What are the causes of a mildly elevated parathyroid hormone level with normal serum calcium, magnesium, and phosphate?

Causes of Mildly Elevated PTH with Normal Calcium, Magnesium, and Phosphate

The most common cause of mildly elevated PTH with normal calcium, magnesium, and phosphate is early chronic kidney disease (CKD Stage 2-3), where phosphate retention begins before serum phosphorus becomes measurably elevated, triggering compensatory PTH secretion. 1

Primary Differential Diagnosis

Early Chronic Kidney Disease (Most Common)

• PTH levels begin rising when GFR falls below 60 mL/min/1.73 m² (Stage 3 CKD), even when serum phosphorus, calcium, and magnesium remain normal. 1
• Phosphate retention occurs as early as Stage 1-2 CKD and directly stimulates PTH secretion as a compensatory mechanism to increase renal phosphate excretion, maintaining normal serum phosphorus levels at the cost of elevated PTH. 1, 2, 3
• The kidney's reduced capacity to produce 1,25-dihydroxyvitamin D (calcitriol) decreases intestinal calcium absorption, contributing to PTH elevation despite normal serum calcium. 3, 4
• Check: Obtain serum creatinine and calculate eGFR to assess kidney function; even mild reductions (eGFR 60-89 mL/min/1.73 m²) can cause PTH elevation. 1

Vitamin D Insufficiency/Deficiency

• Vitamin D insufficiency (25-hydroxyvitamin D levels <30 ng/mL) is extremely prevalent (80-90% in CKD patients, but also common in the general population) and reduces intestinal calcium absorption, triggering compensatory PTH elevation. 3
• Check: Measure 25-hydroxyvitamin D levels; levels between 16-30 ng/mL indicate insufficiency that can drive secondary hyperparathyroidism. 3, 5

Calcium Deficiency/Insufficient Calcium Intake

• Inadequate dietary calcium intake is an underrecognized cause of normocalcemic PTH elevation that can mimic primary hyperparathyroidism. 6
• A recent study demonstrated that approximately 50% of patients with normocalcemic PTH elevation had secondary hyperparathyroidism due to insufficient calcium intake, which resolved with calcium supplementation (mean baseline calcium 9.5 ± 0.3 mg/dL, PTH 109.9 ± 34.9 pg/mL). 6
• Diagnostic approach: Implement a calcium challenge with supplemental calcium (typically 1000-1500 mg/day) and vitamin D3 for 2-3 months; normalization of PTH confirms secondary hyperparathyroidism from calcium deficiency, while development of hypercalcemia with persistent PTH elevation suggests primary hyperparathyroidism. 6

Normocalcemic Primary Hyperparathyroidism (NPHPT)

• NPHPT represents autonomous parathyroid function with normal total and ionized calcium but elevated PTH, accounting for approximately 19% of primary hyperparathyroidism cases in referral populations. 7
• This diagnosis should only be made after careful exclusion of all causes of secondary hyperparathyroidism, including CKD, vitamin D deficiency, calcium deficiency, medications, and malabsorption. 5, 6
• NPHPT may represent the earliest form of primary hyperparathyroidism that will progress to hypercalcemic disease over time, but it is not an indolent condition—patients present with high prevalence of nephrolithiasis (36%), fragility fractures (12%), and osteoporosis (25%). 7

Medication-Induced PTH Elevation

• Loop diuretics increase urinary calcium excretion, potentially causing compensatory PTH elevation. 6
• Bisphosphonates can transiently lower serum calcium and stimulate PTH secretion. 5
• Review medication list for drugs that affect calcium homeostasis or increase PTH secretion. 5

Gastrointestinal Malabsorption

• Prior gastric bypass or gastric sleeve surgery impairs calcium and vitamin D absorption, leading to secondary hyperparathyroidism. 6
• Celiac disease, inflammatory bowel disease, and chronic pancreatitis can cause malabsorption of calcium and vitamin D. 5

Diagnostic Algorithm

1. Measure serum creatinine and calculate eGFR to assess for early CKD (most common cause). 1

2. Measure 25-hydroxyvitamin D levels to identify vitamin D insufficiency/deficiency. 3, 5

3. Assess dietary calcium intake through detailed history; if inadequate (<1000 mg/day), implement calcium challenge with 1000-1500 mg/day elemental calcium plus vitamin D3 supplementation. 6

4. Recheck PTH, calcium, and vitamin D levels after 2-3 months of calcium/vitamin D supplementation:

   • PTH normalization with normal calcium = secondary hyperparathyroidism from calcium/vitamin D deficiency 6
   • Development of hypercalcemia with elevated PTH = primary hyperparathyroidism 6
   • Persistent normocalcemic PTH elevation = consider NPHPT or ongoing secondary causes 5, 7

5. Measure ionized calcium if total calcium is borderline, as ionized calcium is more sensitive for detecting early primary hyperparathyroidism. 5, 7

6. Review medications for loop diuretics, bisphosphonates, or other drugs affecting calcium homeostasis. 5, 6

7. Assess for malabsorption through history of gastrointestinal surgery, celiac disease, or inflammatory bowel disease. 5, 6

Critical Pitfalls to Avoid

• Do not diagnose normocalcemic primary hyperparathyroidism without first excluding all secondary causes, particularly early CKD, vitamin D deficiency, and calcium deficiency—this prevents unnecessary parathyroidectomy. 5, 6

• Do not overlook early CKD (Stage 2-3) as the cause; PTH elevation precedes abnormalities in serum phosphorus, calcium, and magnesium by months to years. 1, 2

• Do not assume normal vitamin D levels based on supplementation history alone—measure 25-hydroxyvitamin D, as insufficiency is extremely common even with supplementation. 3

• Do not rush to parathyroid imaging or surgery in normocalcemic patients; a conservative approach with calcium challenge and repeat testing in 2-3 months identifies approximately 50% who have reversible secondary hyperparathyroidism. 6

• Do not ignore medications that increase urinary calcium losses (loop diuretics) or affect calcium homeostasis, as these are easily reversible causes. 6