¿Degradation of PTH
¿Degradation of PTH
^Pre-proPTH* Nucleus/ Parathyroid cell
Pathogenesis of secondary hyperparathyroidism (HPT) in chronic renal failure (CRF). Decreased numbers of proximal tubular (PT) cells, owing to loss of renal mass, cause a quantitative decrease in synthesis of 1,25-dihydroxy-vitamin D3 (1,25(OH)2D3). Loss of renal mass also impairs renal phosphate (P) and acid (H+) excretion. These impairments further decrease the activity of the 1-a-hydroxy-lase enzyme in the remaining PT cells, further contributing to the decrease in levels of 1,25(OH)2D3. 1,25(OH)2D3 deficiency decreases intestinal absorption of calcium (Ca), leading to hypocalcemia, which is augmented by the direct effect of hyperphosphatemia. Hypocalcemia and hyperphosphatemia stimulate PTH release and synthesis and can recruit inactive parathyroid cells into activity and PTH production. Hypocalcemia also may decrease intracellular degradation of PTH. The lack of 1,25(OH^D3, which would ordinarily feed back to inhibit the transcription of prepro-PTH and exert an antiproliferative effect on parathyroid cells, allows the increased PTH production to continue. In CRF there may be decreased expression of the Ca-sensing receptor (CaSR) in parathyroid cells, making them less sensitive to levels of plasma Ca. Patients with the b allele or the bb genotype vitamin D receptor (VDR) may be more susceptible to HPT, because the VDR-1,25(OH)2D3 complex is less effective at suppressing PTH production and cell proliferation. The deficiency of 1,25(OH^D3 may also decrease VDR synthesis, making parathyroid cells less sensitive to 1,25(OH)2D3. Although the PTH receptor in bone cells is downreg-ulated in CRF (ie, for any level of PTH, bone cell activity is lower in CRF patients than in normal persons), the increased plasma levels of PTH may have harmful effects on other systems (eg, cardiovascular system, nervous system, and integument) by way of alterations of intracellular Ca. Current therapeutic methods used to decrease PTH release in CRF include correction of hyperphosphatemia, maintenance of normal to high-normal levels of plasma Ca, administration of 1,25(OH^D3 orally or intravenously, and administration of a Ca-ion sensing receptor (CaSR) agonist [14-16,19-22].
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