What causes hypercalcemia with a normal parathyroid hormone level in a patient with impaired renal function (creatinine ~1.7 mg/dL)?

Differential Diagnosis of Hypercalcemia with Normal PTH and Impaired Renal Function

In a patient with hypercalcemia, normal PTH, and a creatinine of 1.7 mg/dL (eGFR <60 mL/min/1.73 m²), the most likely diagnosis is primary hyperparathyroidism with "inappropriately normal" PTH—a PTH that fails to suppress below 20 pg/mL despite elevated calcium—and this diagnosis is further supported by the impaired renal function, which is itself a surgical indication for parathyroidectomy. 1, 2

Understanding "Normal" PTH in Hypercalcemia

The key concept here is that PTH should be suppressed (typically <20 pg/mL) when calcium is elevated. 3 A PTH value in the "normal" laboratory reference range in the setting of hypercalcemia is actually inappropriately elevated and indicates autonomous parathyroid hormone secretion—the hallmark of primary hyperparathyroidism. 1, 2

• Primary hyperparathyroidism is defined by hypercalcemia with elevated OR inappropriately normal PTH levels, where the parathyroid glands autonomously secrete PTH despite elevated calcium. 1, 2
• This represents a failure of the normal negative feedback mechanism that should suppress PTH secretion when calcium rises. 1
• Approximately 90% of hypercalcemia cases are due to either primary hyperparathyroidism or malignancy, with primary hyperparathyroidism being the dominant cause in ambulatory patients. 3

Diagnostic Algorithm

Step 1: Confirm True Hypercalcemia

• Measure ionized calcium (normal: 4.65-5.28 mg/dL) or calculate corrected calcium if albumin is abnormal to avoid misleading total calcium measurements. 1
• Rule out pseudo-hypercalcemia. 1

Step 2: Interpret PTH in Context

• If PTH is elevated or "inappropriately normal" (fails to suppress <20 pg/mL): This confirms PTH-dependent hypercalcemia, most commonly primary hyperparathyroidism. 1, 3
• If PTH is truly suppressed (<20 pg/mL): Consider PTH-independent causes including malignancy (measure PTHrP), granulomatous disease, vitamin D intoxication, or medications. 1, 3

Step 3: Essential Laboratory Panel

Obtain simultaneously:

• Serum calcium (corrected or ionized), intact PTH, 25-hydroxyvitamin D, serum phosphorus, serum creatinine, and eGFR. 1
• Measure 1,25-dihydroxyvitamin D if PTH is suppressed to distinguish vitamin D intoxication (markedly elevated 25-OH vitamin D) from granulomatous disease (low 25-OH vitamin D but elevated 1,25-dihydroxyvitamin D). 1
• 24-hour urine calcium or spot urine calcium/creatinine ratio to assess urinary calcium excretion. 1

Step 4: Exclude Secondary Causes of PTH Elevation

Before confirming primary hyperparathyroidism, rule out:

• Vitamin D deficiency: Aim for 25-hydroxyvitamin D >20 ng/mL (>50 nmol/L), as deficiency is the most frequent cause of secondary hyperparathyroidism. 1, 2
• Inadequate dietary calcium intake: Confirm intake of 1,000-1,200 mg/day for adults. 1, 2
• Chronic kidney disease: Your patient's creatinine of 1.7 mg/dL (eGFR likely <60 mL/min/1.73 m²) complicates interpretation, but hypercalcemia with elevated/normal PTH in CKD stage G3b still suggests primary hyperparathyroidism rather than secondary hyperparathyroidism, because secondary hyperparathyroidism presents with hypocalcemia or normal calcium, not hypercalcemia. 1, 2

Critical Pitfall: CKD and PTH Interpretation

Secondary hyperparathyroidism due to CKD presents with hypocalcemia or normal calcium—never hypercalcemia. 1, 2 The combination of hypercalcemia + normal/elevated PTH + impaired renal function (eGFR <60) indicates:

1. Primary hyperparathyroidism (most likely), or
2. Tertiary hyperparathyroidism (autonomous parathyroid function after prolonged secondary hyperparathyroidism, typically in dialysis patients or post-transplant). 2

In your patient with creatinine 1.7 (CKD stage G3), the impaired kidney function is itself a surgical indication for parathyroidectomy if primary hyperparathyroidism is confirmed. 1

PTH Assay Considerations

• PTH assays vary markedly between generations—differences of up to 47% have been reported—so always use assay-specific reference values. 1, 2
• Use EDTA plasma rather than serum for PTH measurement, as PTH is most stable in EDTA plasma at 4°C. 1
• Biological factors including race, age, BMI, and vitamin D status influence PTH concentration: PTH is higher in Black individuals, increases with age, and correlates positively with BMI. 1, 2
• Biotin supplements can interfere with PTH assays, causing underestimation or overestimation depending on assay design. 2

Other Causes of Hypercalcemia with Normal PTH

If PTH is truly in the normal range (not inappropriately elevated) or suppressed, consider:

Malignancy-Associated Hypercalcemia

• Measure PTHrP if PTH is suppressed; elevated PTHrP with hypercalcemia defines humoral hypercalcemia of malignancy (HHM), most commonly from squamous cell carcinoma of lung, head-and-neck, renal cell carcinoma, or breast carcinoma. 1
• Median survival is approximately 1 month after detection of HHM, so imaging (chest CT, abdominal/pelvic CT or MRI, PET-CT) and oncology consultation must proceed urgently. 1

Granulomatous Disease (e.g., Sarcoidosis)

• Low 25-OH vitamin D but elevated 1,25-dihydroxyvitamin D due to increased 1α-hydroxylase activity in granulomas. 1
• PTH is suppressed by hypercalcemia. 1

Vitamin D Intoxication

• Markedly elevated 25-OH vitamin D with suppressed PTH. 1
• Discontinue all vitamin D supplements immediately if calcium >10.2 mg/dL. 1

Medications

• Thiazide diuretics, calcium supplements, vitamin D, lithium can all cause or exacerbate hypercalcemia. 1, 3
• Discontinue these agents. 1

Familial Hypocalciuric Hypercalcemia (FHH)

• Moderate hypercalcemia with normal PTH and relative hypocalciuria suggests a calcium-sensing receptor gene mutation. 4
• Measure 24-hour urine calcium; calcium/creatinine clearance ratio <0.01 supports FHH. 4
• Often difficult to distinguish from primary hyperparathyroidism without family history. 4

Management Based on Severity

Mild Hypercalcemia (10.2-12 mg/dL)

• Ensure adequate oral hydration and discontinue calcium supplements, vitamin D, and thiazide diuretics. 1
• In CKD patients, reduce or discontinue calcium-based phosphate binders if corrected calcium exceeds 10.2 mg/dL. 1
• Monitor serum calcium every 3 months. 1

Moderate to Severe Hypercalcemia (>12 mg/dL)

• IV crystalloid fluids (normal saline) for aggressive hydration to restore intravascular volume and promote calciuresis—this is the cornerstone of acute management. 1, 3
• Loop diuretics after volume restoration (not before, to avoid worsening dehydration). 1
• IV bisphosphonates (zoledronic acid or pamidronate) are first-line pharmacologic therapy, achieving calcium reduction within 2-4 days. 1, 3
• Glucocorticoids are effective for vitamin D-mediated hypercalcemia (sarcoidosis, lymphomas, vitamin D intoxication). 1, 3
• In patients with kidney failure, denosumab and dialysis may be indicated. 3

Severe Hypercalcemia (>14 mg/dL or ionized calcium ≥5.9 mg/dL)

• Associated with mental status changes, bradycardia, hypotension, severe dehydration, and acute renal failure. 1
• Measure ionized calcium every 4-6 hours during initial treatment. 1
• Initiate aggressive IV hydration and bisphosphonates immediately. 1

Surgical Indications for Primary Hyperparathyroidism

Refer to endocrinology and an experienced parathyroid surgeon if primary hyperparathyroidism is confirmed and any of the following criteria are met: 1, 2

• Corrected calcium >1 mg/dL above upper limit of normal (>11.3 mg/dL if upper limit is 10.3 mg/dL)
• Age <50 years
• Impaired kidney function (eGFR <60 mL/min/1.73 m²)—your patient meets this criterion
• Osteoporosis (T-score ≤-2.5 at any site)
• History of nephrolithiasis or nephrocalcinosis
• 24-hour urinary calcium >300 mg/24hr
• Symptomatic disease (neurocognitive symptoms, refractory depression, "brain fog," memory loss)

Parathyroidectomy is the definitive therapy and outcomes are significantly better with high-volume, experienced parathyroid surgeons. 1, 2

Summary Algorithm

1. Confirm hypercalcemia (ionized or corrected calcium)
2. Measure intact PTH simultaneously with calcium
3. If PTH is elevated or inappropriately normal (not suppressed <20 pg/mL): Diagnose primary hyperparathyroidism after excluding vitamin D deficiency and inadequate calcium intake
4. If PTH is suppressed (<20 pg/mL): Measure PTHrP, 25-OH vitamin D, 1,25-dihydroxyvitamin D; consider malignancy, granulomatous disease, vitamin D intoxication, medications
5. In your patient with creatinine 1.7: The combination of hypercalcemia + normal PTH + eGFR <60 strongly suggests primary hyperparathyroidism, and the impaired renal function is itself a surgical indication
6. Refer to endocrinology and parathyroid surgery for definitive management

1, 2, 3