Effect of vitamin D nutrition on disease indices in patients with primary hyperparathyroidism

Highlights

• Vitamin D deficiency is common in primary hyperparathyroidism and is associated with severe form of the disease and larger parathyroid adenomas.

• Restriction of vitamin D has very little effect on serum calcium.

• Avoidance of vitamin D in patients with primary hyperparathyroidism for fear of worsening hypercalcemia is not warranted.

• Patients with primary hyperparathyroidism need as much vitamin D and calcium and perhaps more than the general population.

Abstract

In patients with primary hyperparathyroidism, the size of the adenoma is a major determinant of biochemical indices, disease severity, and manner of presentation. However, the large variation in adenoma weight, both within and between populations and a steady decline in parathyroid adenoma weights over time remain largely unexplained. Based on the results in a small number of patients almost two decades ago we proposed that vitamin D nutritional status of the patient explains both the disease manifestations and much of the variation in adenoma size.

Accordingly, we examined the relationship between vitamin D nutrition, as assessed by serum levels of 25-hydroxyvitamin D, and parathyroid gland weight, the best available index of disease severity, in a large number of patients (n = 440) with primary hyperparathyroidism. A significant inverse relationship was found between serum 25-hydroxyvitamin D level and log adenoma weight (r = −0.361; p < 0.001). Also, the adenoma weight was significantly related directly to serum PTH, calcium, and alkaline phosphatase as dependent variables. In patients with vitamin D deficiency (defined as serum 25-hydroxyvitamin D levels 15 ng/mL or lower), gland weight, PTH, AP, and adjusted calcium were each significantly higher than in patients with 25-hydroxyvitamin D levels of 16 ng/mL or higher, but serum 1,25-dihydroxyvitamin D levels were similar in both groups. We interpret this to mean that suboptimal vitamin D nutrition stimulates parathyroid adenoma growth by a mechanism unrelated to 1,25-dihydroxyvitamin D deficiency. We conclude that variable vitamin D nutritional status in the population may partly explain the differences in disease presentation.

Introduction

Vitamin D nutrition has long been implicated both in clinical expression and changing pattern of presentation of primary hyperparathyroidism (PHPT) [[1], [2], [3], [4], [5], [6]]. The clinical phenotype of sporadic PHPT in the Western world has changed dramatically over the last century largely related to the improvements in vitamin D and calcium nutrition of the population and partly to early detection of the condition with routine biochemical screening [3,[7], [8], [9], [10]]. These two seminal secular changes account for the almost complete disappearance of the classical description of PHPT from an earlier era as “the disease of the bones, stones, moans and groans with psychic overtones” [8,[11], [12], [13]]. However, the classical phenotype of PHPT is still prevalent in parts of the world where vitamin D deficiency remains endemic [[12], [13], [14], [15]]. Asymptomatic PHPT of the type seen in developed countries also exists in pockets of these endemic areas where vitamin D nutrition of the population is adequate or improved [16,17].

Although the critical role of vitamin D in the pathogenesis, prevention and treatment of rickets and osteomalacia is virtually unassailable, the role of vitamin D in other skeletal and in non-skeletal conditions is less well defined [[18], [19], [20]]. By contrast, the importance of calcium and vitamin D nutrition in the clinical manifestation of PHPT has been known since the classical descriptions of Fuller Albright [1,2]. The critical role of vitamin D nutrition in the clinical expression of the disease was first suggested by Kleeman et al. [6], and the concept was first confirmed by Rao et al. in 1997 [7], and subsequently by others [8,17,[21], [22], [23], [24], [25], [26], [27]]. Despite several studies demonstrating the safety of vitamin D supplementation in patients with mild to moderate PHPT using low, moderate, or even high doses of vitamin D [28,29], an unfounded concern prevails that vitamin D supplementation might aggravate existing hypercalcemia in patients with PHPT.

Almost two decades ago, we were the first to report on the relationship between vitamin D nutrition as assessed by serum 25-hydroxyvitamin D level, the best available index of vitamin D nutrition, and parathyroid gland weight, the best available index of parathyroid cell number, in a small number of patients with surgically verified sporadic PHPT [8]. In addition, we suggested that vitamin D depletion was associated with a blunted calcemic, but an exaggerated skeletal response to parathyroid hormone (PTH), which explains why some patients with sporadic PHPT have normal or even lower serum calcium levels [14,15,26]. However, despite significant vitamin D deficiency all patients had single adenoma without hyperplasia as would be expected [30]. Furthermore, most previous studies included a small number of patients with a relatively narrow range of serum 25-hydroxyvitamin D levels, which might have limited the exploration of the concept [5,6]. Accordingly, we now extend our previous small study to present the effect of vitamin D nutrition on parathyroid adenoma weight in a larger number of patients with surgically verified sporadic PHPT.