Normocalcemic Primary Hyperparathyroidism: Need for a Standardized Clinical Approach

Abstract

Since normocalcemic primary hyperparathyroidism (NHPT) was first defined at the Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism in 2008, many papers have been published describing its prevalence and possible complications. Guidelines for the management of this condition are still lacking, and making the diagnosis requires fulfillment of strict criteria. Recent studies have shown that intermittent oscillations of serum calcium just below and slightly above the normal limits are very frequent, therefore challenging the assumption that serum calcium must be consistently normal to make the diagnosis. There is debate if these variations in serum calcium outside the normal range should be included under the rubric of NHPT or, rather, a milder form of classical primary hyperparathyroidism. Innovative approaches to define NHPT have been proposed that still need to be validated in prospective studies. Non-classical complications, especially cardiovascular complications, have been associated with NHPT, indicating that hyperparathyroidism may be a cardiovascular risk factor. New associations between parathyroid hormone (PTH) and several other comorbidities have also been reported from observational studies, suggesting that excessive PTH secretion might cause tissue dysfunction independent of serum calcium. Heterogeneous studies using different definitions of NHPT, however, make it difficult to draw definitive conclusions regarding the role of PTH excess when complications other than osteoporosis or kidney stones are described. This review will focus on clinical aspects and suggest an approach to NHPT.

European expert consensus on practical management of specific aspects of parathyroid disorders in adults and in pregnancy: recommendations of the ESE Educational Program of Parathyroid Disorders (PARAT 2021)

“…Over an 8-year follow-up of 64 subjects identified through community screening, only 1 person developed hypercalcemic PHPT, and only 13 retained the biochemical findings of normocalcemic PHPT (61). Published series have used inconsistent definitions of normocalcemic PHPT and it is thus difficult to estimate the true prevalence and complication rate (62). Reported complication rates vary from zero in population-based studies (63,64,65) to 11-35% of patients with renal stones and 5-40% with lowtraumatic fractures and osteoporosis, as assessed in tertiary referral centers (60,66,67,68,69).…”

Applications of Metabolomics in Calcium Metabolism Disorders in Humans

“…Due to advances in diagnostics, the clinical presentation of PHPT evolved in developed countries from a symptomatic to an incidentally discovered and asymptomatic disorder [ 47 ]. Recent observational studies suggested that excessive PTH secretion in normocalcemic PHPT, the first subclinical phase of PHPT, might exhibit metabolic disturbances and induce the risks of cardiovascular diseases and tissue dysfunctions [ 48 , 49 ].…”

“…Nutritional rickets is still endemic in many countries and occurs due to calcium or vitamin D deficiency. Vitamin D supplementation for all infants and young children significantly reduced the incidence of nutritional rickets in Europe and North America [ 48 ].…”

Incidental Normocalcemic Primary Hyperparathyroidism Presenting With Symptomatic Hypophosphatemia: A Case Report

“…Although the clinical presentation of PHPT is highly variable, asymptomatic hypercalcemia detected incidentally is the most common presentation [ 2 ]. Normocalcemic primary hyperparathyroidism (NHPT) is a newly defined variant of PHPT which has led to new questions regarding its diagnosis and management [ 3 ]. In contrast to PHPT, NPHP is characterised by consistently normal total and ionised calcium (Ca) levels with elevated PTH in the absence of secondary causes of hyperparathyroidism [ 4 ].…”