Whether regression of parathyroid hyperplasia occurs in animals or patients with chronic renal failure remains a matter of debate. According to some authors regression must be an extremely slow process, if it occurs at all. This is in sharp contrast to the rapid reversibility of excessive parathyroid function in uremic rats after normalization of renal function by kidney transplantion, although parathyroid mass probably remained markedly increased in this experimental model.

The issue of regression is of clinical importance. If for example a chronic dialysis patient with a dramatic increase in total parathyroid mass has practically no chance to experience regression of hyperplastic glands after uremia correction by a succesful kidney graft it would seem appropriate to perform a surgical parathyroidectomy prior to renal transplantation. If however significant regression of hyperplasia occurs as an active or passive process, namely by enhanced apoptosis or reduced proliferation, prophylactic surgery should be avoided. That regression of parathyroid hyperplasia secondary to vitamin D deficiency can occur has been convincingly demonstrated many years ago in experiments done in chicks . Thus the administration of cholecaciferol to birds that had developed an increase in parathyroid gland mass when fed a rachitogenic, vitamin D-free diet for 8-10 weeks led to a significant (50%) reduction in gland weight. Calcitriol failed to achieve same effect at low, albeit hypercalcemic, dose but was capable of reducing gland mass at higher dose. However, in an experimental dog model no regression was found. Thus in dogs first submitted to a low-calcium, low-sodium and vitamin D deficient diet for two years and subsequently to the reintroduction of a normal diet for another 17 months, no involution of hyperplastic parathyroid glands was observed. In uremic animals, evidence for or against regression of increased parathyroid mass is contradictory. Wada et al reported that the calcimimetic drug, NPS R-568 was able to prevent parathyroid hyperplasia in 5/6th nephrectomized rats, but unable to reverse it. In contrast, more recent studies found regression of parathyroid gland weight in uremic rats in response to cinacalcet , and regression of either parathyroid hyperplasia, hypertrophy, or both in response to calcitriol or maxacalcitol.

In patients, a rapid remission of parathyroid overfunction may occur either due to parathyroid “apoplexy”, that is necrosis, as has been shown in rare cases of 1° hyperparathyroidism , or due to enhanced apoptosis. The diagnosis of necrosis is more difficult in 2° than in 1° forms of hyperparathyroidism because the hyperplasia of the former is not limited to one gland.

Regression of parathyroid hyperplasia in hemodialysis patients in response to calcitriol pulse therapy for 12 weeks has been reported by Fukagawa et al using ultrasonography. These authors observed a significant decrease in mean gland volume from 0.87 to 0.51 cm3 of this time period, concomitantly with a reduction in serum iPTH of more than 50%. In contrast, Quarles et al who also examined parathyroid gland anatomy in hemodialysis patients in vivo in response to intermittent i.v. or oral calcitriol treatment for 36 weeks failed to observe a decrease in parathyroid gland size as assessed by high resolution ultrasound and/or magnetic resonance imaging . Mean gland size was 1.9 and 2.1 cm3 before and 3.3 and 2.3 cm3 after oral and i.v. calcitriol therapy, respectively. The authors achieved an overall maximum average serum PTH reduction of 43% over this time period. There were marked differences between these two studies. Hyperparathyroidism probably was more severe in the latter than in the former. Although initial mean serum iPTH levels were similar, serum phosphorus was higher and the decrease in serum PTH achieved in response to calcitriol was less marked in the latter. Moreover, parathyroid mass was more than double.

In another study, Fukagawa et al examined the possible relation between parathyroid size and the long-term outcome after calcitriol pulse therapy, by subdividing patients into different groups according to estimation of initial parathyroid gland volume. In two hemodialysis patients with detectable gland(s), in whom the size of all parathyroid glands as well as PTH hypersecretion regressed to normal, 2° hyperparathyroidism remained controllable for at least 12 months after switching to conventional oral active vitamin D therapy. In contrast, in seven hemodialysis patients, in whom the size of all parathyroid glands did not regress to normal by calcitriol pulse therapy, 2° hyperparathyroidism relapsed after switching to conventional therapy although PTH hypersecretion could be controlled temporarily. Similarly, in a recent study Okuno et al. showed that in hemodialysis patients plasma PTH levels and the number of detectable parathyroid glands decreased in response to maxicalcitol (22-oxacalcitriol) given for 24 weeks only when the maximum diameter of one of the parathyroid glands was less than 11.0 mm, but not when it was above that value.

Taken together, these findings suggest that the degree of parathyroid hyperplasia, as detected by ultrasonography, is an important determinant for regression in response to calcitriol therapy. It is probable, although not proven, however, that the type of hyperplasia, namely monoclonal, multiclonal or polyclonal growth, is even more important with respect to regression than the actual size of each gland.