A New, Vitamin D-Based, Multidimensional Nomogram for the Diagnosis of Primary Hyperparathyroidism

Adrian Harvey, MD; MengJun Hu, MS; Manjula Gupta, PhD; Robert Butler, MS; Jamie Mitchell, MD; Eren Berber, MD; Allan Siperstein, MD; Mira Milas, MD, FACS

Disclosures

Endocr Pract. 2012;18(2):124-131. 

In This Article

Abstract and Introduction

Abstract

Objective: To refine the diagnostic criteria for primary hyperparathyroidism (1°HPT) to identify atypical patients, in whom serum calcium, parathyroid hormone (PTH), or both are within the "normal" range.
Methods: Total serum calcium, intact PTH, and 25-hydroxyvitamin D [25(OH)D] levels were measured in patients with 1°HPT and healthy patient groups. Multivariate analysis of healthy patient data first identified factors that significantly affected PTH levels and defined a new PTH reference range with a mathematical model. That nomogram was then validated for prediction of atypical 1°HPT in patients with surgically confirmed disease.
Results: On multivariate analysis, calcium (P = .0002), 25(OH)D (P<.0001), and age (P = .015) independently affected PTH. With these variables, we created a 4-dimensional nomogram that distinguished normal patients from those with hyperparathyroid states. Mathematically, this nomogram predicts 1°HPT when the measured serum PTH value is higher than PTH calculated by the following formula: PTH (pg/mL) = 120 - [6 × calcium (mg/dL)] - [0.52 × 25(OH)D (ng/mL)] + [0.26 × patient age (years)]. When applied to our surgical group of patients, this nomogram successfully identified 100% of patients (238 of 238) with classic 1°HPT, 84% (64 of 76) with normocalcemic 1°HPT, and 54% (20 of 37) with 1°HPT and normal PTH.
Conclusion: This study uniquely defines a patient-specific upper limit of normal for PTH based on the readily available variables of serum calcium, 25(OH)D, and patient age. Our nomogram may allow for more rapid definitive diagnosis and treatment of 1°HPT in patients with atypical presentations.

Introduction

Primary hyperparathyroidism (1°HPT) is the most common cause of hypercalcemia in the outpatient population.[1–3] Traditionally, the diagnosis of 1°HPT has depended on the demonstration of concomitantly elevated levels of serum total or ionized calcium (or both) and parathyroid hormone (PTH), in the setting of normal or high calcium excretion in the urine.[1,4] A considerable number of patients, however, present with biochemical variables that do not fit this classic description but are nonetheless found to have 1°HPT.[1,5–9] This includes at least the following 2 atypical presentations: normocalcemic 1°HPT (with a normal total serum calcium concentration but a high PTH level) and 1°HPT with high serum calcium values but PTH values that are "inappropriately" within the reference range. Normocalcemic 1°HPT has been relatively well characterized with respect to phenotype. Despite borderline laboratory values, these patients have kidney stones, develop osteoporosis, and have fractures.[5,9] The other form of 1°HPT with high serum calcium and normal PTH levels has not been well characterized.

With these shortcomings in the diagnosis of 1°HPT, several authors have sought to clarify the issue through the use of additional tests and by redefining the reference range for PTH. Oral and intravenous calcium suppression tests have been used to assist in these challenging diagnostic scenarios.[10–12] Titon et al[12] used an infusion of 0.33 mmol/kg of calcium gluconate during a 3-hour period and measured serum PTH values at the beginning and end of the infusion and 3 hours after the infusion to determine a PTH suppression cutoff that distinguished patients with hyperparathyroidism from normal control subjects. Unfortunately, performance of such tests may necessitate an additional office visit and take several hours.

The role of vitamin D in the interpretation of diagnostic laboratory values for 1°HPT has also garnered some attention in the literature.[13–19] Citing the high prevalence of vitamin D deficiency in "healthy" persons, Souberbielle et al[18,19] redefined the PTH reference range to <46 pg/mL (previously, 65 pg/mL) in a population of vitamin D-sufficient patients with osteopenia or osteoporosis. The authors proposed that the new reference range would facilitate the diagnosis of patients with mild 1°HPT. This reference standard, however, was defined in a group of patients with metabolic bone disease. In an attempt to replicate these findings in healthy patients, Aloia et al[20] measured relevant biochemical analytes in a cohort of 503 healthy women between the ages of 20 and 80 years. Although many factors were identified that were significantly predictive of PTH, the authors found that a substantial portion of healthy patients had PTH values above the reference standard proposed by Souberbielle et al.[18,19] Thus, a general lowering of the reference standard could not be supported.

What is clear from the existing literature is that cases of "mild" 1°HPT with borderline laboratory results present a diagnostic challenge. Although numerous factors have been identified to affect PTH, as previously noted herein, such knowledge has not translated successfully into a modified reference standard with increased diagnostic accuracy and general applicability to all patients. Therefore, the purpose of the current study was to determine whether we could develop a new, multidimensional PTH nomogram that would yield clearer distinction between normal and disease phenotypes of parathyroid disorders, with the expectation that it should enhance the diagnostic accuracy in challenging 1°HPT scenarios.

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