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PARATHYROID HORMONE, HYPERPARATHYROIDISM CKD, & PTH ASSAYS David Plaut & Shanti Narayanan Summer, 2012 PARATHYROID HORMONE, HYPERPARATHYROIDISM CKD, & PTH ASSAYS David Plaut & Shanti Narayanan Summer, 2012

Parathyroid Hormone - PTH is a hormone secreted by the Parathyroid gland. There are Parathyroid Hormone - PTH is a hormone secreted by the Parathyroid gland. There are four Parathyroid glands located behind the thyroid.

Role of PTH – To Regulate Calcium Levels The Parathyroid glands have only one Role of PTH – To Regulate Calcium Levels The Parathyroid glands have only one major function – regulate the calcium level in the body within a very narrow range (8. 5 – 10. 2 mg/d. L) so that the nervous and muscular systems can function properly.

How does PTH regulate Calcium Levels? Ca Parathyroid Ca TH P PTH PT H How does PTH regulate Calcium Levels? Ca Parathyroid Ca TH P PTH PT H Increases Absorption of Ca and P Calcitriol Bl o o d Increases Calcitriol formation Decreases excretion of Ca Increases excretion of P lcit rio l Bo Store House of Ca & P Ca ne s P

Causes of Elevated Calcium In 70% of hypercalcaemia (n = 99), the cause was Causes of Elevated Calcium In 70% of hypercalcaemia (n = 99), the cause was unknown. The second most common diagnosis was skeletal disorders followed by kidney disease. Therefore, PTH analyses should be used more frequently.

Signs and Symptons Roughly three in 10, 000 persons are affected by 1 o Signs and Symptons Roughly three in 10, 000 persons are affected by 1 o HPT One of the more common causes of hypercalcemia. “Stones, bones, and groans” kidney stones, accelerated bone loss, and GI disomfort. About 15 percent of patients with hypercalcemia have: Weakness. Nausea and vomitting Weight loss for no known reason. Being much more thirsty than usual Frequent urination. Feeling very tired. Loss of appetite Constipation Trouble thinking clearly

Factors Affecting Prognosis and Treatment There are certain issues: · Whether the calcium level Factors Affecting Prognosis and Treatment There are certain issues: · Whether the calcium level in the blood can be controlled. · The stage of the cancer. · Whether the tumor and the capsule around the tumor can be completely removed by surgery. · The patient’s general health.

Treatment of 1 o Hyperparathyroidism Surgery – remove the diseased Parathyroid gland leave the Treatment of 1 o Hyperparathyroidism Surgery – remove the diseased Parathyroid gland leave the normal glands. One bad gland is removed – 95% 3 or 3 ½ glands are removed – 5%

Secondary Hyperparathyroidism Secondary implies that the Parathyroid glands grew larger and producing excess PTH Secondary Hyperparathyroidism Secondary implies that the Parathyroid glands grew larger and producing excess PTH in response to kidney disease. All 4 glands will be enlarged. Occurs in patients with renal failure. Occurs in patients who have been on kidney dialysis for several years.

Levels of PTH in CKD – NKF Guidelines CKD Stage GFR Range (m. L/min. Levels of PTH in CKD – NKF Guidelines CKD Stage GFR Range (m. L/min. /1. 73 m 2) I- PTH Ca / P Intact PTH Target Range (pg/m. L) 3 30 -59 Every 12 Months 35 -70 4 15 -29 Every 3 Months 70 -110 5 <15 or dialysis Every 3 Months Every Month 150 -300 The NKF/K-DOQI Guidelines are derived from studies that used the Allegro Intact PTH assay. NKF / K-DOQI: National Kidney Foundation /Kidney-Dialysis Outcome Quality Initiative

The PTH Molecule Peptide consisting of 84 Amino acids. Breaks into small fragments. Intact The PTH Molecule Peptide consisting of 84 Amino acids. Breaks into small fragments. Intact PTH is the whole molecule – 1 to 84. 1 84 1 -84 7 -84 1 -34 13 -34 39 -84 53 -84

PTH Assay Design Labeled Ab 1 -34 39 - 84 1 -84 Capture Ab PTH Assay Design Labeled Ab 1 -34 39 - 84 1 -84 Capture Ab 7 -84 1 -34 13 -34 39 -84 53 -84

PTH Assays 1 st Gen Assays: Not Specific for Intact PTH. Epitope of labeled PTH Assays 1 st Gen Assays: Not Specific for Intact PTH. Epitope of labeled coated Ab Ab High cross reaction with PTH fragments. Assay 2 nd Gen Assays: Used different epitopes for the N -terminal and C-terminal fragments. DPC 44 -84 1 -34 Bayer 39 -84 1 -34 Roche 26 -32 55 -64 Allegro 39 -84 1 -34 3 rd Gen Assays: Not commercialized. Significant variation in assay results between different manufacturers. Use of different epitopes for antibody binding Lack of standardization.

Intra-operative PTH: Cost Benefit Analysis Conventional Surgery without using Intra -operative PTH Standard operation Intra-operative PTH: Cost Benefit Analysis Conventional Surgery without using Intra -operative PTH Standard operation using Intra-operative PTH MIRP using Intra -operative PTH Surgery cost : ~ $ 4500. Surgery cost : ~ $ 3200. Frozen sections: $ 0. ~ $ 1000. PTH assay: ~ $ 100. Hospital stay: ~ $ 3200. Hospital stay: $ 0. Total cost: ~ $ 8700. Total cost: ~ $ 6500. SAVE $2200 Total cost: ~ $ 3300. SAVE $5400

PTH Assays and Parathyroidectomy Intraoperative PTH measurement with a decrease of at least 90% PTH Assays and Parathyroidectomy Intraoperative PTH measurement with a decrease of at least 90% in intra -operative PTH is highly predictive of successful parathyroidectomy and normalization of postoperative calcium and PTH levels.

How Many Samples Are Needed? The study found that an intraoperative PTH determination with How Many Samples Are Needed? The study found that an intraoperative PTH determination with a > 50% change is an excellent prognostic marker of resolution and that only 2 samples are required: one at baseline another 10 min. after removal of the abnormal tissue.

PTH in Renal Patients Intraoperative decay of PTH during operation for renal HPT is PTH in Renal Patients Intraoperative decay of PTH during operation for renal HPT is somewhat slower in patients with renal HPT than for patients with normal renal function. 20 min after resection, a decline to < 50% of the pre-operative level predicts cure, while <40% predicts a failure to cure.

Calcium Assays with PTH Assays? The mean baseline PTH level dropped by 70% at Calcium Assays with PTH Assays? The mean baseline PTH level dropped by 70% at 5 minutes after removal of the abnormal glands and by 83% at 10 minutes. The mean baselines of both TSC and ICa dropped by 4% at 5 minutes after removal of the abnormal glands and remained at 4% at 10 minutes. Decreases in TSC and ICa during parathyroidectomy are minimal. Unlike PTH levels, TSC and ICa levels do not consistently decrease at 5 and 10 minutes after gland resection.

Calcium Levels and Parathyroidism Doubling the number of serum calcium analyses did not increase Calcium Levels and Parathyroidism Doubling the number of serum calcium analyses did not increase the detected number of raised calcium levels. More frequent PTH analyses resulted in a corresponding increase in detected high PTH levels. 15% of the patients with hypercalcaemia were diagnosed with primary hyperparathyroidism. Over 40% of patients with primary hyperparathyroidism in the study had only slightly raised serum calcium levels.

PTH Assays vs. Other Tools. The positive predictive values: sestamibi scanning 81% radioguided surgery PTH Assays vs. Other Tools. The positive predictive values: sestamibi scanning 81% radioguided surgery 88% PTH 99. 5% Perioperative PTH testing has the highest sensitivity, positive predictive value, and accuracy. The inherent variability of sestamibi scanning and radioguided techniques emphasizes the critical role of PTH testing during parathyroid surgery.

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