Laboratory Studies
Serum biochemistry studies include the following:
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Parathyroid hormone (PTH) level using immunometric assays to detect the intact PTH molecule (PTH 1-84).
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Serum calcium, total or ionized calcium. Note that if the patient has hypoalbuminemia, the serum calcium level should be corrected for the albumin level, or serum ionized calcium level should be measured ( adjusted total Ca=measured total Ca +[0.8x(4.0- albumin)]). In primary hyperparathyroidism there are high levels of calcium and PTH, whereas in secondary disease, levels of calcium are within the reference range or low.
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Serum albumin
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Serum phosphorus. Phosphorus levels in primary hyperparathyroidism are in the low or low-normal range. In secondary hyperparathyroidism due to renal failure phosphorus serum levels are elevated because of the inability of the kidney to excrete phosphorus. In Vitamin D deficiency, serum phosphorus levels may be low.
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25 OH Vitamin D level should be determined and treated if deficient to differentiate primary from secondary hyperparathyroidism
Urine studies include the following:
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A calcium/creatinine ratio from a spot urine sample may be used as a screening test for hypercalciuria. Urinary calcium excretion is measured in a timed urine collection to determine fractional excretion of calcium. This will distinguish primary hyperparathyroidism from FHH since the former will usually present with hypercalciuria, while FHH is associated with a fractional excretion of calcium of less than 1%. There is however some overlap in urinary calcium excretion within these two entities. [18] Hypercalciuria in children is defined by a calcium excretion which is higher than an age appropriate Ca/creat ratio, or greater than 4mg/kg/day.
Biochemical markers of bone turnover include the following:
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Serum levels of osteocalcin or bone-specific alkaline phosphatase are elevated reflecting increased bone formation
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Serum C-telopeptide of type I collagen and Urinary N-telopeptide (NTx) are elevated because of increased bone resorption.
Genetic tests include the following:
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Genetic tests for familial forms of primary hyperparathyroidism are available and should be done to determine further work-up, management and genetic counseling. CASR mutation studies are recommended in cases suggestive of FHH or NHSHPT. MEN1, RET, CDKN1B and CDC73 in cases of MGD or those with a positive family history of endocrine neoplasia. [9]
Note that a case has been reported describing a 14-year-old girl with a parathyroid adenoma who presented with hypercalcemia, pancreatitis, and nephrolithiasis, yet had a low serum intact PTH level. [19] A turbo assay, however, showed very high PTH levels, as did a C-terminal assay. There was no mutation in the PTH gene sequence, which may well indicate that there was a post-translational modification of PTH not recognized by DNA sequencing. More than one assay may be required if there is biochemical evidence of hyperparathyroidism.
Imaging Studies
Imaging studies of the parathyroids to confirm the biochemical diagnosis of primary hyperparathyroidism
Sestamibi scanning paired with single-photon emission computerized tomography (SPECT)/CT to localize the parathyroid lesions prior to surgery is complementary with ultrasonography (US). Sestamibi scan was found to have an accuracy of 86% in a recent review of all studies to date in children, while the accuracy for US was 79% in the same review. In adult hyperparathyroidism, the largest review found a sensitivity of 88% for sestamibi scan and 75.5% for US. [2, 17] The sensitivity of both US and sestamibi scans was much lower for MGD (35 and 45% respectively) as well as for double adenomas (16 and 30% respectively) in the adult hyperparathyroidism review. Ectopic adenomas, mediastinal, intrathyroidal and intrathymic, accounted for 9.5%-12% in some of the larger pediatric series, leading to the lower sensitivity for US. [2, 8]
Complementary imaging studies to look at the effect of hyperparathyroidism on target organs
Bone densitometry, determined by dual energy x-ray absorptiometry (DEXA) is an areal or 2-dimensional measurement but can be followed longitudinally to evaluate the severity of the effect on bone and the effectiveness of therapy. Bone mineral density in the lumbar spine and whole body less head are expected to be low compared with age-related reference range values. In children with short stature these values must be adjusted for height.
Renal US is used to look for nephrocalcinosis and nephrolithiasis.
Skeletal radiographs may exhibit stigmata of hyperparathyroidism in relatively few cases are not need for the diagnosis of hyperparathyroidism. Cortical bone is primarily affected, as opposed to cancellous or trabecular bone.
Radiography may reveal the following:
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Multiple areas of subperiosteal bone resorption of the distal phalanges
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Tapering of the clavicles
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Brown tumors of the long bones and a salt-and-pepper appearance of the skull: These occur in less than 5% of US patients with primary disease.
Histologic Findings
In most cases of primary hyperparathyroidism, an adenoma involving only 1 of 4 glands is present. Less frequently, adenomas involve multiple glands, and parathyroid carcinoma is very rare. MGD involves hyperplasia of 2 or more glands.
All histologic findings have been described in adults. An adenoma is defined by shape, size, consistency and histology. Histological findings include decreased intracellular and stromal fat. [20]
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Normal parathyroid glands as seen during a thyroidectomy. The large arrow points to the superior parathyroid. The thinner arrow points to the inferior parathyroid. The forceps points toward the recurrent laryngeal nerve. The patient's head is toward the right.
Tables
Cause |
Gene |
OMIM |
1. Neonate/Infant |
||
|
||
- Familial hypocalciuric hypercalcemia |
Heterozygous inactivating CASR mutations |
145980 |
- Neonatal severe hyperparathyroidism |
Homozygous inactivating CASR mutations |
239200 |
|
||
- Maternal hypoparathyroidism |
||
- Maternal pseudohypoparathyroidism |
||
- Maternal Vitamin D deficiency |
||
2. Child/adolescent |
||
|
||
- Sporadic adenomas |
||
- Familial |
||
* Familial hypocalciuric hypercalcemia (FHH) |
CASR |
145980 |
* Multiple Endocrine Neoplasia type 1 (MEN1) |
MEN1 |
131100 |
* Multiple Endocrine Neoplasia type 2a |
RET |
171400 |
* Multiple Endocrine Neoplasia type 4 |
CDKN1B |
|
* Familial hyperparathyroidism jaw tumor syndrome (HRPT2) |
CDC73 | 145001 |
|
||
- Autoantibodies to the CASR |
||
|
||
- Renal failure/post renal transplant |
||
- Chronic hyperphosphatemia |
||
- Vitamin D deficiency |
||
* Nutritional |
||
* Malabsorption |
||
-Vitamin D dependent rickets type 1 VDDR1 |
CYP27B1 | 264700 |
|
|
|
- Vitamin D dependent rickets type 2 VDDR2 |
Vitamin D receptor | 277440 |
|
|
|
-Other causes of hypocalcemia |
||
Poor intake Drugs |
