Primary Hyperparathyroidism: A Case-based Review

Secondary ­hyperparathyroidism

In secondary hyperparathyroidism, calcium levels are either normal or low. Normocalcemic hyperparathyroidism is characterized by normal ionized and total calcium levels and elevated PTH levels; it has no known cause.⁶ Secondary hyperparathyroidism occurs when excess PTH is excreted as a result of a chronic condition that leads to hypocalcemia. Examples of these disease states include vitamin D deficiency, chronic kidney disease (CKD), and intestinal malabsorption. The most common cause of secondary hyperparathyroidism is CKD; glomerular filtration insufficiency results in hyperphosphatemia, hypocalcemia, and low 1,25(OH)₂D, stimulating the release of PTH. Other causes include deficient intake or decreased absorption of calcium or vitamin D; chronic use of medications such as lithium, phenobarbital, or phenytoin; bariatric surgery; celiac disease; and pancreatic disease.^4,6,14 Lithium decreases urinary calcium excretion and reduces the sensitivity of the parathyroid gland to calcium.⁴

Tertiary hyperparathyroidism

Tertiary hyperparathyroidism, marked by hypercalcemia and excessive PTH secretion, can occur after prolonged secondary hyperparathyroidism. In this disorder, persistent parathyroid stimulation leads to gland hyperplasia, resulting in autonomous production of PTH despite correction of calcium levels.⁶ It most commonly occurs in patients with chronic secondary hyperparathyroidism with renal failure who receive a kidney transplant.^2,6 In some cases, parathyroid hyperplasia may not regress after transplantation and parathyroidectomy may be necessary.

EVALUATION AND DIAGNOSTIC WORK-UP

Laboratory tests

Hypercalcemia is the most common initial finding that leads to the diagnosis of PHPT. Elevated serum calcium and PTH is characteristic of the condition. When evaluating a patient with hypercalcemia, the diagnostic work-up includes tests to differentiate between PTH- and non–PTH-mediated causes of elevated calcium (see Table 3).⁷ Evaluation should begin with measurement of PTH by second- or third-generation immunoassay along with phosphorus, alkaline phosphatase, 25(OH)D, creatinine, estimated glomerular filtration rate (eGFR), and albumin. Additionally, a 24-hour urine collection for calcium, creatinine, and creatinine clearance should be considered in patients with overt nephrolithiasis or nephrocalcinosis. If the urine calcium is > 400 mg/24 h, a renal stone risk profile is indicated because nephrolithiasis is one of the most common complications of PHPT.¹⁴ There is a high prevalence of nephrolithiasis in patients with normocalcemic PHPT, even after parathyroidectomy.¹⁶ If the 24-hour urine calcium level is low, the diagnosis of FHH is considered. If the urine calcium is high and the intact PTH is elevated or inappropriately normal, the diagnosis of PHPT is considered; urine calcium will be normal in 60% of PHPT cases.^4,11

Imaging studies

Imaging is useful for localization of adenomas and abnormal parathyroid tissue to guide surgical planning but is not necessary for diagnosis or medical management. Understanding the strengths and weaknesses of imaging modalities enables the clinician to order the most appropriate option. There are three primary imaging modalities used to locate parathyroid adenoma(s) or aberrant parathyroid tissue: ultrasound, nuclear medicine sestamibi parathyroid scans, and CT. Some clinicians start with an ultrasound, but its operator-dependent results can vary widely; in addition, ultrasound often provides poor anatomic definition and has limited value in locating ectopic parathyroid tissue.¹⁷

Nuclear medicine parathyroid scan with technetium-99m sestamibi is a sensitive method for localizing hyperfunctioning, enlarged parathyroid glands or tissue in normal anatomic positions or ectopic locations. Uptake is enhanced and prolonged in parathyroid adenomas as well as in aberrant tissue found in the mediastinum or subclavicular areas. Sestamibi parathyroid scan detects up to 89% of single adenomas, but studies of this imaging modality have demonstrated a wide range of sensitivities (44%-95%).^5,17 A drawback of nuclear medicine studies is that they provide little anatomic detail.¹⁷ Nonetheless, the ability of the parathyroid scan to locate parathyroid glands has contributed to the success of the minimally invasive parathyroidectomy, and it is considered the most successful imaging modality available.^5,10 Identifying the precise location of the parathyroid adenoma is essential for a successful surgical outcome; this is best achieved by combining the sestamibi parathyroid scan with CT.¹²

Emerging imaging modalities are the multidetector CT (MDCT) and 4D-CT techniques. In an evaluation of the diagnostic accuracy of contrast-enhanced MDCT in the detection of parathyroid adenomas and aberrant parathyroid tissue, MDCT demonstrated the ability to differentiate between adenomas and hyperplasia and display important anatomic structures such as nerves and blood vessels.¹⁷ The specificity of MDCT for ruling out abnormal parathyroid tissue was 75%, and the sensitivity for detecting a single adenoma was 80%. Overall, MDCT demonstrated an 88% positive predictive value (PPV) in localizing hyperfunctioning parathyroid glands but showed poor sensitivity in detecting multigland disease.¹⁷ The PPV is a key value in determining the ability of an imaging study to precisely locate aberrant parathyroid tissue. MDCT provides detailed definition of anatomy, locating ectopic parathyroid glands in the deeper paraesophageal areas and mediastinum while defining relationships between the tissue and its surrounding vasculature, lymph nodes, and thyroid tissue.¹⁷ The 4D-CT technique employs three-dimensional technology and accounts for the movement of the patient’s body over time (the “fourth dimension”). It is an accurate method for identifying parathyroid adenomas but exposes the patient to higher radiation doses.¹⁸ The sensitivity of 4D-CT in localizing abnormal parathyroid tissue is comparable to that of MDCT.^16,18,19