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J. D. Merrill et al.
Second- andThird-Generation Assays
Immunometric assays for PTH are referred to as second- and third-generation
assays but may also be referred to as rst- and second-generation immunometric
assays. They are more sensitive and specic than the older radioimmunoassays [47].
Second-generation assays are also known as intact PTH assays and rely on the use
of two antibodies. The traditional second-generation assays measure both intact
PTH (1–84) and cross-react with large carboxy-terminal PTH fragments [7]. The
third-generation assays (whole, bioactive, or biointact PTH assays) are more specic, because they use a labeled antibody directed at PTH (1–4), detect only PTH
(1–84), and have less cross-reactivity with C-terminal fragments. These assays do
react with a post-translational modied form of PTH, known as non-truncated
amino-terminal PTH (N-PTH), representing up to 10% of PTH in normal individuals and 15% of patients with renal failure [7]. Second- and third-generation assays
for PTH are equally helpful in diagnosing PHPT [6, 7]. The sensitivity of these
assays for detecting PHPT ranges from 73% to 97% [7].
As measured by second- and third-generation assays, PTH concentrations are
inuenced by several conditions that interfere with the establishment of a reference interval [48]. PTH elevations have been described in older individuals,
especially women, black people, people with lower calcium intake, and obese
people [20]. Furthermore, 25-hydroxyvitamin D (vitamin D) deciency frequently drives PTH elevation, and there is not yet a consensus on the optimal
reference range for vitamin D [49–51]. An optimal reference interval for PTH in
vitamin D replete individuals has yet to be established for second- and thirdgeneration PTH assays using large population cohorts [7, 20]. The upper limit of
the PTH reference interval is lower in individuals with vitamin D levels >20ng/
mL (50nmol/L).
In the classic presentation of PHPT, PTH is high or inappropriately normal in the
setting of hypercalcemia. When PTH is within the reference range in PHPT, it is
more likely to be in the upper end of the reference range. In one large case series,
only 1% of patients with PHPT had PTH levels within the lower half of the reference range [52]. PTH that is not suppressed in the setting of hypercalcemia is compatible with PHPT [7].
Measurement ofRenal Function
Glomerular ltration rate (GFR) must be higher than 60ml/min to substantiate the
diagnosis of normocalcemic PHPT [39]. All glands are affected to a variable degree
in patients with chronic renal failure. Surgical intervention requires inspection of all
glands; therefore, localization is of limited value.
2 Clinical, Laboratory, andRadiological Diagnosis ofHyperparathyroidism
21
Serum Phosphate
Measurement of serum phosphate is recommended in the evaluation of PHPT [6].
In PHPT, serum phosphate levels may be low or low normal due to the phosphaturic
effects of PTH [53]. In one series, there was no difference in serum phosphate levels
between patients with and those without PHPT [54].
25-Hydroxyvitamin D (Vitamin D)
The vitamin D level should be measured in all patients evaluated for PHPT [6, 7,
20]. People from the same geographic region with PHPT appear to be more likely
to have vitamin D deciency than people without PHPT [27, 55]. The most likely
cause of abnormally low vitamin D in PHPT is an increased metabolic clearance
rate (24 hydroxylation) induced by calcitriol and possibly PTH [56]. After parathyroidectomy, vitamin D returns to concentrations found in the normal population [57].
There are consequences to low vitamin D levels in PHPT.PHPT appears to be
more severe in patients with vitamin D deciency, and low vitamin D levels are
associated with larger parathyroid adenoma size [27, 58]. There is evidence that
replacement of vitamin D to a level higher than 20ng/mL in patients with PHPT and
vitamin D insufciency is associated with a decline in PTH as well as other markers
of bone turnover, including alkaline phosphatase and urinary N-telopeptide [59, 60].
The diagnostic accuracy for PHPT is improved in a vitamin D replete population
[61]. Despite this, the denition of normal vitamin D remains controversial. The
Institute of Medicine (IOM) recommends a threshold for vitamin D of 20ng/mL
(50nmol/L) [49, 50], but the Endocrine Society recommends a threshold of 30ng/
mL (75 nmol/L) [51]. Preoperative vitamin D deciency is predictive of hungry
bone syndrome postoperatively, and it is recommended that vitamin D be supplemented to a level greater than 20mg/mL prior to parathyroidectomy [7, 62]. This
should be done cautiously with low doses of up to 2000 units of cholecalciferol daily.
24-Hour Urine Calcium
A 24-hour urinalysis measuring urine creatinine and calcium should be performed
to assess the urinary calcium excretion. This is important to evaluate the risk for
developing nephrolithiasis and rule out other diagnostic considerations. This testing
is ideally performed in the outpatient setting while the patient adheres to their regular diet and activities. Instructions for collecting a 24-hour urine sample vary by the
laboratory, but typically the patient’s rst voided urine is discarded [63]. Then, all
22
subsequent urine voided for the next 24h, including the next morning’s rst voided
urine, is collected in containers provided by the laboratory. A 24-hour urine collection can be inconvenient and difcult for some patients; therefore, it can be helpful
to assess the accuracy of the urine collection. Urinary creatinine excretion is used to
measure the adequacy of a 24-hour urine collection. Creatinine is a byproduct of
muscle metabolism, so the excretion of creatinine is stable based on muscle mass.
The average daily excretion of creatinine is 18–24mg/kg for males and 15–20mg/
kg for females. A lower than expected creatinine excretion suggests an incomplete
collection [63]. A urinary calcium to creatinine clearance ratio (UCCR) should be
calculated as follows:
J. D. Merrill et al.
Urinary calcium to creatinine
clea
rrance ratio
Patients with a UCCR less than 0.01 should be evaluated for familial hypocalciuric hypercalcemia [6, 7].
hour urine calcium serum
serum calcium hour urine creatinine
24
24
creatinine
Biochemical Stone Risk Analysis
If a patient demonstrates marked hypercalciuria with 400mg/day of urinary calcium excretion on the 24-hour urine calcium study, then a urinary biochemical stone
risk prole should be obtained. This is available through many commercial laboratories. Patients with PHPT that experienced nephrolithiasis had higher urinary calcium excretion and 24-hour urine oxalate levels than patients that did not form
stones. Hypercalciuria and relatively high oxaluria were associated with the stone
formation in PHPT [64].
Markers ofBone Turnover
Increased bone turnover is characteristic of PHPT.Biochemical markers of bone
formation, such as osteocalcin and alkaline phosphatase, and markers of bone
resorption, such as deoxypyridinoline, N-telopeptide (NTX), and C-telopeptide
(CTX), are typically markedly elevated in severe PHPT [24]. Patients with high
bone turnover markers are more likely to have the skeletal disease. Alkaline phosphatase is signicantly elevated in almost all patients with osteitis brosis cystica
[65]. After parathyroidectomy, bone resorption markers rapidly improve, followed
by a more gradual reduction in bone formation markers [66].
2 Clinical, Laboratory, andRadiological Diagnosis ofHyperparathyroidism
23
Tests ofLow Clinical Utility
1,25-Dihydroxy Vitamin D (Calcitriol)
When measured in PHPT, calcitriol levels are typically at the upper limit of normal
or occasionally mildly elevated [54]. High concentrations of calcitriol are associated with higher 24-hour urine calcium excretion and lower BMD [67]. Routine
measurement of this active metabolite is not recommended since the additional
information does not change management [6].
Laboratory Interpretation andDifferential Diagnosis
Secondary Hyperparathyroidism
Secondary hyperparathyroidism (SHPT) is characterized by an increase in PTH that
is an appropriate response to a stimulus. By denition, the serum calcium is normal,
and the PTH is elevated. SHPT must be ruled out before a diagnosis of normocalcemic PHPT can be made.
Renal dysfunction can cause secondary elevation of PTH in normocalcemic individuals. PTH begins to rise when estimated GRF (eGFR) falls below 60mL/min
[7]. Long-standing chronic kidney disease is associated with several metabolic disturbances that lead to increased PTH secretion, including hyperphosphatemia, calcitriol deciency, and hypocalcemia [22].
Vitamin D deciency, increased urinary calcium excretion, and gastrointestinal
malabsorption of calcium are also potential causes of SHPT. Vitamin D insufciency or deciency may cause secondary elevation of PTH in the setting of normal
calcium concentrations. Vitamin D should be replaced until a level>30ng/mL is
achieved in patients with vitamin D deciency and elevated PTH level before a
diagnosis of normocalcemic hyperparathyroidism can be made [39]. Notably, it
may take 6–12months for PTH to decrease after vitamin D is replaced. Patients
thought to have normocalcemic PHPT can develop hypercalcemia when
25-hydroxyvitamin D is increased above 30ng/mL (75nmol/L), thus making the
diagnosis of hypercalcemic PHPT that was masked by 25-hydroxyvitamin D deciency [7].
Hypercalciuria as a primary renal abnormality can be associated with normal
serum calcium and a secondary increase in PTH levels [68].
Decient calcium intake or gastrointestinal disorders associated with calcium
malabsorption can also cause secondary elevations in PTH [69, 70]. These individu-
als will typically have a low-normal serum calcium concentration, vitamin D deciency, and low urinary calcium excretion [39]. In general, malabsorption syndromes
24
J. D. Merrill et al.
are clinically obvious. However, gluten enteropathy can cause calcium malabsorption in individuals with no symptoms of gastrointestinal disease.
A wide variety of secondary causes of PTH elevation can be mistaken for PHPT
and especially normocalcemic PHPT.A thorough laboratory evaluation as described
above is required to exclude these causes.
Medication Effects
The use of several medications is associated with elevated PTH, hypercalcemia, or
both. The antiresorptive medications used to treat osteoporosis are associated with
PTH elevation. Bisphosphonate treatment causes an early reduction in bone resorption. This induces a decrease in serum calcium, which leads to an increase in PTH
[71]. This PTH elevation is a response to the change in serum calcium level and can
occur even in the setting of hypercalcemia. The reduction in serum calcium occurs
within days to weeks of the initiation of bisphosphonate treatment, earlier with
intravenous therapy than with oral treatment. These changes may persist for weeks
to months following the initiation of treatment [71]. Similarly, denosumab use
causes PTH concentrations to be elevated for 3months of the 6 months between
doses [72].
Lithium can cause both transient and persistent hypercalcemia. Lithium decreases
the sensitivity of the parathyroid gland to circulating calcium and lowers urinary
calcium excretion [73]. This results in an increased calcium level and PTH in a
majority of patients. This ultimately leads to parathyroid hyperplasia. After cessation of lithium, the patient should be monitored for 2–4weeks to determine whether
calcium metabolism has normalized [73]. If practical in light of any psychiatric
comorbidities, discontinuation of lithium should be considered before making the
diagnosis of PHPT [7].
Thiazide diuretics are some of the most frequently prescribed antihypertensive
agents and are commonly associated with hypercalcemia. Thiazides exert their antihypertensive effects through an increase in sodium excretion by blocking the
thiazide- sensitive NaCl transporter in the distal convoluted tubule, which causes
increased renal tubular reabsorption of calcium and reduced urinary calcium excretion [74]. Thiazide-associated hypercalcemia occurs after an average of 5.2years of
treatment, and severe hypercalcemia is not usually observed despite continuation of
thiazide [75]. About 20% of patients, who develop hypercalcemia while taking thiazide diuretics, are later found to have hyperparathyroidism, while hypercalcemia
resolves in another 30% [75]. Prior to the diagnosis of PHPT, and especially in
normocalcemic PHPT, thiazide diuretics should be discontinued, and diagnostic
testing should be repeated when the patient has been off of thiazide treatment for
several weeks [7].
2 Clinical, Laboratory, andRadiological Diagnosis ofHyperparathyroidism
25
Tertiary Hyperparathyroidism
Tertiary hyperparathyroidism (THPT) is characterized by excessive secretion of
PTH causing hypercalcemia after long-standing SHPT. This typically occurs in
individuals with chronic kidney disease and may occur after renal transplant. In
these patients, long-standing hypocalcemia and hyperphosphatemia cause an
increase in the number of cells secreting PTH [76]. The size of the parathyroid
glands progressively increases as chronic kidney disease worsens and the glands
may become autonomously functioning. These patients are most often identied by
the persistence of hyperparathyroidism with hypercalcemia after renal transplantation [22].
Other rare causes of THPT include X-linked hypophosphatemic rickets, adultonset (autosomal dominant) hypophosphatemic rickets, and oncogenic osteomalacia [22]. These diseases are typically treated chronically with high doses of oral
phosphate. The increased phosphate transiently decreases ionized calcium and
decreases the production of calcitriol. This can lead to increased secretion of PTH,
which can become autonomous and eventually be associated with frank hypercalcemia and inappropriately elevated PTH [77–81].
Symptoms and signs of THPT may be similar to PHPT and are attributed to the
level of PTH or degree of hypercalcemia. These symptoms can include bone pain,
decreased bone mineral density, fractures, nephrolithiasis, soft tissue or vascular
calcications, muscle weakness, mental status changes, and impaired graft function
in transplant patients [82]. There are no evidenced-based guidelines for when and
how to treat THPT.Still, many clinicians intervene when the patient has long-term
sustained hypercalcemia with PTH greater than nine times the upper limit of normal
[22]. The decision to pursue parathyroidectomy should be deferred to at least 1year
after renal transplant. Subtotal parathyroidectomy is the treatment of choice because
it decreases the risk of hypocalcemia and hyperphosphatemia postoperatively compared to total parathyroidectomy [83].
Familial Hypocalciuric Hypercalcemia
The key differential diagnosis in a patient with hypercalcemia and either a high PTH
or PTH in the upper half of the reference interval is between PHPT and familial
hypocalciuric hypercalcemia (FHH) [7]. FHH has been misdiagnosed as PHPT,
because a signicant number of these patients will have elevated PTH levels [84].
To rule out FHH, it is essential to measure the urinary calcium to creatinine clearance ratio (UCCR) [7]. A UCCR less than 0.01 is typically consistent with FHH.One
caveat is that patients with vitamin D deciency, renal insufciency, or African
origins may have low UCCR [85, 86]. In these patients and patients with UCCR
between 0.01 and 0.02, genetic evaluation with mutational analysis for CaSR,
GNA11, and APS2S1 genes can identify patients with FHH1, FHH2, and FHH3,
respectively [87–89]. A UCCR greater than 0.02 is more consistent with a diagnosis
26
J. D. Merrill et al.
of PHPT [90]. FHH is generally considered a benign condition due to a different
calcium set point, and parathyroid surgery is not indicated in these patients. Although
calcimimetics such as cinacalcet have not been approved for the treatment of THPT,
a handful of small studies showed benet with the improvement of serum calcium
and a signicant decrease in PTH [91–93].
Autoimmune Hypocalciuric Hypercalcemia
Anti-CaSR autoantibodies have been described in a handful of patients with PTHdependent hypercalcemia. These patients tended to have decreased urinary calcium
excretion and other autoimmune disorders and had either previously normal serum
calcium levels or tested negative for the genetic mutations associated with FHH
[94]. These patients are found to have blocking antibodies against the
CaSR.Scant information is available to guide the diagnosis of this condition or the
treatment of the associated hypercalcemia. The hypercalcemia does not respond to
parathyroidectomy or bisphosphonate treatment but may respond to glucocorticoids
[94–96].
Pseudohypoparathyroidism
Pseudohypoparathyroidism refers to a group of heterogeneous disorders whose
common feature is renal resistance to PTH due to impaired activation of cAMPdependent pathways via the Gsα protein [97]. Patients with pseudohypoparathyroidism present with hypocalcemia, hyperphosphatemia, and secondary
hyperparathyroidism. They may have the physical ndings of Albright hereditary
osteodystrophy. Since PTH resistance only occurs in the kidney, these patients may
develop osteitis brosa cystica and other PTH-mediated bone diseases. In the setting of prolonged hypocalcemia, people with pseudohypoparathyroidism can
develop THPT requiring localization of the affected gland and potentially parathyroidectomy [98].
Genetic Evaluation forPrimary Hyperparathyroidism
PHPT may occur as a sporadic disorder, a familial disorder that is a nonsyndromic
isolated endocrinopathy, or a syndromic familial disorder. Syndromic forms of
PHPT occur in MEN syndromes type 1 to 4 and hyperparathyroidism-jaw tumor
syndrome. PHPT is the most common feature of MEN1 and occurs in approximately 90% of affected patients [99]. PHPT in patients with MEN1 occurs with an
equal male to female ratio, at an earlier age (25years compared to 55years) and a
more signicant reduction in bone mineral density than in the general population
[99–101]. It is helpful to know that the patient has a syndromic form of PHPT
2 Clinical, Laboratory, andRadiological Diagnosis ofHyperparathyroidism
during clinical evaluation, because all four parathyroid glands may be affected, and
imaging for localization is of little benet [14, 99]. Inspection of all glands is necessary during surgery, even if localization studies show a unilateral abnormality.
Genetic evaluation should be sought in a patient who presents with typical familial forms of PHPT.Family history should be obtained in all patients with PHPT to
determine whether rst-degree relatives are affected. Patients who are less than
45years old at the time of diagnosis [102] and have a multiglandular disease, parathyroid carcinoma, or atypical adenoma should be tested [7]. Mutational analysis
should include evaluation for MEN1; CaSR; APS2S1; GNA11; CDKN-1A,
CDKN-1B, CDKN-2B, and CDKN-2C; RET; and PTH in order of frequency of
occurrence [7]. Genetic testing should use DNA obtained from non-tumor cells,
including leukocytes, salivary cells, skin cells, or hair follicles, because DNA from
parathyroid adenomas may contain multiple mutations [103]. Genetic testing should
include informed consent from the patient with access to genetic counselors and
occur at accredited centers [99].
If a germline mutation is identied, the patient should be started on an appropriate routine clinical, biochemical, and radiological screening for other diseases.
First-degree relatives of a patient with a PHPT mutation should be identied and
offered genetic counseling and genetic testing [7]. If the rst-degree relative tests
are negative for the causative mutation, they require no further follow-up.
27
Imaging Evaluation
PHPT is a biochemical diagnosis and should not be diagnosed using imaging studies [6]. Instead, imaging should be used to guide surgical decision-making and to
localize abnormal glands.
Radiographic Findings ofHyperparathyroidism
Plain Radiography
The characteristic skeletal features of PHPT, as seen on plain radiographs, result
from increased osteoclastic activity and bone resorption. A wide range of imaging
ndings may be present, including a “salt and pepper” appearance of the skull,
tapering of the distal clavicle, subperiosteal resorption of the distal phalanges (typically bilateral and symmetric), bone cysts, and brown tumors (osteitis brosa cystica) [41]. Diffuse demineralization is often observed along with pathologic
fractures, typically in the long bones of the extremities [24]. The cortex of long
bones may be very thin and almost absent in some patients. Plain radiography is not
sensitive for detecting bone loss due to hyperparathyroidism. Approximately
20–30% of bone mass must be depleted before osteoporosis can be detected on
X-ray [104].
28
Age
T-score
J. D. Merrill et al.
Dual-Energy X-ray Absorptiometry
Since routine measurement of serum calcium became widespread, it is rare for
patients to have characteristic ndings of hyperparathyroidism on plain radiography; however, evidence of such is more commonly seen on dual-energy X-ray
absorptiometry (DEXA). This technique uses a fraction of the radiation dose of
plain radiography. It allows calculation of BMD values (g/cm2), which are compared against a reference population as T-scores or Z-scores [105, 106]. The BMD
at the femoral neck, total hip, and L1–L4 vertebra are typically measured.
Additionally, the distal 1/3 forearm BMD should be measured, if the hip or spine
cannot be interpreted in the setting of hyperparathyroidism and in patients whose
weight is over the limit of the DEXA table [107]. T-scores for the femoral neck and
total hip are calculated against a white female reference population ages 20–29years
from the National Health and Nutritional Examination Survey III database. The
device manufacturer database is used as the reference population for the lumbar
spine measurements [107]. Z-scores are calculated to compare the patient’ BMD
against an age-, sex-, and ethnicity-matched reference population. The use of
T-scores is preferred in postmenopausal women and men over age 50, while Z-scores
are used in other populations. T-scores of −2.5 or less at the femoral neck meet the
WHO international reference standard for osteoporosis.
PHPT has more catabolic impact on cortical bone than trabecular bone [31]. The
densitometric prole of PHPT is reduced BMD at the distal 1/3 forearm, since it is
composed primarily of cortical bone, while the lumbar spine shows relative preservation, as it is a predominantly trabecular site [11, 108]. DEXA of the distal 1/3
radius should be obtained in all patients with PHPT to evaluate for the catabolic
effects of PTH in cortical bones (Fig.2.2) [6]. In PHPT that is severe enough to
1.0
0.8
0.6
BMD
0.4
0.2
20 25 30 35 40 45 50 55 60 65 70 75 80 85
Fig. 2.2 DEXA scan in a 68-year-old female with primary hyperparathyroidism. Total T-score for
the radius was −3.2 (indicated by the crosshair symbol in the graph) consistent with osteoporosis.
(Image courtesy of Edgar Zamora, MD, Monteore Medical Center, Bronx, NY)
1/3 (Radius + Ulna)
–1.0
–2.5
2 Clinical, Laboratory, andRadiological Diagnosis ofHyperparathyroidism
29
cause osteitis brosa cystica, bone mineral density is often extremely low. In one
case series of these patients, the mean T-scores by DEXA were−4.42in the lumbar
spine, −5.58in the femoral neck, and−5.85in the distal 1/3 radius [65].
Vertebral Fracture Assessment by DEXA
Vertebral fracture assessment (VFA) can be performed in patients undergoing
DEXA at a fraction of the radiation dose of conventional radiography. VFA is indicated either in patients with a DEXA T-score of < −1.0 and one or more of the following conditions: (1) women ≥ age 70 or men ≥ age 80years, (2) historical height
loss greater than 4cm, (3) self-reported but undocumented prior vertebral fracture,
and (4) glucocorticoid therapy equivalent to ≥5mg of prednisone or equivalent per
day for 3months or longer [109]. The spatial resolution of DEXA is much lower
than that of plain radiography, and therefore, its utility for diagnosing mild vertebral
fractures is limited [110]. Additionally, patients with multiple fractures are more
easily identied than those with a single fracture [111]. In a systematic review, the
sensitivity and specicity of VFA by DEXA on a per-vertebra basis ranged from
70% to 93% and from 96% to 100%, respectively [112].
Trabecular Bone Score by DEXA
One limitation of DEXA is the lack of information on bone microstructure, which
is an essential determinant of bone strength. There is a signicant overlap in density
values between patients with and without fractures, and values in patients with
degenerative sclerosis may be artifactually increased [110]. Trabecular bone score
(TBS) is a post-processing technique based on textural analysis of grayscale pixel
variations that can be applied to DEXA scans, providing a complementary measure
of bone microarchitecture and strength. In essence, lower TBS values are associated
with decreased bone strength, and differences are detectable in vertebral bodies that
have similar densitometry values [113]. One large cohort study demonstrated that
TBS values were not signicantly affected by degenerative osteoarthrosis, as
opposed to DEXA, where they may be artifactually increased [114]. In patients with
PHPT, one study has correlated TBS values with parameters obtained from highresolution peripheral quantitative CT (HRpQCT), where the authors found a positive association with volumetric density, cortical thickness, whole bone stiffness,
trabecular number, and trabecular separation [115].
High-Resolution Peripheral Quantitative CT
HRpQCT is a three-dimensional imaging modality that permits noninvasive assessment of cortical and trabecular microarchitecture as well as volumetric mineral bone
density of the distal radius and tibia [24, 116]. HRpQCT allows imaging of the