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Diagnosis and differential diagnosis of hypercalcemia
Diagnosis of primary, secondary, and tertiary hyperparathyroidism
Diagnosis of hypoparathyroidism
Monitoring end-stage renal failure patients for possible renal osteodystrophy
Parathyroid hormone (PTH) is produced and secreted by the parathyroid glands, which are located along the posterior aspect of the thyroid gland. The hormone is synthesized as a 115-amino acid precursor (pre-pro-PTH), cleaved to pro-PTH and then to the 84-amino acid molecule, PTH (numbering, by universal convention, starting at the amino-terminus). The precursor forms generally remain within the parathyroid cells.
Secreted PTH undergoes cleavage and metabolism to form carboxyl-terminal fragments (PTH-C), amino-terminal fragments (PTH-N), and mid-molecule fragments (PTH-M). Only those portions of the molecule that carry the amino terminus (ie, the whole molecule and PTH-N) are biologically active. The active forms have half-lives of approximately 5 minutes. The inactive PTH-C fragments, with half-lives of 24 to 36 hours, make up >90% of the total circulating PTH and are primarily cleared by the kidneys. In patients with renal failure, PTH-C fragments can accumulate to high levels. PTH 1-84 is also elevated in these patients, with mild elevations being considered a beneficial compensatory response to end organ PTH resistance, which is observed in renal failure.
The serum calcium level regulates PTH secretion via negative feedback through the parathyroid calcium sensing receptor (CASR). Decreased calcium levels stimulate PTH release. Secreted PTH interacts with its specific type II G-protein receptor, causing rapid increases in renal tubular reabsorption of calcium and decreased phosphorus reabsorption. It also participates in long-term calciostatic functions by enhancing mobilization of calcium from bone and increasing renal synthesis of 1,25-dihydroxy vitamin D, which, in turn, increases intestinal calcium absorption. In rare inherited syndromes of parathyroid hormone resistance or unresponsiveness and in renal failure, PTH release may not increase serum calcium levels.
Hyperparathyroidism causes hypercalcemia, hypophosphatemia, hypercalcuria, and hyperphosphaturia. Long-term consequences are dehydration, renal stones, hypertension, gastrointestinal disturbances, osteoporosis and sometimes neuropsychiatric and neuromuscular problems. Hyperparathyroidism is most commonly primary and caused by parathyroid adenomas. It can also be secondary in response to hypocalcemia or hyperphosphatemia. This is most commonly observed in renal failure. Long-standing secondary hyperparathyroidism can result in tertiary hyperparathyroidism, which represents the secondary development of autonomous parathyroid hypersecretion. Rare cases of mild, benign hyperparathyroidism can be caused by inactivating CASR mutations.
Hypoparathyroidism is most commonly secondary to thyroid surgery, but can also occur on an autoimmune basis, or due to activating CASR mutations. The symptoms of hypoparathyroidism are primarily those of hypocalcemia, with weakness, tetany, and possible optic nerve atrophy.
Reference values apply to all ages.
About 90% of the patients with primary hyperparathyroidism have elevated parathyroid hormone (PTH) levels. The remaining patients have normal (inappropriate for the elevated calcium level) PTH levels. About 40% of the patients with primary hyperparathyroidism have serum phosphorus levels <2.5 mg/dL and about 80% have serum phosphorus <3.0 mg/dL.
An (appropriately) low PTH level and high phosphorus level in a hypercalcemic patient suggests that the hypercalcemia is not caused by PTH or PTH-like substances.
An (appropriately) low PTH level with a low phosphorus level in a hypercalcemic patient suggests the diagnosis of paraneoplastic hypercalcemia caused by parathyroid related peptide (PTHRP). PTHRP shares N-terminal homology with PTH and can transactivate the PTH receptor. It can be produced by many different tumor types.
A low or normal PTH in a patient with hypocalcemia suggests hypoparathyroidism, provided the serum magnesium level is normal. Low magnesium levels inhibit PTH release and action and can mimic hypoparathyroidism.
Low serum calcium and high PTH levels in a patient with normal renal function suggest resistance to PTH action (pseudohypoparathyroidism type 1a, 1b, 1c, or 2) or, very rarely, bio-ineffective PTH.
A limited number of the PTH-C fragments, which accumulate in renal failure, chiefly PTH 7-84, cross-react in this and other intact PTH assays. PTH 1-84 is also elevated in renal failure, with mild elevations being considered beneficial. Consequently, when measured with an intact PTH assay, concentrations of 1.5 to 3 times the upper limit of the healthy reference range appear to represent the optimal range for end-stage renal failure patients. Lower concentrations may be associated with adynamic renal bone disease, while higher levels suggest possible secondary or tertiary hyperparathyroidism, which can result in high-turnover renal osteodystrophy.
Some patients with moderate hypercalcemia and equivocal phosphate levels, who have either mild elevations in PTH or (inappropriately) normal PTH levels, may be suffering from familial hypocalciuric hypercalcemia, which is due to inactivating CASR mutations. The molar renal calcium to creatinine clearance is typically <0.01 in these individuals. The condition can be confirmed by CASR gene mutation screening (CSRSP / Calcium Sensing Receptor [CASR] Gene, Full Gene Analysis).
Parathyroid hormone (PTH) values should be interpreted in conjunction with serum calcium and phosphorus levels, and the overall clinical presentation and history of the patient.
Do not interpret an elevated PTH value with a normal serum calcium as necessarily indicative of primary hyperparathyroidism. It is possible that the elevation in PTH is due to secondary causes, the most likely being vitamin D deficiency.
Normal reference ranges may vary based on geographical locations of the populations studied.
The carboxyl-terminal fragments (PTH-C) fragment 7-84, which accumulates in renal failure, shows substantial cross-reactivity in this assay. Healthy population reference ranges, therefore, do not apply in renal failure.
As with all tests containing monoclonal mouse antibodies, erroneous findings may be obtained from specimens taken from patients who have been treated with monoclonal mouse antibodies or have received them for diagnostic purposes.
In rare cases, interference due to extremely high titers of antibodies to ruthenium or streptavidin can occur.
In patients receiving high dose (>5 mg/day) biotin therapy, the specimen should be collected at least 8 hours after the last biotin administration.
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