Investigations
1st investigations to order
serum calcium
Test
If elevated, suggests disease. If high-normal and high suspicion, should be rechecked on separate day after fast. Diagnosis of PHPT requires elevated serum calcium, inappropriately unsuppressed serum intact PTH levels, and a normal or raised urinary calcium in the presence of normal kidney function. Patients with normocalcaemic PHPT have normal serum and ionised calcium levels.[2] Fasting and avoiding venous stasis in blood draw will aid in accuracy. Also if taking a thiazide diuretic, this medicine should be stopped at least 2 weeks before a blood draw. When testing for serum intact PTH level, should repeat simultaneous calcium level.
Result
from high-normal to raised
serum intact PTH with immunoradiometric or immunochemical assay
Test
The diagnosis of PHPT, along with repeated elevated serum calcium, is confirmed with an inappropriate elevation in serum intact PTH. If calcium is high, and the feedback loop is intact, PTH should be low. If instead PTH is high, then it is inappropriately elevated and the diagnosis of PHPT is secured so long as the urinary calcium is not low (instead suggestive of familial hypocalciuric hypercalcaemia). When testing for serum intact PTH level, should repeat simultaneous calcium level.
The diagnosis of PHPT has been greatly facilitated by the development of immunometric 'sandwich' assays.[56] The assay uses a pair of antibodies that recognise different regions of PTH. One of these antibodies, preferentially monoclonal, is immobilised, whereas a polyclonal antiserum with greater affinity is labelled with radio-iodine or chemiluminescence. Because of the 2, the 'sandwich' assay is more sensitive than either test alone. The immunometric assay is specific and sensitive for serum intact PTH. The process is fast and the analysis can be done in 15 to 30 minutes.
Result
from high-normal to elevated
Investigations to consider
25-hydroxyvitamin D level
Test
Vitamin D deficiency and PHPT frequently co-exist. However, a low vitamin D may artificially elevate the PTH level in patients without PHPT and mislead the diagnosis.[29]
Result
may be low
serum alkaline phosphatase
Test
Patients with elevated alkaline phosphatase with other normal liver enzymes have high turnover bone disease and are susceptible to post-parathyroidectomy hypocalcaemia.
Result
may be raised
serum phosphorus
Test
Concomitant electrolyte shifts occur typically as a result of multiple endocrine neoplasia 1 or 2.
Result
low or low normal
24-hour urinary calcium
Test
In patients with presumed hyperparathyroidism, urinary calcium measurements should be performed.[2] Hypercalciuria is a marker of renal involvement in PHPT. International PHPT guidelines recommend a urinary calcium level of >250 mg/day in women; >300 mg/day in men as an indication for parathyroidectomy, although the UK National Institute for Health and Care Excellence do not recommend referral for surgery based on urinary calcium measurements.[1][30]
Familial hypocalciuric hypercalcaemia (FHH) can often be differentiated from PHPT by measuring the renal calcium to creatinine excretion ratio, which generally is much lower in patients with FHH than in patients with PHPT due to other causes. FHH should be considered in patients with long-standing hypercalcaemia with urinary calcium levels <100 mg/day, and a calcium to creatinine clearance ratio less than 0.01.[1]
Result
high or normal in PHPT; low in familial hypocalciuric hypercalcaemia
dual-energy x-ray absorptiometry (DXA) scan
Test
Once diagnosis of PHPT is confirmed, a DXA scan should be completed to assess progression of disease in 3 sites: lumbar spine, hip, and forearm.[2]
This is a non-invasive test assessing risk of fractures. Two values are given: young normal and age-matched. Young normal (T-score) compares bone mineral density (BMD) versus the optimal density of a 30- to 40-year-old healthy adult and then assesses the fracture risk. Age-matched (Z-score) compares the BMD to the expected result at the patient's age and size; it may be useful for evaluation of pre-menopausal women or men aged under 50 years.
Result
T-score: -1 to +1 = normal; -1 to -2.5 = osteopenia; < -2.5 = osteoporosis
trabecular bone score
Test
The trabecular bone score (TBS) is an imaging technology adapted directly from the DXA image of the lumbar spine that provides information about skeletal microstructure. Several studies have assessed TBS in patients with PHPT, and their results suggest that TBS may identify trabecular abnormalities not captured by lumbar spine bone mineral density (BMD) in PHPT.[41]
Result
low TBS value correlates with weaker skeletal texture (a reflection of degraded microarchitecture)
neck ultrasound
Test
Not required for diagnosis, but important for localisation of disease in planning surgery. Neck ultrasonography will also assess for concomitant thyroid disease.[2]
Combining tests is more effective than any one test alone.
Result
may be positive for solitary adenoma or multi-gland involvement
technetium-99m sestamibi scanning
Test
Not required for diagnosis, but important for localisation of disease in planning surgery.
Combining tests is more effective than any one test alone.
Result
may be positive for solitary adenoma or multi-gland involvement
single photon emission CT (SPECT)
Test
Not required for diagnosis, but important for localisation of disease in planning surgery.
Combining tests is more effective than any one test alone. Technetium-99m sestamibi SPECT/CT has a sensitivity of 88%.[36]
Result
may be positive for solitary adenoma or multi-gland involvement
CT neck
Test
Not required for diagnosis, but important for localisation of disease in planning surgery. A protocol with 2 contrast phases seems to offer a good balance of acceptable sensitivity (sensitivity 76% [95% CI 71% to 87%]) with limitation of radiation exposure, compared with protocols with 1 or 3 contrast phases (sensitivity of 71% [95% CI 61% to 80%] and 80% [95% CI 74% to 86%], respectively).[57]
Combining tests is more effective than any one test alone.
Result
may be positive for solitary adenoma or multi-gland involvement
4-Dimensional (4D) CT neck
Test
Not required for diagnosis, but important for localisation of disease in planning surgery. The 4D refers to time. It appears to have at least a similar diagnostic performance compared to tomographic parathyroid scintigraphy and is useful in the case of negative previous imaging studies or in patients with distorted neck anatomy.[31]
Combining tests is more effective than any one test alone.
Result
may be positive for solitary adenoma or multi-gland involvement
MRI neck
Test
Not required for diagnosis, but important for localisation of disease in planning surgery. Less commonly used except in certain circumstances (e.g., pregnancy).[2]
Combining tests is more effective than any one test alone.
Result
may be positive for solitary adenoma or multi-gland involvement
Emerging tests
radiolabelled choline PET
Test
A number of studies have examined the role of radiolabelled 11C- or 18F-choline PET, which can be combined with CT (PET/CT) or magnetic resonance imaging (PET/MRI), for the detection of hyperfunctioning parathyroid glands in patients with primary hyperparathyroidism with positive results.[37][38][39][40] However, large multicentre and cost-effectiveness studies are needed to clarify the role of this imaging in a clinical setting.
Result
may be positive for solitary adenoma or multi-gland involvement
machine learning to identify primary hyperparathyroidism
Test
Machine learning involves applying a collection of methods that allow a computer to learn rules from known/existing data sets to make predictions. Research has demonstrated a way to diagnose PHPT without a knowledge of calcium or PTH values.[42] Some researchers are exploring its use to distinguish between multigland disease and single adenomas preoperatively, thereby optimising operative planning.[43]
Result
predicts likelihood of diagnosis of PHPT; distinguish multi-gland disease
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