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Parathyroid Hormone

Parathyroid hormone (PTH) is initially synthesized as a 115 amino acid precursor polypeptide that is called preproPTH, by the parathyroid chief cells.  It is then cleaved to proPTH (90 amino acids) and finally to intact PTH molecule (84 amino acids).  Intact PTH is the principal form of PTH secreted into the bloodstream in response to decreased serum calcium levels. In the peripheral tissues, intact PTH is catabolized to C-terminal (carboxy), N-terminal (amino), and mid-molecule fragments. Only intact PTH and the N-terminal fragment are metabolically active. PTH secretion exhibits a prominent circadian rhythm with peak concentration occurring between 0200 and 0400 hours.  This peak level corresponds to the nadir in ionized calcium concentration.

All forms of PTH are filtered by the kidney and metabolized by other organs. The normal half-life of intact PTH is 5 minutes, C-terminal fragment 30-40 minutes, and N-terminal fragment 5 minutes. In renal failure the half-lives may extend to as much as 30 minutes for the intact molecule, 24-36 hours for the C-terminal fragment, and 30 minutes for the N-terminal fragment. With normal renal function the concentration of metabolically inactive C-terminal fragment is approximately 10 times higher than intact molecule. The N-terminal fragment concentration is < 10% of that of the intact molecule.  Prolongation of the half-life of the C-terminal fragment in renal failure means that it may account for as much as 10,000 times as much serum hormone as the intact PTH.  For this reason, it is very important that the PTH assay measures only intact PTH and does not cross-react with the metabolically inactive C-terminal fragment. 

Calcium homeostasis is maintained by the concerted actions of PTH, Vitamin D, and calcitonin. The stimulus for PTH secretion by the parathyroid gland is low circulating levels of plasma ionized calcium.  Normal calcium levels are restored when PTH causes reabsorption of calcium from bone, reabsorption of calcium by the renal tubules, and increased synthesis of 1,25 hydroxyvitamin D₃.  The latter increases intestinal calcium absorption.  The C-cells of the thyroid gland produce calcitonin, which decreases serum calcium largely by stimulating the incorporation of calcium into bone.  Calcitonin is secreted at a rate directly proportional to plasma ionized calcium. 

The differential diagnosis of hypercalcemia depends on the clinical setting.  Overall, primary hyperparathyroidism and malignancy account for 80 – 90% of hypercalcemia cases.  However, primary hyperparathyroidism is the cause of ~60% of ambulatory cases and of ~25% of inpatient cases, whereas malignancy causes ~35% of ambulatory cases and 65% of inpatient cases.  

Hyperparathyroidism is due to overactivity of one or more of the parathyroid glands, which leads to overproduction of PTH.  Hypersecretion of PTH can be due to primary, secondary or tertiary causes.  Primary hyperparathyroidism is associated with hypercalcemia, whereas secondary and tertiary hyperparathyroidism are associated with hypocalcemia. 

Primary hyperparathyroidism has an overall incidence of 1 in 1,000 and is the most common cause of hypercalcemia in outpatients.  It occurs approximately three times as often in women as in men and occurs with increasing frequency after the age of 40.  In primary hyperparathyroidism the gland is overactive, producing an excessive amount of PTH that leads to hypercalcemia.  The consequences of hypercalcemia range from dehydration, extreme thirst, lethargy, muscular weakness, and renal damage with polyuria to production of renal calculi.  In approximately 85% of cases, primary hyperparathyroidism is caused by a solitary, benign parathyroid adenoma.  The remaining cases are caused by diffuse hyperplasia of all of the parathyroid glands (12%) or by multiple adenomas (3%).  Serum total calcium levels are usually less than 13.0 mg/dL and the patients are asymptomatic when hypercalcemia is initially discovered. Most patients with hyperparathyroidism have borderline increased or high normal concentrations of intact PTH.  Even high normal PTH values should be considered abnormal because patients with increased calcium values should normally have suppressed PTH concentrations.   However, high normal PTH and hypercalcemia may be present in patients with familial hypocalciuric hypercalcemia.  A low 24-hour urinary calcium concentration (<100 mg/24 hours) suggests this disorder, but a normal concentration does not rule it out.  

Malignancy is the most common cause of hypercalcemia in hospitalized patients. The hypercalcemia of malignancy is largely due to the production of parathyroid hormone related protein (PTHrP) by the tumor that interacts with PTH receptors, leading to hypercalcemia.  Serum total calcium levels are usually between 11.0 - 15.0 mg/dL and are associated with low to undetectable PTH levels.

Diagnosis of Hypercalcemia

	Primary HPT	FHH	Malignancy	Tertiary HPT	Vit D Intox
Total calcium	NC or Inc	NC or Inc	Inc	NC to Inc	NC to Inc
Ionized calcium	Inc	Inc	Inc	NC to Inc	Inc
Phosphate	NC to Dec	NC to Dec	Dec	Dec to Inc	Inc
Creatinine	NC to Inc	NC	NC to Inc	NC to Inc	NC to Inc
PTH	NC to Inc	NC to Inc	Dec	Inc	Dec
25-OH vit D	NC to Dec	NC	NC to Dec	Dec to Inc	Dec to Inc
1,25-OH vit D	NC to Inc	NC to Inc	NC to Inc	Dec to Inc	NC to Inc

FHH = familial hypercalciuric hypercalcemia; NC, no change; Inc, Increase; Dec, Decrease

Hypoparathyroidism is suspected in patients with a low ionized calcium, hyperphosphatemia, and a parathyroid hormone (PTH) level that is low or inappropriately in the normal range.

The most common cause of hypoparathyroidism is thyroid surgery. Several other clinical syndromes may be associated with hypocalcemia including hypoparathyroidism, hypomagnesimia, PTH resistance, renal failure with secondary hyperparathyroidism, and vitamin D deficiency with secondary hyperparathyroidism. Most patients with hypoparathyroidism exhibit neuromuscular signs and symptoms of hypocalcemia, such as paresthesias, muscle cramps, and prolonged QT interval

Diagnosis of Hypocalcemia

	HypoPTH	HypoMg	PTH resist	Renal Fail	Vit D Defic
Total calcium	Dec	Dec	NC to Dec	Dec	NC to Dec
Ionized calcium	Dec	Dec	NC to Dec	NC to Dec	NC to Dec
Phosphate	Inc	Inc	Inc	Inc	NC to Dec
Creatinine	NC	NC to Inc	NC to Inc	Inc	NC
PTH	NC to Dec	NC to Dec	Inc	Inc	Inc
25-OH vit D	Dec to Inc	Dec to Inc	Dec to Inc	Dec to Inc	Dec
1,25-OH vit D	ND to Dec	NC to Dec	NC to Dec	Dec	Dec
Magnesium	NC to Dec	Dec	NC to Dec

 

Commonly used drugs may affect serum PTH level.  Diltiazem, a calcium channel antagonist, acts as an agonist in the parathyroid cells and inhibits PTH release by increasing cytosolic calcium.  Furosemide produces a mild increase in serum PTH.  Approximately 10% of patients taking lithium develop increased PTH and hypercalcemia.

There have been three generations of PTH immunoassays.

• First generation PTH assays included assays that detected C-terminal, N-terminal, and mid-molecule. These assays are no longer used clinically.
• Second generation PTH assays are called intact PTH. This name is somewhat of a misnomer because these assays measure not only intact PTH with amino acids 1-84, but also PTH molecules with 7-84 amino acids and possibly other N-terminal fragments.
• Third generation PTH assays are called bio-intact. They detect PTH molecules with 1-84 amino acids, but not PTH with 7-84 amino acids or other N-terminal truncated forms.  

So far, there is little data indicating that bio-intact PTH is clinically superior to intact PTH. Intact PTH and bio-intact PTH assays are highly correlated in patients who are on dialysis, uremic, or have primary hyperparathyroidism. Furthermore, bio-intact PTH measurements do not correlate better with markers of bone turnover than intact PTH

Intact PTH immunoassays use two antibodies in sequence, the first recognizing the N-terminal and the second the C- terminal. 

Reference range using an automated chemiluminescent analyzer is 10 to 69 pg/mL. 

Specimen requirement is one SST tube of blood. The tube should be centrifuged within one hour after drawing and the serum frozen.

References

Gao P, Scheibel S, D'Amour P, John MR, Rao SD, Schmidt-Gayk H, et al. Devel- opment of a novel immunoradiometric assay exclusively for biologically active whole parathyroid hormone 1-84: implications for improvement of accurate assessment of parathyroid function. J Bone Miner Res 2001;16:605–14.

Souberbielle J-C, Friedlander G, Cormier C. Practical considerations in PTH testing. Clin Chem Acta 2006;366:81–9.

Salusky IB, Goodman WG, Kuizon BD, Lavigne JR, Zahranik RJ, Gales B, et al. Similar predictive value of bone turnover using first- and second-generation immunometric PTH assays in pediatric patients treated with peritoneal dialysis. Kidney Int 2003;63:1801–8.

Friedman PA, Goodman WG. PTH(1-84)/PTH(7-84): a balance of power. Am J Physiol 2006;290:P975–84