Parathyroid Hormone

Parathyroid hormone (PTH) is an 84 amino acid peptide secreted by the chief cells of the four parathyroid glands in response to a fall in ionised calcium, detected by the calcium sensing receptor. It raises calcium by increasing bone resorption, renal tubular calcium reabsorption and renal conversion of 25-hydroxyvitamin D to calcitriol, and it lowers phosphate by increasing urinary phosphate excretion.

Intact PTH has a half life of 2 to 4 minutes, so the measurement reflects the current secretory state. It is measured by two site immunoassay (second and third generation assays differ slightly) and reported in pmol/L or ng/L (pg/mL).

PTH is interpreted only with a simultaneous calcium and vitamin D result. The pair separates PTH-dependent from PTH-independent disorders of calcium, which is the key step in the investigation of both hypercalcaemia and hypocalcaemia.

Primary hyperparathyroidism affects about 1 in 500 women and 1 in 2000 men, with a peak after the menopause, and is the cause of about 60 to 70% of outpatient hypercalcaemia. Hypoparathyroidism affects about 25 to 40 in 100 000 people, most often after neck surgery.

Indications. Hypercalcaemia, hypocalcaemia, suspected primary hyperparathyroidism, kidney stones, osteoporosis and fragility fracture, chronic kidney disease (monitoring of mineral and bone disorder), suspected hypoparathyroidism, vitamin D deficiency with raised alkaline phosphatase, monitoring after parathyroidectomy or thyroidectomy, and assessment during parathyroid surgery (intraoperative).

Specimen. EDTA plasma on ice is preferred, since PTH is more stable than in serum. Separate within 4 hours. Serum is acceptable with prompt separation. A morning fasting sample reduces diurnal and meal variation. Sample calcium, albumin and creatinine together.

Reference range (intact PTH). About 1.6 to 6.9 pmol/L (15 to 65 ng/L), assay specific. Conversion: pg/mL multiplied by 0.106 gives pmol/L. Values are higher in older adults, in obesity, in people of African ancestry, and in vitamin D deficiency.

Combined interpretation with calcium.

• High calcium with raised or inappropriately normal PTH: PTH-dependent hypercalcaemia. Primary hyperparathyroidism (single adenoma 80 to 85%, multiglandular hyperplasia 10 to 15%, carcinoma under 1%), tertiary hyperparathyroidism, familial hypocalciuric hypercalcaemia, and lithium or thiazide effects.
• High calcium with suppressed PTH (under 1.6 pmol/L): PTH-independent hypercalcaemia. Malignancy (PTH-related peptide or bone metastases), myeloma, vitamin D excess, granulomatous disease, thyrotoxicosis, immobilisation, milk alkali syndrome, and adrenal insufficiency.
• Low calcium with raised PTH: secondary hyperparathyroidism. Vitamin D deficiency, chronic kidney disease, malabsorption, calcium deficiency, and PTH resistance (pseudohypoparathyroidism, with high phosphate).
• Low calcium with low or inappropriately normal PTH: hypoparathyroidism. Post-surgical, autoimmune, 22q11 deletion, activating calcium sensing receptor mutation, infiltration (iron, copper, metastases), radiation, and severe hypomagnesaemia or hypermagnesaemia.
• Normal calcium with raised PTH: secondary hyperparathyroidism (vitamin D deficiency), or normocalcaemic primary hyperparathyroidism after exclusion of secondary causes.

Primary hyperparathyroidism. Calcium over the upper limit, PTH not suppressed, phosphate low or low normal, hypercalciuria, and often reduced bone density, kidney stones, nephrocalcinosis or fractures.

Indications for surgery include corrected calcium more than 0.25 mmol/L over the upper limit, osteoporosis or fragility fracture, eGFR under 60 mL/min, kidney stones, hypercalciuria over 10 mmol/24 h, or age under 50.

Multiple endocrine neoplasia types 1, 2A and 4 and hyperparathyroidism jaw tumour syndrome are the genetic forms and present at younger ages with multiglandular disease.

Familial hypocalciuric hypercalcaemia. Mild lifelong hypercalcaemia with normal or mildly raised PTH and a calcium to creatinine clearance ratio under 0.01. It is benign and does not need surgery.

Chronic kidney disease. Phosphate retention, low calcitriol and hypocalcaemia drive secondary hyperparathyroidism. In dialysis patients, PTH is maintained at about 2 to 9 times the upper limit of the assay, and values outside this range are corrected by vitamin D analogues, calcimimetics, phosphate control or parathyroidectomy. Persistent hypercalcaemia after kidney transplant indicates tertiary hyperparathyroidism.

Hypoparathyroidism. Low calcium, high phosphate, low or undetectable PTH, low magnesium in some, and normal alkaline phosphatase. Post-thyroidectomy PTH measured on day 1 predicts permanent hypoparathyroidism when under 1.0 pmol/L.

Intraoperative PTH. A fall of more than 50% from the highest pre-excision value within 10 minutes of removing an adenoma indicates cure.

Critical values and findings needing immediate action.

• Corrected calcium over 3.5 mmol/L (hypercalcaemic crisis), or over 3.0 mmol/L with confusion, vomiting, dehydration or kidney injury, whatever the PTH.
• Corrected calcium under 1.9 mmol/L, or ionised calcium under 0.9 mmol/L, with tetany, seizures, stridor, QT prolongation or heart failure.
• Low PTH with low calcium after neck surgery, which needs treatment within hours.
• Very high PTH (over 100 pmol/L) with hypercalcaemia, a palpable neck mass or bone lesions (parathyroid carcinoma).

Interferences and pitfalls.

• Vitamin D deficiency raises PTH and can hide primary hyperparathyroidism by lowering calcium, so vitamin D is corrected and measurements repeated.
• Biotin supplements interfere with some immunoassays.
• Heterophile antibodies can give false high or low results.
• Delayed separation and storage at room temperature lower the result, especially in serum.
• PTH fragments accumulate in kidney failure and are detected by some assays, so assay generation matters.
• Thiazides and lithium raise calcium and PTH and can unmask or mimic primary hyperparathyroidism.
• A normal PTH does not exclude primary hyperparathyroidism when calcium is high, because the value is inappropriately normal.
• Albumin and acid base state alter total calcium, so ionised calcium or corrected calcium is used.

Special groups.

• Neonates: transient hypoparathyroidism occurs in infants of mothers with hypercalcaemia or diabetes, and in DiGeorge syndrome.
• Children: primary hyperparathyroidism is uncommon and often genetic.
• Pregnancy: PTH is low normal, and maternal primary hyperparathyroidism risks neonatal hypocalcaemia and tetany.
• Older adults: PTH rises with age, vitamin D deficiency and falling eGFR.
• Regions: nutritional rickets and calcium deficient diets cause secondary hyperparathyroidism in children and adults.

Follow up tests. Corrected and ionised calcium, albumin, phosphate, magnesium, 25-hydroxyvitamin D, alkaline phosphatase, urea and creatinine, 24-hour urinary calcium, calcium to creatinine clearance ratio, PTH-related peptide, 1,25-dihydroxyvitamin D, serum protein electrophoresis, thyroid function tests, bone density scan, neck ultrasound, sestamibi scan, four dimensional CT, calcium sensing receptor and MEN1 genetic testing.