Normocalcemic Hyperparathyroidism: A Heterogeneous Disorder Often Misdiagnosed?

Abstract

Normocalcemic primary hyperparathyroidism (NHPT) was first described over 10 years ago, but uncertainties still remain about its definition, prevalence, and rates of complications. As a result, consensus management guidelines for this condition have not yet been published. Several hypotheses have been proposed for the pathophysiology of NHPT, but it may be a heterogeneous disorder with multiple causes, rather than a single etiology that explains this biochemical phenotype. A common clinical concern is whether NHPT should be treated surgically when complications are already present at first recognition of the disorder, rather than following patients clinically over time. The literature on NHPT is based mostly on larger studies of population-based cohorts and smaller studies from referral centers. Lack of rigorous diagnostic criteria and selection bias inherent in populations seen at tertiary referral centers may explain the heterogeneity of reported rates of bone and renal complications in relation to consistently mild laboratory alterations. Unresolved questions remain about the significance of NHPT when it is diagnosed biochemically without evident bone or kidney complications. Moreover, its natural history remains to be elucidated because a proportion of what is classified as NHPT may revert to normal spontaneously, thus revealing previously unrecognized secondary hyperparathyroidism. These issues indicate that caution should be used in recommending surgery for NHPT. This review will focus on recent issues regarding the pathophysiology, evaluation, and management of NHPT. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Keywords: HYPERCALCEMIA; HYPERCALCIURIA; NEPHROLITHIASIS; NORMOCALCEMIC HYPERPARATHYROIDISM; OSTEOPOROSIS; PRIMARY HYPERPARATHYROIDISM; SECONDARY HYPERPARATHYROIDISM.

Fig 1

Normal physiology: Under normal physiology the parathyroid glands secrete PTH to stimulate bone turnover and reabsorb calcium (Ca) from the renal tubules. If serum Ca decreases, the parathyroid cell Ca‐sensing receptors (CaSRs) sense this, and induce the parathyroid glands to secrete more PTH to reabsorb more Ca from the kidneys and to mobilize more Ca from the bones to restore previous normal serum Ca. Given stable intestinal Ca absorption, the renal tubules reabsorb the amount of Ca needed to maintain negative feedback on the parathyroid glands, preserving normal PTH secretion and stable bone density. The parathyroid glands, small intestine, and kidneys work synergistically to maintain normal physiology.

Fig 2

Patients with hyperparathyroidism appear to present with different phenotypes. It has not yet been observed that the recognized phenotypes progress to more severe phenotypes, or regress to less severe forms over time, with the possible exception of classical mild primary hyperparathyroidism regressing to normal when observed over years without surgery. Phenotype 1. Mild changes within the physiologic range: Subclinical increased renal calcium (Ca) losses stimulate the parathyroid glands to secrete increased PTH within the physiologic range. Phenotype 2. Normocalcemic hyperparathyroidism: PTH oversecretion stabilizes at a new set‐point, in which renal Ca filtration and reabsorption are increased to allow preservation of bone density, but not enough to cause Ca‐sensing receptor function to inhibit the parathyroid glands. Phenotype 3. Asymptomatic primary hyperparathyroidism: PTH oversecretion is associated with parathyroid gland enlargement and eventual parathyroid autonomy, with no evidence of bone or renal complications. Phenotype 4. Primary hyperparathyroidism: Clinical features of classical primary hyperparathyroidism with possible kidney malfunction and bone loss starting with the cortical sites.