Primary Hyperparathyroidism: A Case-based Review

Measuring PTH levels is key in determining the underlying mechanism of hypercalcemia.^2,7 If the hypercalcemia is not PTH-mediated, malignancy and granulomatous diseases such as sarcoidosis must be considered.^2,7 PTH is suppressed in malignancy except for rare cases of PTH-producing tumors.⁴ Bone metastases cause calcium resorption, and sarcoidosis causes an excess of vitamin D, both resulting in hypercalcemia. Lymphomas and sarcoid granulomas express 1α-hydroxylase, an enzyme that increases the conversion of 25(OH)D to 1,25-dihydroxyvitamin D [1,25(OH)₂D].² When malignancy is suspected, it is appropriate to check a 1,25(OH)₂D level. Thiazide diuretics, such as hydrochlorothiazide, decrease urinary calcium excretion and may result in mild hypercalcemia.² Other possibilities in the differential include hypervitaminosis A or D, dehydration, and excess calcium ingestion, but these are less common.^6,7

CALCIUM REGULATION

The parathyroid glands stem from four poles on the back of the thyroid gland; there are typically four, but the number can vary from two to 11. Secreted PTH, the primary regulator of calcium homeostasis, maintains calcium levels within a narrow physiologic range.^2,8 PTH increases bone resorption, stimulating release of calcium into the blood, and signals the kidneys to increase reabsorption of calcium and excrete phosphorus. It also converts 25(OH)D to 1,25(OH)₂ D, the active form of vitamin D that increases gastrointestinal calcium absorption. In a negative feedback loop, PTH secretion is regulated by serum calcium levels, stimulated when levels are low and suppressed when levels are high (see Figure 3).³ Calcium-sensing receptors, located in the chief cells of parathyroid tissue, are essential to calcium homeostasis. These receptors will either increase or decrease PTH release in response to small changes in blood ionized calcium levels. The receptors also play an independent role in the renal tubules by promoting secretion of calcium in the setting of hypercalcemia.^5,9 The precise regulation of intracellular and extracellular calcium is necessary for normal functioning of physiologic processes, including bone metabolism, hormone release and regulation, neuromuscular function, and cell signaling.⁵

PATHOPHYSIOLOGY

Hyperparathyroidism is defined as excess secretion of PTH and is categorized as primary, secondary, or tertiary based on pathophysiologic mechanisms.

Primary hyperparathyroidism

PHPT is defined as PTH levels that are elevated or inappropriately normal in patients with hypercalcemia and no known history of kidney disease.^2,6 This occurs when the normal feedback mechanism fails to inhibit excess hormone secretion by one or more of the parathyroid glands.⁶ With uninhibited PTH secretion, hypercalcemia will result from increased gastrointestinal absorption and bone resorption.

The most common causes of PHPT are an abnormal proliferation of parathyroid cells (parathyroid adenomas) and parathyroid tissue overgrowth (hyperplasia). PHPT may result from a single parathyroid adenoma (80%-90%), multigland hyperplasia (10%-15%), multiple adenomas (2%-3%), or malignancy (< 1%).^6,10 Adenomas can occur sporadically or less commonly as part of an inherited syndrome.¹ It is estimated that more than 10% of patients with PHPT have a mutation in one of 11 genes associated with PHPT.¹¹ Approximately 5% of PHPT cases are familial, resulting from adenomas or carcinomas associated with mutations in the tumor suppressor genes MEN1 and CDC73 and the RET proto-oncogene.⁵ Multiple endocrine neoplasia (MEN) syndrome type 1 or 2a is associated with the development of parathyroid adenomas and other endocrine tumors.^1,5 Mutations in the CDC73 gene can lead to parathyroid cancer, familial isolated hyperparathyroidism, and familial hyperparathyroidism-jaw tumor syndrome.⁵ Parathyroid cancer is rare and is linked to a history of radiation to the head and neck.³ Ectopic parathyroid adenomas represent 3% to 4% of all parathyroid adenomas and are often found in the mediastinum.¹²PHPT is the third most common endocrine disorder, with a prevalence of 1 case per 1,000 men and 2 to 3 cases per 1,000 women.⁵ Most women with PHPT are postmenopausal and older than 50.¹ The condition can occur in younger adults but is rare in childhood and adolescence, with an incidence of 2 to 5 cases per 100,000.¹³

PHPT affects multiple organ systems, but the most commonly involved are the renal and musculoskeletal systems (see Table 2). The hypersecretory state causes excessive bone resorption and increased osteoclastic activity, resulting in osteoporosis and increased risk for pathologic fractures of the hip, wrist, and spine. The most common osteoporotic fractures are vertebral compression fractures.¹⁴ Fractures involving the thoracic spine contribute to the development of kyphosis.¹⁵

In the kidney, an increased filtered load of calcium leads to hypercalciuria, precipitation of calcium phosphate in the renal pelvis and collecting ducts, metabolic acidosis, alkaline urine, and hyperphosphaturia. The combination of alkaline urine, hyperphosphaturia, and hypercalciuria leads to the formation of kidney stones.⁶ Nephrolithiasis and alkaline urine predispose patients to recurrent urinary tract infections and subsequent renal impairment.⁶ In addition, hypercalcemia impairs the renal collecting system and decreases its response to antidiuretic hormone, resulting in polyuria.⁶