Distinguishing hyperparathyroidism from insulin-like growth factor I–driven calcium–phosphate metabolism changes in acromegaly

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Abstract
Objectives: Acromegaly is frequently associated with disturbances in calcium–phosphate metabolism, including mild hypercalcemia. Hypercalcemia may also reflect primary hyperparathyroidism (PHPT), which can occur with or without variants in MEN1 or the related genes. Distinguishing PHPT from insulin-like growth factor I (IGF-I)–related alterations in mineral metabolism remains challenging. We aimed to assess the prevalence and characteristics of PHPT in patients with acromegaly and explore biochemical approaches for identifying parathyroid autonomy. Design: We conducted a retrospective study at 2 French university hospitals, including adults with acromegaly who had at least 1 serum calcium measurement obtained during uncontrolled disease. Three diagnostic approaches based on serum calcium and phosphate levels were evaluated: a threshold-based decision rule, logistic regression, and a support vector machine model. Results: Among 393 patients (54% women; median age 43 years [interquatile range 33-55]), 23 (5.9%) had concomitant PHPT. In isolated acromegaly, hyperphosphatemia occurred in 37.3% and mild hypercalcemia in 3.2% of patients; both resolved after acromegaly treatment. Patients with PHPT had persistent mild hypercalcemia (median calcium 2.72 mmol/L [interquatile range 2.66-2.86]), elevated PTH, and low-to-normal phosphate levels, these abnormalities resolved after parathyroid surgery in the 10 operated patients. No pathogenic variants were identified in the tested genes. A threshold-based rule combining calcium >2.60 mmol/L and phosphate <1.46 mmol/L showed excellent diagnostic performance for identifying parathyroid autonomy, with bootstrap 0.632+ corrected sensitivity and specificity of 0.940 and 0.993, respectively, and was preferred because of its simplicity. Conclusions: PHPT may be more frequent in acromegaly than in the general population. In patients with acromegaly and hypercalcemia, a nonelevated phosphate level strongly suggests concomitant PHPT, whereas an elevated phosphate level favors IGF-I–related mineral disturbances.

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