Pathophysiology

Role of Calcium

The major factor involved in the regulation of PTH secretion is the ionized calcium concentration in the extracellular fluid (Table 6-1). Low calcium levels stimulate increased PTH secretion, whereas high levels suppress PTH secretion. Even high blood levels of calcium, however, fail to completely suppress

PTH secretion. The blood calcium level appears to have an initial direct effect on parathyroid cell membrane potential. Calcium may also affect PTH secretion by regulating the amount of hormone available for secretion as a result of calcium-dependent regulation of hormone degradation within the parathyroid glands. After a prolonged decrease in extracellular ionized calcium, newly synthesized PTH is available for secretion. Subsequently, hypocalcemia stimulates increased PTH secretion over days and is associated with an increase in parathyroid cell growth and number.4

Role of Phosphorus

Hyperphosphatemia occurs as a result of impaired renal excretion of phosphate. Several investigators have demonstrated that phosphorus retention plays an important role in the pathogenesis of secondary HPT. The mechanisms considered are as follows:

1. A phosphorus-induced decrease in 1,25-dihy-droxyvitamin D3 (calcitriol) that is independent of changes in ionized calcium and calcitriol. This results from decreased activity of the renal enzyme 1 a-hydroxylase, with consequent diminished 1,25-dihydroxyvitamin D secretion and decreased intestinal calcium absorption.

2. Phosphorus-induced hypocalcemia and hyper-phosphatemia lead to a reciprocal fall in the serum calcium-phosphate product. A decrease in

Hypocalcemia

IGI absorption î PTH secretion Calcium supplementation

I Dietary consumption î Parathyroid cell growth Low-phosphorus diet

Phosphate binders

Hyperphosphatemia

î a1-Hydroxylase activity 1,25-Dihydroxyvitamin D supplementation

I 1,25-Dihydroxyvitamin D Calcitriol PO Metabolic acidosis

Parathyroid resistance to 1,25-Dihydroxyvitamin D Calcitriol IV or IP

GI = gastrointestinal; PTH = parathyroid hormone; PO = orally; IV = intravenous; IP = intraperitoneal.

Table 6-1. PATHOPHYSIOLOGY OF SECONDARY HYPERPARATHYROIDISM

Initiating Factors Results Treatment the synthesis of calcitriol possibly affects phosphorus retention. In patients with moderate renal insufficiency, phosphate restriction increases plasma calcitriol with a concomitant normalization of plasma PTH. In severe chronic renal failure, phosphorus appears to regulate PTH secretion by a mechanism independent of calcitriol. When phosphate binders are given and dietary phosphorus is reduced, serum PTH levels decrease substantially, although the values remain higher than normal.

Some investigators have also observed that phosphate restriction prevents parathyroid cell growth in uremic rats.5 In vitro studies have demonstrated that phosphorus increases PTH synthesis and secretion by an unknown mechanism. In the presence of hyperphosphatemia, the parathyroid glands are resistant to the action of calcitriol.6

Role of Vitamin D

Vitamin D is hydroxylated at the 25 position in the liver and then requires activation by a second hydroxylation at the number one position in the kidney to become active. As renal function worsens and renal mass decreases, renal hydroxylation of vitamin D3 decreases because of decreased 1 a-hydroxylase activity.7 Deficiency of calcitriol, the most active form of vitamin D, causes defective synthesis of calcium binding protein in the intestine and decreased gastrointestinal absorption of calcium. A decreased serum concentration of calcitriol directly stimulates PTH secretion and synthesis.1,3 Because larger doses of calcitriol can induce the regression of parathyroid hyperplasia, calcitriol may not only suppress parathyroid cell proliferation but may play a role in defining the overall cellular turnover rate in the parathyroid gland.8

The parathyroid glands in chronic dialysis patients with secondary HPT appear to be somewhat resistant to the physiologic concentration of cal-citriol but are not as resistant to the pharmacologic concentrations of calcitriol.3,9 Resistance of parathyroid cells to calcitriol may serve as another stimulus for PTH secretion in patients with chronic renal fail-ure.3 In vitro studies have shown that calcitriol inhibits serum-stimulated proliferation of parathyroid cells.9 Vitamin D deficiency results in parathyroid hyperplasia, but this situation is in part owing to concomitant hypocalcemia. Undoubtedly, the reduced number of vitamin D and calcium-sensing receptors in hyperplastic and adenomatous parathyroid disease also plays an important role in the development of secondary HPT.4

The reduction of calcitriol receptor density in parathyroid glands has been considered the central mechanism of the resistance of parathyroid cells to calcitriol. It has been shown that larger hyperplastic parathyroid glands are more resistant to calcitriol pulse therapy than are smaller hyperplastic glands.9 Calcitriol receptor density is inversely correlated with the weight of enlarged gland.3 Parathyroid hyperplasia is divided into two types: nodular hyperplasia and diffuse hyperplasia (Figure 6-1). The calcitriol receptor density is less in nodular hyperplasia than in diffuse hyperplasia even in the same patient. Nodular hyperplasia, a more severe type of parathyroid hyperplasia, is usually seen in larger glands (90% of glands are heavier than 500 mg).

Figure 6-1. Nodular parathyroid hyperplasia: intraoperatively (A) and ex vivo (B).

Figure 6-1. Nodular parathyroid hyperplasia: intraoperatively (A) and ex vivo (B).

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