The secretion of parathyroid hormone (PTH) is stimulated by a decrease in serum calcium levels, which is detected by the CaSR on parathyroid chief cells. PTH, in turn, increases the reabsorption of calcium in the distal tubule of the kidney and to a lesser extent in the distal thick ascending limb of the loop of Henle. In bone, elevated levels of PTH stimulate osteoblast lineage cells to express RANKL, which increases osteoclast activity, resulting in increased bone resorption and the release of calcium and phosphorus into the blood. PTH also stimulates the expression of 1α-hydroxylase in the proximal renal tubule, leading to an increase in 1,25-dihydroxyvitamin D levels. 1,25-dihydroxyvitamin D, in turn, stimulates the absorption of calcium and phosphorus in the small intestine and upregulates the expression of RANKL in osteoblasts, amplifying the effect of PTH on bone resorption. In the kidney, PTH inhibits NPT2 in the proximal tubule, reducing the reabsorption of phosphorus and increasing phosphorus clearance, thus counterbalancing the phosphorus mobilized from the bone and gut.

Although not as tightly regulated as calcium, hormonal responses are also triggered by perturbations in serum phosphorus levels. Low serum phosphorus levels stimulate the production of 1,25-dihydroxyvitamin D in the kidney, which in turn mobilizes calcium and phosphorus from the intestine. The rise in serum calcium levels suppresses the secretion of PTH to prevent hypercalcemia. This decrease in PTH enhances the reabsorption of phosphorus in the proximal tubule, aiding in the restoration of serum phosphorus levels. Over a longer period of time, a decrease in serum phosphorus levels inhibits the production of FGF23, which favors the reabsorption of phosphorus in the proximal tubule. These integrated responses allow for the correction of hypophosphatemia while maintaining normal calcium levels.

Primary hyperparathyroidism is primarily caused by excessive production of PTH by the parathyroid glands. It is most commonly caused by a single adenoma confined to one of the parathyroids. Due to elevated PTH levels, patients with primary hyperparathyroidism often have high serum calcium levels and, in most cases, low serum phosphorus levels. Hypercalcemia occurs as a result of increased bone resorption, increased gastrointestinal absorption of calcium (mediated by 1,25-dihydroxyvitamin D), and increased renal reabsorption of calcium. The major symptoms of this disorder are related to increased bone resorption, hypercalcemia, and hypercalciuria. These symptoms include radiographic manifestations of excessive bone resorption, psychological disorders (particularly depression), and progressive neurological symptoms such as fatigue, mental confusion, and, at very high levels (>15mg/dL), coma. Kidney stones composed of calcium phosphate are common in primary hyperparathyroidism due to hypercalcemia leading to hypercalciuria, and increased phosphorus clearance causing phosphaturia. Fortunately, routine blood chemistry screening over the past several decades has resulted in the earlier detection of primary hyperparathyroidism, preventing the development of severe symptoms in most cases.

The rate of calcium absorption, bone formation and resorption, and renal excretion determine serum calcium levels. On the other hand, serum phosphorus levels are determined by the rate of phosphorus absorption by the gastrointestinal tract, bone resorption and formation, soft tissue influx and efflux, and renal excretion. Serum calcium levels are normally maintained within a very narrow range, while serum phosphorus levels fluctuate over a relatively wider range.
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.