Normocalcemic Hyperparathyroidism: A Heterogeneous Disorder Often Misdiagnosed?

Bart L Clarke,Guido Zavatta

doi:10.1002/jbm4.10391

Abstract

ABSTRACTNormocalcemic 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.

Highlights

Normocalcemic primary hyperparathyroidism (NHPT) is the newest phenotype of pathologic parathyroid overactivity, initially formally recognized and defined as a distinct entity in 2008 at the Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism.[1]. This marked the recognition of the third subtype presentation of primary hyperparathyroidism (PHPT),(2) which was initially described with classical manifestations and symptoms in the early 1900s, as the more frequently recognized asymptomatic form with the advent of automated calcium (Ca) analyzers in the 1970s
The rapid response to Ca in the NHPT cohort is consistent with physiology, pointing toward a form of secondary rather than PHPT. Another hypothesis is that over-production of PTH by patients with NHPT may be lower compared with that in patients with PHPT.[4]. Proving this hypothesis is difficult and, as yet, no substantial differences in basal PTH levels have been found between patients with PHPT and NHPT,(22) except in one cohort studied by Maruani and colleagues.[23]. This study suggested that relatively lower secretion of PTH in NHPT might result in serum Ca concentrations remaining within the normal range
One study has examined the relationship between NHPT and quality of life.[52]. This study addressed both physical and mental aspects of patients with NHPT and PHPT

Summary

Introduction

Normocalcemic primary hyperparathyroidism (NHPT) is the newest phenotype of pathologic parathyroid overactivity, initially formally recognized and defined as a distinct entity in 2008 at the Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism.[1]. The importance of vitamin D in NHPT has recently been highlighted by Wang and colleagues[24] who identified 10 patients meeting criteria for NHPT out of 500 patients diagnosed with PHPT and another 400 patients screened for hyperparathyroidism after exclusion of obvious secondary causes of PTH elevation They evaluated these 10 NHPT patients and 20 age-, sex- and BMI-matched control subjects, and reported that the NHPT patients had lower serum-free 25(OH)D levels compared with the controls when measured by an immunometric assay. Schini and colleagues[42] suggested that strict application of the international diagnostic criteria for NHPT would have resulted in a prevalence of zero in their cohort, despite a large population of 6280 subjects They demonstrated that patients classified as having NHPT had frequent oscillation of their serum Ca values during the follow-up period, sometimes going above the upper reference limit. NHPT patients had similar BMD at the lumbar spine, hip, and one-third distal radius, and similar prevalence of morphometric vertebral fractures (28% versus 23%; NS) and n NORMOCALCEMIC HYPERPARATHYROIDISM 7 of 14 n 8 of 14 ZAVATTA AND CLARKE

Summary

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Conclusions