Diagnosis: Mild Primary Hyperparathyroidism Unmasked by Vitamin D Supplementation
Your patient has mild primary hyperparathyroidism (PHPT) that was biochemically masked by severe vitamin D deficiency, then revealed when vitamin D supplementation normalized the deficiency and removed the secondary hyperparathyroid stimulus. 1
Understanding the Biochemical Evolution
Your initial workup appropriately ruled out the major PTH-independent causes of hypercalcemia:
- Normal PTHrP excluded malignancy-associated hypercalcemia, which typically presents with suppressed PTH (<20 pg/mL), elevated PTHrP, and low or normal 1,25(OH)2D 2, 1
- Normal 1,25(OH)2D excluded granulomatous disease (sarcoidosis, tuberculosis), where ectopic 1α-hydroxylase in macrophages produces elevated 1,25(OH)2D despite low 25(OH)D 3, 4, 5
However, the critical diagnostic clue you initially missed was that "inappropriately normal" PTH in the presence of hypercalcemia IS diagnostic of primary hyperparathyroidism 1, 6. The parathyroid glands autonomously secrete PTH despite elevated calcium, which is the hallmark of PHPT 1.
Why Vitamin D Deficiency Masked the Diagnosis
Vitamin D deficiency causes secondary hyperparathyroidism and must be excluded before diagnosing PHPT 1. In your patient's case:
- Initial 25(OH)D of 28 ng/mL (deficient) drove compensatory PTH elevation to maintain calcium homeostasis 1
- This secondary stimulus artificially elevated the PTH, masking the autonomous hypersecretion from adenomatous parathyroid tissue 7
- The calcium of 10.7 mg/dL represented the combined effect of both autonomous parathyroid function AND compensatory response to vitamin D deficiency 1
What Happened After Vitamin D Supplementation
When you supplemented vitamin D to 65 ng/mL (replete):
- The secondary hyperparathyroid stimulus was removed, allowing the true autonomous PTH secretion to become apparent 1
- PTH dropped to 25 pg/mL (still inappropriately normal-to-elevated for a calcium of 10.7 mg/dL) 1
- This paradoxical pattern—persistent hypercalcemia with non-suppressed PTH despite vitamin D repletion—confirms autonomous parathyroid function 1, 6
- The vitamin D supplementation increased intestinal calcium absorption, which in a normal person would suppress PTH to <20 pg/mL, but your patient's PTH remained at 25 pg/mL 4, 7
Research demonstrates that 1,25(OH)2D indeed suppresses PTH secretion even in PHPT patients, but cannot normalize it due to autonomous adenomatous tissue 7. Your patient's PTH of 25 is the suppressed level—without the vitamin D, it would likely be 40-60 pg/mL.
Confirming the Diagnosis
Elevated or inappropriately normal PTH (>20-25 pg/mL depending on assay) in the presence of hypercalcemia confirms PHPT 1, 6. Your patient meets diagnostic criteria:
- Corrected calcium >10.2 mg/dL (specifically 10.7 mg/dL, which is >0.4 mg/dL above upper limit of 10.3 mg/dL) 1
- PTH 25 pg/mL is inappropriately normal for this calcium level (should be suppressed to <20 pg/mL) 1, 6
- PTH reference values are 20% lower in vitamin D-replete individuals, making your patient's PTH of 25 even more diagnostic 1
Recommended Next Steps
Discontinue vitamin D supplementation immediately 3, 1. You correctly stopped it, as continued supplementation in PHPT increases intestinal calcium absorption and worsens hypercalcemia 4.
Complete the PHPT workup 1:
- Measure 24-hour urine calcium or spot urine calcium/creatinine ratio to assess hypercalciuria 1
- Obtain renal ultrasound to evaluate for nephrocalcinosis or kidney stones 1
- Measure serum creatinine and calculate eGFR 1
- Consider bone density scan if chronic hyperparathyroidism suspected 1
Refer to endocrinology and an experienced parathyroid surgeon for surgical evaluation 1. Parathyroidectomy indications include 1:
- Age <50 years
- Corrected calcium >1 mg/dL above upper limit (your patient has 10.7 vs. 10.3 = 0.4 mg/dL elevation, approaching this threshold)
- eGFR <60 mL/min/1.73 m²
- Osteoporosis (T-score ≤-2.5)
- History of nephrolithiasis or nephrocalcinosis
If surgery is planned, obtain preoperative localization imaging with ultrasound and/or 99mTc-sestamibi scintigraphy with SPECT/CT 1. However, do not order imaging before confirming biochemical diagnosis, as imaging is for surgical planning, not diagnosis 1.
Management Pending Surgical Decision
For patients >50 years with calcium <1 mg/dL above upper limit and no skeletal or kidney disease, observation may be appropriate 6. If observation is chosen:
- Maintain normal calcium intake (1000-1200 mg/day) and avoid high or low calcium diets 1
- Total elemental calcium intake should not exceed 2000 mg/day 1
- Ensure adequate oral hydration 1
- Monitor serum calcium every 3 months initially 3, 1
Critical Pitfall You Avoided
You correctly did not resume vitamin D supplementation after stopping it 3, 1. The K/DOQI guidelines state that vitamin D should not be resumed until serum calcium is consistently below 9.5 mg/dL, the underlying cause is identified and treated, and 24-hour urinary calcium normalizes 1.
In PHPT patients, vitamin D supplementation creates a dangerous situation where increased intestinal calcium absorption combines with autonomous PTH-mediated bone resorption and renal calcium reabsorption, producing severe hypercalcemia 4. Never supplement vitamin D without measuring both 25(OH)D and 1,25(OH)2D in patients with hypercalcemia 3, 4.
Why This Case Was Diagnostically Challenging
PTH assays vary significantly between laboratories (up to 47% variation), and biological variation of PTH is substantial (20% in healthy individuals) 1. Your patient's PTH of 25 pg/mL sits in a diagnostic gray zone where assay variability matters. However, the combination of persistent hypercalcemia (10.7 mg/dL) with non-suppressed PTH (25 pg/mL) after vitamin D repletion is diagnostic 1, 6.
The prognosis for asymptomatic PHPT is excellent with either medical or surgical management 6. Your diagnostic approach was methodical and appropriate—you systematically excluded malignancy and granulomatous disease before arriving at the correct diagnosis of mild PHPT unmasked by vitamin D repletion.