Vitamin D status in normocalcaemic primary hyperparathyroidism

Abstract

The evaluation of vitamin D status in primary hyperparathyroidism (PHPT) [ [1] Saliba W. Lavi I. Rennert H.S. Rennert G. Vitamin D status in primary hyperparathyroidism. Eur J Intern Med. 2012; 23: 88-92 Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar ] should, for the sake of completeness, also include a comment on the role of documentation of vitamin D status in the characterisation of normocalcaemic hyperparathyroidism, the latter now recognised as a distinct phenotype in its own right [ [2] Lowe H. McMahon D.J. Rubin M.R. Bilezikian J.P. Silverberg S.J. Normocalcemic primary hyperparathyroidism: further characterisation of a new clinical phenotype. J Clin Endocrinol Metab. 2007; 92: 3001-3005 Crossref PubMed Scopus (261) Google Scholar ]. For this diagnosis to be valid vitamin D(25OHD) status has to be evaluated so as to rule out hypovitaminosis D as the underlying cause of elevation in serum parathyroid hormone (PTH). Other causes of secondary hyperparathyroidism, such as renal insufficiency, also have to be ruled out, all this in the context of total serum calcium which falls within the normal range when corrected for serum albumin. In a study which utilised those criteria 37 patients aged 32–78 were identified, 29 of whom were postmenopausal women, and only 2 of whom were male. In spite of normocalcaemia 14% of those patients had a history of kidney stones, and 57% had osteoporosis [ [2] Lowe H. McMahon D.J. Rubin M.R. Bilezikian J.P. Silverberg S.J. Normocalcemic primary hyperparathyroidism: further characterisation of a new clinical phenotype. J Clin Endocrinol Metab. 2007; 92: 3001-3005 Crossref PubMed Scopus (261) Google Scholar ]. On median follow up of 3 years seven of those patients subsequently became hypercalcaemic [ [2] Lowe H. McMahon D.J. Rubin M.R. Bilezikian J.P. Silverberg S.J. Normocalcemic primary hyperparathyroidism: further characterisation of a new clinical phenotype. J Clin Endocrinol Metab. 2007; 92: 3001-3005 Crossref PubMed Scopus (261) Google Scholar ]. Diagnostic criteria for normocalcaemic PHPT were further refined in a workshop which specified that patients with this diagnosis should also have normal levels of ionised calcium [ [3] Silverberg S.J. Lewiecki M.E. Mosekilde L. Peacock M. Rubin M.R. Presentation of asymptomatic primary hyperparathyroidism: proceedings of the Third International Workshop. J Clin Endocrinol Metab. 2009; 94: 351-365 Crossref PubMed Scopus (266) Google Scholar ], a recommendation supported by the observation that patients with primary hyperparathyroidism may have raised levels of ionised serum calcium even when total serum calcium and serum albumin levels are normal [ 4 Forster J. Monchik J.M. Martin H.F. A comparative study of serum ultrafiltrable, ionized, and total calcium in the diagnosis of primary hyperparathyroidism in patients with intermittent or no elevation in total calcium. Surgery. 1988; 104: 1137-1142 PubMed Google Scholar , 5 Wade T.J. Yen T.W.F. Amin A.L. Wang T.S. Surgical management of normocalcemic primary hyperparathyroidism. World J Surg. 2012; https://doi.org/10.1007/s00268-012-1438-y Crossref PubMed Scopus (51) Google Scholar ]. Although, according to one view, “many patients once thought to have normocalcaemic PHPT (primary hyperparathyroidism) are instead patients with the more usual hypercalcaemic PHPT who have coexisting vitamin D deficiency, which lowers their serum calcium levels into the reference range” [ [3] Silverberg S.J. Lewiecki M.E. Mosekilde L. Peacock M. Rubin M.R. Presentation of asymptomatic primary hyperparathyroidism: proceedings of the Third International Workshop. J Clin Endocrinol Metab. 2009; 94: 351-365 Crossref PubMed Scopus (266) Google Scholar ], correction of coexisting vitamin D deficiency does not necessarily generate an increase in serum calcium to the hypercalcaemic range. The absence of post-treatment increase in serum calcium was exemplified by two patients with normocalcaemic PHPT in whom pretreatment serum 25-hydroxy vitamin D levels amounted to 9 ng/ml, and 11 ng/ml, respectively (reference range 11–55 ng/ml), and in whom vitamin D replacement therapy resulted in an increase in serum vitamin D levels to 21 ng/ml in each instance [ [6] Kantorovich V. Gacad M.A. Seeger L.L. Adams J.S. Bone mass density increases with vitamin D repletion in patients with coexistent vitamin D insufficiency and primary hyperparathyroidism. J Clin Endocrinol Metab. 2000; 85: 3541-3543 Crossref PubMed Scopus (98) Google Scholar ]. What is also uncertain is whether, in the event of coexistence of raised PTH levels, hypovitaminosis D, and normocalcaemia, a therapeutic trial of vitamin D repletion can achieve a diagnostic separation between normocalcaemic PHPT and secondary hyperparathyroidism. In theory, a sustained increase in PTH concentration (as was the case in two normocalcaemic patients who participated in the therapeutic trial of vitamin D repletion) [ [6] Kantorovich V. Gacad M.A. Seeger L.L. Adams J.S. Bone mass density increases with vitamin D repletion in patients with coexistent vitamin D insufficiency and primary hyperparathyroidism. J Clin Endocrinol Metab. 2000; 85: 3541-3543 Crossref PubMed Scopus (98) Google Scholar ], validates the diagnosis of normocalcaemic PHPT. An alternative view, however, is that, in that context, a sustained increase in PTH concentration is merely indicative of refractory secondary hyperparathyroidism [ [7] Bollerslev J. Marcocci C. Henriquez M.S. Nordenstrom J. Bouillon R. Mosekilde L. Current evidence for recommendation of surgery, medical treatment, and vitamin D repletion in mild hyperparathyroidism. Eur J Endocrinol. 2011; https://doi.org/10.1530/EJE-11-0589 Crossref Scopus (60) Google Scholar ]. The complex interplay between serum calcium intact PTH, 25OH vitamin D levels and age in PHPT and in normal subjects has now been defined in a four-dimensional nomogram which is intended to facilitate definitive diagnosis of atypical presentations such as normocalcaemic PHPT [ [8] Harvey A. Hu M.J. Gupta M. Butler R. Mitchell J. Berber E. et al. A new, vitamin D-based, multidimensional nomogram for the diagnosis of primary hyperparathyroidism. Endocr Pract. 2011; https://doi.org/10.4158/EP10389.OR Crossref Scopus (20) Google Scholar ]. Even though this nomogram relies on total rather than on ionised serum calcium, the fact that it is vitamin D-based bears testimony to the crucial relevance of vitamin D status in the evaluation of all subtypes of PHPT [ [8] Harvey A. Hu M.J. Gupta M. Butler R. Mitchell J. Berber E. et al. A new, vitamin D-based, multidimensional nomogram for the diagnosis of primary hyperparathyroidism. Endocr Pract. 2011; https://doi.org/10.4158/EP10389.OR Crossref Scopus (20) Google Scholar ].