Normocalcemic Primary Hyperparathyroidism

Abstract

Primary hyperparathyroidism, a common endocrine disorder, is traditionally defined by hypercalcemia and elevated levels of parathyroid hormone (PTH). A newer presentation of primary hyperparathyroidism has been described over the past decade, in which PTH is elevated but serum calcium is consistently normal, in the absence of secondary causes of hyperparathyroidism, such as renal disease or vitamin D deficiency. Recognition of this phenotype of primary hyperparathyroidism, normocalcemic primary hyperparathyroidism, supports a biphasic chronological time course in some individuals in which PTH levels are first elevated but serum calcium is normal, followed by the development of frank hypercalcemia. This review focuses on the available literature regarding this newly described phenotype of primary hyperparathyroidism.

Introduction

Primary hyperparathyroidism is a disorder characterized traditionally by hypercalcemia and elevated levels of parathyroid hormone (PTH). It is one of the most common endocrine disorders with an estimated prevalence between 0.1% and 0.5% in the United States. Before the advent of the multichannel autoanalyzer in the 1970s, classical primary hyperparathyroidism most often presented as a symptomatic disorder, with bone loss and kidney stones. However, with serum calcium values routinely available as a biochemical screening test result, the clinical profile of primary hyperparathyroidism has evolved into a disorder that presents most commonly asymptomatically 1, 2. In these patients, the biochemical screening test leads to the discovery of hypercalcemia when there was no obvious rationale for checking the serum calcium. Despite the fact that most patients are discovered incidentally, bone mass is typically reduced when it is measured by dual-energy X-ray absorptiometry (DXA). The densitometric profile of primary hyperparathyroidism favors reductions at the distal one-third forearm, a site that is enriched in cortical bone 3, 4. The characteristic densitometric findings of primary hyperparathyroidism are usually noted at the time of diagnosis.

A newer clinical presentation of primary hyperparathyroidism has been described over the past decade 5, 6, 7, 8. It is characterized by normal total and ionized serum calcium concentrations and consistently elevated PTH levels. These patients have no obvious causes for secondary elevations of PTH, such as renal disease or vitamin D deficiency. Recognition of this new phenotype of primary hyperparathyroidism supports a concept, first proposed by Rao et al (7), that describes a biphasic chronology of its clinical development. During the first phase, PTH levels are elevated but the serum calcium is normal. Until recently, this first phase was a subclinical one because PTH levels were rarely measured when the serum calcium concentration was normal. The second phase is the one that has traditionally been recognized because hypercalcemia surfaces.

The discovery of these individuals raises the question: Why would the PTH be measured when the serum calcium is normal? The answer can be found in the fact that many osteoporosis and metabolic bone diseases units have become more proactive in their comprehensive approach to biochemical evaluation of the skeleton. Now, PTH levels are often measured even in patients whose serum calcium is normal. It is in this context that most individuals have been discovered with normocalcemic primary hyperparathyroidism.

Although normocalcemic primary hyperparathyroidism was first formally recognized at the time of the Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism in 2008 (9), the entity remains incompletely described, particularly regarding its epidemiology, natural history, and management. In this report, we summarize what is known about normocalcemic primary hyperparathyroidism and present approaches to gain greater insights into this phenotypic variant.