Appropriate Cutoff for 25OHD Levels in the Diagnosis of Normocalcemic Primary Hyperparathyroidism (NPHPT): A Systematic Review

Introduction: The Fourth International Workshop in 2014 delineated guidelines for the diagnosis of NPHPT which include ruling out secondary causes of hyperparathyroidism, and recommended cutoffs for 25 vitamin D (25OHD) to be ≥20ng/mL. Keeping in mind that the exact levels to optimize 25OHD in hyperparathyroid states are unknown, we aim to review possible variation in the prevalence of NPHPT if 25OHD cutoffs were to be raised to rule out vitamin D deficiency with more specificity. Methods: A PubMed search was conducted with key words “normocalcemic primary hyperparathyroidism” to review studies about NPHPT and 25OHD status. 533 articles were found, and 127 articles were identified by title/abstract screening with year of publication between 2014 to 2020. Ten studies were identified for the systematic review based on full text review for relevance. Results: Studies have been conducted in various countries across all continents to characterize NPHPT further. 5/10 studies used 25OHD cutoff of ≥20ng/mL and 4 studies had a cutoff of ≥30ng/mL and 1 study looked into the difference in prevalence with both cutoffs. All 3 studies from Italy used the higher cutoff. Rosario et al from Brazil reported a decrease in prevalence of NPHPT from 6.8% (25OHD≥20ng/mL) to 0.74% by supplementing those subjects to 25OHD ≥30ng/mL without any increase in serum calcium or parathyroid hormone (PTH) levels.(1) Wang et al found that when total 25OHD levels were kept between 30–40 ng/mL, free 25OHD levels were actually lower compared to normal subjects.(2) Conclusion: The levels of 25OHD that would define deficiency in NPHPT remain undetermined and both >20 ng/mL and >30ng/mL have been studied as cutoffs. It is well known that vitamin D insufficiency (25D 20-30ng/mL) drives up PTH and supplementation to 30-40ng/mL is required to reduce such effects. Wang et al suggest that free 25OHD levels correlate better with PTH as compared to total 25OHD and maybe a more reliable marker of 25OHD status. We suggest that a diagnostic criterion of ≥30ng/mL would be more appropriate in ruling out 25OHD deficiency in this special population. The role of free 25OHD levels in PHPT needs further evaluation. References: 1. Rosário PW, Calsolari MR. Normocalcemic Primary Hyperparathyroidism in Adults Without a History of Nephrolithiasis or Fractures: A Prospective Study. Horm Metab Res. 2019 Apr;51(4):243–247. doi: 10.1055/a-0859-1020. Epub 2019 Mar 6. PMID: 30840998. 2. Wang X, Meng L, Su C, Shapses SA. LOW FREE (BUT NOT TOTAL) 25-HYDROXYVITAMIN D LEVELS IN SUBJECTS WITH NORMOCALCEMIC HYPERPARATHYROIDISM. Endocr Pract. 2020 Feb;26(2):174–178. doi: 10.4158/EP-2019-0325. Epub 2019 Sep 26. PMID: 31557077