From the Guidelines
High serum calcium with low parathyroid hormone (PTH) levels is a medical emergency that requires immediate attention to prevent complications such as cardiac arrhythmias, altered mental status, and renal failure. This presentation is indicative of non-parathyroid-mediated hypercalcemia, which can be caused by various factors such as malignancy, granulomatous diseases, vitamin D intoxication, and certain medications. The management of this condition involves a comprehensive approach, including hydration, loop diuretics, and bisphosphonates. According to the K/DOQI clinical practice guidelines for bone metabolism and disease in chronic kidney disease 1, careful monitoring of serum levels of calcium, phosphorus, and intact PTH is essential, especially in patients with chronic kidney disease.
Initial Evaluation and Management
The initial evaluation should include a comprehensive metabolic panel, complete blood count, PTH-related protein (PTHrP), vitamin D levels, and imaging studies to identify the underlying cause. Common etiologies include:
- Malignancy (especially lung, breast, renal cell carcinoma)
- Granulomatous diseases (sarcoidosis, tuberculosis)
- Vitamin D intoxication
- Certain medications (thiazide diuretics, lithium) Initial management involves hydration with intravenous normal saline at 200-300 mL/hour to promote calcium excretion, followed by loop diuretics like furosemide 20-40 mg IV after adequate hydration.
Definitive Treatment
For severe hypercalcemia (>14 mg/dL), bisphosphonates such as zoledronic acid 4 mg IV or pamidronate 60-90 mg IV may be needed. Calcitonin 4-8 IU/kg subcutaneously every 12 hours can provide rapid but temporary relief. The definitive treatment depends on addressing the underlying cause, whether it's treating malignancy, discontinuing offending medications, or managing granulomatous disease. It is crucial to note that the administration of small doses of active vitamin D sterols, such as calcitriol and alfacalcidol, can reduce serum levels of intact PTH and improve bone histology, but this should be done with caution and careful monitoring of serum calcium levels 1.
From the FDA Drug Label
The principal pharmacologic action of zoledronic acid is inhibition of bone resorption. Zoledronic acid inhibits the increased osteoclastic activity and skeletal calcium release induced by various stimulatory factors released by tumors. Clinical studies in patients with hypercalcemia of malignancy (HCM) showed that single-dose infusions of zoledronic acid injection are associated with decreases in serum calcium and phosphorus and increases in urinary calcium and phosphorus excretion
High serum calcium and low PTH may indicate a condition other than hyperparathyroidism, as PTH is typically elevated in hypercalcemia.
- Zoledronic acid can help decrease serum calcium levels by inhibiting bone resorption.
- However, the use of zoledronic acid in this scenario would depend on the underlying cause of the high serum calcium and low PTH.
- The FDA label does not provide direct guidance on the use of zoledronic acid in patients with high serum calcium and low PTH 2.
From the Research
High Serum Calcium and Low PTH
- High serum calcium levels can be caused by various factors, including primary hyperparathyroidism, malignancies, and familial hypocalciuric hypercalcaemia (FHH) 3, 4.
- Primary hyperparathyroidism is characterized by hypercalcemia and elevated or inappropriate parathyroid hormone (PTH) elevation 5.
- However, in some cases, PTH levels can be suppressed in patients with primary hyperparathyroidism, as seen in a case report where a patient presented with severe hypercalcemia and an undetectable PTH level 6.
- FHH is a rare, lifelong, benign condition caused by inactivating mutations in the calcium sensing receptor (CASR) gene, leading to a general calcium-hyposensitivity, compensatory hypercalcaemia, and hypocalciuria 4.
- The diagnosis of FHH is based on a two-step diagnostic procedure, including the measurement of the calcium/creatinine clearance ratio and testing for mutations in the CASR gene 4.
- In patients with high serum calcium and low PTH, it is essential to consider the clinical context and repeat measurements of PTH and serum calcium levels, as dynamic changes in calcium metabolism may occur in the presence of secondary contributing factors 6.
Differential Diagnosis
- The differential diagnosis of primary hyperparathyroidism includes FHH, hypercalcaemia of malignancy, and use of thiazide diuretics 4, 5.
- Secondary hyperparathyroidism (SHP) consists of PTH elevation secondary to a stimulus that needs to be corrected, such as 25 OHvitD deficiency, kidney failure, renal hypercalciuria, malabsorption, and some drugs 5.
- Tertiary hyperparathyroidism (THP) consists of autonomous PTH secretion by the parathyroid glands after prolonged stimulation under SHP, of whatever cause 5.
Management
- The management of hypercalcemia depends on the underlying cause and may involve vigorous intravenous hydration, drugs to reduce bone resorption, and treatment of the underlying condition 3.
- In patients with FHH, no treatment is usually required, as the condition is benign and asymptomatic 4.
- In patients with primary hyperparathyroidism, treatment may involve surgical resection of a parathyroid adenoma or other interventions to reduce PTH levels and alleviate symptoms 5, 6.