently observed in our patients (personal
observation) and also reported in previous studies from our Centre in healthy volunteers and
in community dwelling females (2, 3). The same findings have been reported from India in a
retrospective review of laboratory database (14). Similar to the findings reported by
Subramanian et al magnesium deficiency, which is considered an important factor for
functional hypoparathyroidism; did not relate with the blunted response of parathyroid gland
in VDD in subjects studied in present dataset. As all the samples were collected in fasting
state therefore, circadian variation as a cause of blunted response of iPTH was also ruled out
(15).
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2016 AACE.
NCHP is recognized as the next frequent PTH abnormality (8.5%) in this study. Subjects
grouped as NCHP, showed higher measured iPTH levels than calculated maxPTH using PTH
nomogram of Harvey et al (8) indicating altered secretion. High prevalence of bone pains,
myalgias, osteopenia, and osteoporosis were identified on chart reviews in NCHP.
Although NCHP has long been recognized as a phenotype of PHP; little is known about its
epidemiology or natural history. In 2013 NCHP was reported for the first time among
community-dwelling individuals by screening of unselected, non-referral populations from
subjects enrolled in Osteoporosis in Men & Dallas Heart Study (16). NCHP can be easily
missed if only serum calcium or PTH is performed or both are performed but on separate
occasions (12-15). Simultaneous screening with multiple biochemical markers including
creatinine and 25OHD is required to diagnose this condition (17).
Hypercalcemia with inappropriately normal iPTH was observed in 10 subjects. The
measured iPTH was lower than the calculated maxPTH in 8 subjects, indicating normal
response of PTH to hypercalcemia. Two patients had high measured iPTH and on chart
review; one of them was identified with parathyroid adenoma on Sestamibi scan and renal
stone. The literature on this manifestation of PHP is scant and consists of mainly case
reports. Patients were easily missed but with increasing awareness more patients are now
being diagnosed and referred for surgical evaluation (18). Recently a systematic analysis of
the largest cohort of hypercalcemia with inappropriately normal PTH has been published.
The term Normohormonal primary hyperparathyroidism has been used (NHPHP) for the
phenotype (19).
Lundgren et al revisited PHP in menopausal women with serum calcium in the upper normal
range (10.0 mg/dl or 2.5mmol/l) 8 years after (2002) population based screening in 19911992 in Sweden. He identified 2.1% (109 out of total 5202) post-menopausal women with
hyperparathyroidism, and 66% of them exhibited normocalcemia (4). Reevaluation of 99
women with NCHP eight years after screening identified 48 women who developed PHP (5).
Based on this and similar findings, NCHP is considered as a subclinical condition, in which
PTH levels are elevated first but serum calcium remains normal; followed by the
development of frank hypercalcemia in some cases. Hence it is important to understand that
NCHP not an indolent condition.
Patients overall health should be critically reviewed for presence of consequences of PHP,
with follow-up and monitoring by biochemical testing at multiple time points. Malignancy
should be excluded as the cause of hypercalcemia. An ultrasound examination and a
Sestamibi scan should be performed. Positive localization provides more evidence in support
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2016 AACE.
of the diagnosis. At the same time, patients should be extensively counseled regarding the
potential benefit of halting the progression of the disease with surgery, risks of surgery, and
the alternative of observation. The patient should also be counseled regarding the possibility
that the parathyroid glands may be found to be normal at surgery.
This BHSP can be performed for routine health screenings or as a preliminary screening tool
for identifying PTH related disorders for those at high risk of MBDs, such as elderly, postmenopausal women, patients with CKD, thyroid disorders, thalassemia, multiple myeloma,
inflammatory bowels disease, rheumatological diseases, metastatic cancers, Pagets diseases,
bone malignancies, rheumatoid arthritis and other connective tissue disorders. By collecting
samples for all analytes at the same time; changes due to pre-analytical variables are
eliminated. It can be helpful for at least yearly screening of high risk population for MBDs
(20-25).
CONCLUSION:
Parathyroid hormone related disorders are not rare and have potential impact on bone health.
Whilst plasma iPTH can identify abnormal levels, full characterization of the type of
hyperparathyroidism requires evaluation of the other parameters included in the BHSP.
BHSP provides early diagnosis and facilitates management of such diseases, especially in
when the world is facing epidemic of VDD. It is therefore desirable to popularize this Test
Panels use amongst physicians especially geriatricians, internists, endocrinologists,
orthopedic surgeons and rheumatologists, in parts of the world with extant VDD.
DOI:10.4158/EP161206.OR
2016 AACE.
COMPETING INTERESTS:
All authors have no competing interests.
AUTHORS CONTRIBUTIONS:
HM: Design of study, acquisition of data, analysis and manuscript writing.
AHK: Conception and design of study, Review and revising manuscript critically for
intellectual content
MR: Conception and design of study, acquisition of data and manuscript review.
HK: Acquisition of data and manuscript review.
JT: Review and revising manuscript critically for intellectual content
All authors read and approved the final manuscript.
DOI:10.4158/EP161206.OR
2016 AACE.
REFERENCES:
1.
Fahim F. The magnitude of low bone mineral [corrected] density in middle and old
Dar FJ, Iqbal R, Ghani F, Siddiqui I, Khan AH. Bone health status of
Khan AH, Iqbal R, Naureen G, Dar FJ, Ahmed FN. Prevalence of vitamin D
screening for primary hyperparathyroidism with serum calcium and parathyroid hormone
values in menopausal women. Surgery. 1997;121:287-94.
5.
in menopausal women with serum calcium in the upper normal range at population-based
screening 8 years ago. World J Surg. 2002;26:931-6.
6.
Boonen
S,
Vanderschueren
D,
Pelemans
W,
Bouillon
R.
Primary
an elderly population in primary care for primary hyperparathyroidism. Scand J Prim Health
Care. 1992;10:192-7.
8.
9.
Bilezikian JP, Khan AA, Potts Jr JT. Guidelines for the management of
Rude RK, Oldham SB, Singer FR. Functional hypoparathyroidism and parathyroid
25(OH)D3 levels: review of parathyroid hormone regulation. Joint Bone Spine. 2012;79:529;
author reply 30.
14.
DOI:10.4158/EP161206.OR
2016 AACE.
16.
Wallace LB, Parikh RT, Ross LV, et al. The phenotype of primary
hyperparathyroidism with normal parathyroid hormone levels: how low can parathyroid
hormone go? Surgery. 2011;150:1102-12.
20.
Martin KJ, Gonzalez EA. Metabolic bone disease in chronic kidney disease. J Am
Jensen CE, Tuck SM, Agnew JE, et al. High prevalence of low bone mass in
Haidar R, Musallam KM, Taher AT. Bone disease and skeletal complications in
25.
the detection and monitoring of metastatic bone disease: What do we know and what
questions need answers? Cancer Metastasis Rev. 2006;25:659-68.
DOI:10.4158/EP161206.OR
2016 AACE.
Figure 1: Consort Diagram Showing the Selection and Distribution of Subjects Tested for
BHSP at AKUH Clinical Laboratories.
BHSP performed January 2011 to December 2013
n = 548
Data Collection and Analysis
Medical records
review
Classification of Parathyroid
Disorders
Hypercalcemia with
Inappropriately normal PTH
n=10
Primary
Hypoparathyroidism
n=2
sHPTH
n=88
n=22
n=3
n=2
Functional
Hypoparathyroidism
n=194
NCHP
n=37
PHP
n=5
n=7
n=0
n=42
Figure 2: Distribution of Subjects Tested for BHSP into Clinical Phenotypes of Parathyroid
Hormone Disorders based on Calcium and iPTH (n=340)
Reference lines on X axis represent upper and lower cut off for PTH (16 & 87 ng/ml) while on Y
axis are cutoffs for Ca (8.6 & 10.2 mg/dl) and each data point is represented by a study subject
tested by bone health profile
Table 1: Biochemical Characteristics of Subjects Tested with BHSP from January 2011 to December 2013 at AKUH Clinical
Laboratories (n = 534)
Analytes
Mean SD
91.8137.9
Vitamin D (25OHD)
(ng/ml)
Corrected Calcium
(Ca)
8.6-10.2 mg/dl
Albumin (Alb)
3.5-5.2 g/dl
Phosphorus (Phos)
2.5-4.5 mg/dl
Alkaline Phosphatase
(ALP) 45-129 IU/l
Magnesium (Mg)
1.6-2.6 mg/dl
Creatinine (Cr)
Female 0.6-1.2mg/dl
Male 0.8-1.3 mg/dl
21.518.3
9.280.78
4.30.4
3.50.8
103.879.5
2.20.3
0.90.8
Hyper/Hypofunctioning
States
High iPTH (>87)
Low iPTH (<16)
Frequency (%)
MeanSD
150 (28.0)
25 (4.6)
177223
7.95
Deficiency (<20)
318 (59.5)
11.24.3
Insufficiency ( 20-30)
109 (20.4)
242.8
Optimal (>30)
7R[LFLW\
106 (19.8)
01 (0.1)
4920
High Ca (>10.2)
20 (3.9)
10.60.59
Low Ca (<8.6)
High Alb (>5.2)
Low Alb (<3.5)
High Phos (>4.5)
Low Phos (<2.4)
High ALP (>129)
Low ALP (<45 )
High Mg (>2.6 )
Low Mg (<1.6 )
45.9 (8.4)
4 (0.7)
15 (0.9)
33 (6.1)
19 (3.5)
66 (12.3)
7 (1.3)
24 (4.4)
4 (0.7)
High Cr
8.30.3
30.4
5.30.05
5.41
2.20.2
228139
394.7
2.90.4
1.40.2
Male (>1.3)
23 (4.3)
2.12
Female(>1.2)
14 (2.6)
3.52.1
The data is presented as the frequency and mean levels of total, high and low results of all analytes.
Table 2: Frequency and Mean Blood Levels of Biochemical Parameters in BHSP for Subjects categorized into Clinical Groups
of Parathyroid Hormone Disorders (n=340)
iPTH
25OHD
Ca
Phos
ALP
Mg
pg/ml
ng/ml
mg/dl
mg/dl
IU/l
mg/dl
5 (1)
9741.1
3727
10.60.3
3.40.5
8849
2.20.2
10 (2)
4311
3219
10.40.11
3.70.7
175210
2.20.2
37 (8.5)
12646
39.619
9.20.39
3.30.7
113110
2.20.2
88 (17.7)
170203
11.76.2
90.6
3.61
10155
2.20.3
Functional Hypoparathyroidism
194 (39)
5621
124.3
9.30.5
3.40.6
10272
2.20.24
Hypoparathyroidism
2 (0.4)
9.48.9
131.27
5.24.9
4.10.6
632
2.40.1
p-value
0.00
0.00
0.00
0.01
0.83
0.22
Parathyroid Gland
Abnormalities
Primary Hyperparathyroidism
Hypercalcemia with
inappropriately normal iPTH
Normocalcemic
Hyperparathyroidism
Secondary
Hyperparathyroidism
n(%)
Table 3: Maximum Estimated PTH of Patients with Primary Hyperparathyroidism, Normocalcemic Hyperparathyroidism,
and Hypercalcemia with Inappropriately Normal PTH using PTH nomogram.
Parathyroid Gland
Abnormalities
Measured
PTH
pg/mL
Calculated
maxPTH
Frequency of
subjects with PTH
> maxPTH
Primary
Hyperparathyroidism
9741.1
5412
Hypercalcemia with
inappropriately normal
iPTH
4311
5111
Normocalcemic
Hyperparathyroidism
12646
5612
37
Clinical Diagnosis
Adenoma
Fracture
Adenoma &
Renal stones
Adenoma
Osteopenia
Renal stones
The maxPTH was calculated using Harvey et al PTH nomogram {120 - (6 calcium) - (0.5 25OHD) + (0.25 age)}. Results are
presented as mean standard deviation, and number (percentages).