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NPHPT is defined as persistent fasting normocalcemia associated with an increased serum PTH concentration.

Fasting Normocalcemia

The diagnostic criteria for NPHPT include consistently normal albumin-adjusted total serum calcium and normal ionized calcium. It should be considered that patients with hypercalcemic PHPT (HPHPT) may have normal serum and ionized calcium levels at times during their disease course, though they are hypercalcemic the majority of the time.

Increased Serum PTH Concentrations

Secondary causes of an elevated PTH level must be ruled out, such as renal disease, vitamin D deficiency, renal hypercalciuria, gastrointestinal disorders associated with calcium malabsorption, or the use of loop diuretics and lithium. Therefore, the definition of “elevated PTH,” depending on the upper limit of the PTH reference values, is crucial. It has been demonstrated that excluding subjects with a low serum 25 hydroxyvitamin D [25(OH)D] concentration from a reference population decreased the upper limit of serum PTH by 20–35% depending on the assay considered [2–4]. Other factors may influence serum PTH levels, such as age and BMI.

The motivating purpose for maxPTH creation was the hypothesis that, by defining a more subject-specific, personalized upper limit of normal PTH, the challenge of discriminating between some diagnostic variants of PHPT and secondary hyperparathyroidism (SHPT) may be easier than using a static PTH lab reference range [5]. maxPTH was calculated using the formula maxPTH = 120 – (6·calcium) – [0.5·26(OH)D] + (0.25·age) [5]. The Mi-PTH (MultIdimensional Predictive Hyperparathyroid) model was created based on retrospective data. The model included all the variables of the original maxPTH equation with the inclusion of the subject’s measured PTH level. With Mi-PTH, the model is designed to account for changes in PTH levels that are expected on the basis of the subject’s age, calcium, and 25(OH)D, whereas in primary hyperparathyroid diseases, PTH production is independent of these factors. Of note, serum creatinine levels were not included in this model because the relationship of PTH with creatinine is not clearly linear in nature as it is with vitamin D and calcium. Mi-PTH improved on specificity and PPV for patients with normocalcemic hyperparathyroidism [6].

Similarly, Lavryk and Siperstein [7] created a nomogram by plotting PTH versus calcium for the 2 groups. The comparison of control and disease groups showed a clear demarcation zone on the plots of calcium versus PTH. In the group of PHPT, 70% had classic PHPT presentation with the concomitant elevation of both calcium (>10.5 mg/dL) and PTH (>65 pg/dL); 21% had “normocalcemic” PHPT with calcium <10.5 mg/dL and PTH >65 pg/dL; 6% had “normohormonal” PHPT with calcium >10.5 mg/dL and PTH <65 pg/dL, and 3% had both calcium and PTH within the reference range. Overall, 68.5% of patients had single adenoma, 16% double adenoma, and 15.5% hyperplasia. The nomogram serves as a diagnostic tool to distinguish normal patients from those with PHPT, particularly those with atypical presentations.

It should be remembered that PTH elevation and concomitant normocalcemia can also be detected in HPHPT patients after 1–24 months from successful parathyroidectomy. Patients who had severe hyperparathyroidism with high preoperative serum calcium and PTH levels are more prone to normocalcemic PTH elevation postsurgery [8].