Fig. 40.10A . A decrease in serum [Ca++] detected by the CaSR on parathyroid chief cells stimulates secretion of PTH. In the kidney, PTH increases Ca++ reabsorption in the distal tubule and to a lesser extent in the distal thick ascending limb of the loop of Henle. In bone, elevated PTH stimulates osteoblast lineage cells to express RANKL, which increases osteoclast activity and leads to increased bone resorption and release of Ca++ and Pi into blood. PTH stimulates 1α-hydroxylase expression in the proximal renal tubule, thereby increasing 1,25-dihydroxyvitamin D levels. 1,25-Dihydroxyvitamin D stimulates absorption of Ca and Pi in the small intestine and upregulates osteoblast expression of RANKL, thereby amplifying the effect of PTH on bone resorption. In the kidney, PTH inhibits NPT2 in the proximal tubule to lower Pi reabsorption and increase Pi clearance, thereby counterbalancing Pi mobilized from the bone and gut.
Although not as tightly regulated as Ca++ , perturbations in serum Pi will also elicit hormonal responses (see
Fig. 40.10B ). Low serum Pi stimulates production of 1,25-dihydroxyvitamin D in the kidney, which in turn will mobilize Ca and Pi from the intestine. The rise in Ca++ will suppress PTH secretion to prevent hypercalcemia. This drop in PTH will enhance Pi reabsorption in the proximal tubule to help restore serum Pi. Over a longer time course, a decrease in serum Pi will inhibit FGF23 production, which will favor Pi reabsorption in the proximal tubule. These integrated responses will allow correction of hypophosphatemia while maintaining normocalcemia. For hormonal responses to vitamin D deficiency, see the In the Clinic box and
Fig. 40.10C
Primary hyperparathyroidism iscausedbyexcessiveproductionofPTHbytheparathyroidglands.Itismostfrequentlycausedbyasingleadenoma confinedtooneoftheparathyroids.OwingtoelevatedPTH,patientswithprimaryhyperparathyroidismhavehighserum[Ca++]and,inmostcases,lowserum[Pi].Hypercalcemia isaresultofboneresorption,increasedgastrointestinalCaabsorption(mediatedby1,25-dihydroxyvitaminD),andincreasedrenalCa++ reabsorption.Themajorsymptomsofthedisorderarerelatedtoincreasedboneresorption,hypercalcemia,andhypercalciuria. Theseincluderadiographicmanifestationsofexcessiveboneresorptionandpsychologicaldisorders,particularlydepression.Progressiveneurologicalsymptomsincludefatigue,mentalconfusion,andatveryhighlevels(>15mg/dL),coma.Kidneystones(nephrolithiasis) composedofcalciumphosphatearecommonbecausehypercalcemialeadstohypercalciuria,andincreasedPiclearancecausesphosphaturia. Fortunately,routinebloodchemistryscreeningoverthepastseveraldecadeshasresultedinearlierdetectionofprimaryhyperparathyroidism,precludingdevelopmentofseveresymptomsinmostcases.
1. Serum [Ca++] is determined by the rate of Ca 2. Serum [Pi] is determined by the rate of Pi absorption absorption by the gastrointestinal tract, bone by the gastrointestinal tract, soft tissue influx and formation and resorption, and renal excretion. Serum efflux, bone formation and resorption, and renal [Ca++] is normally maintained within a very narrow excretion. Serum [Pi] normally fluctuates over a range. relatively wider range.
3.