Parathyroid dysfunction is characterized by abnormal production and secretion of parathyroid hormone (PTH), an 84-amino acid protein important for calcium homeostasis and metabolism. Calcium homeostasis is a complex process that involves PTH, serum calcium, serum phosphate, and 1,25-dihydroxyvitamin D3 (ie, calcitriol or 1,25(OH)2D3), which is the most biologically active form of vitamin D.1,2 Diagnosis and management of parathyroid dysfunction includes laboratory assessment of these and other measures of calcium homeostasis.

Hyperparathyroidism (overproduction of PTH) is the most common form of dysfunction and is associated with hypercalcemia and hypophosphatemia, which result in overt skeletal and renal complications (Table 1).3–5 Hypoparathyroidism (underproduction or no production of PTH) is uncommon and associated with hypocalcemia resulting in cardiovascular, neurological, and renal complications (Table 2) that can be life-threatening and require prompt diagnosis and treatment.1,6,7

This Clinical Focus discusses the important role that laboratory testing plays in the diagnosis and management of parathyroid dysfunction, including primary, secondary, and tertiary categories of hyperparathyroidism and hypoparathyroidism. This information is not intended as medical advice. Test selection and interpretation, diagnosis, and patient management decisions should be based on the physician’s education, clinical expertise, and assessment of the patient.

Primary hyperparathyroidism

Epidemiology and causes

Primary hyperparathyroidism is a frequently diagnosed endocrine disorder and the most common cause of hypercalcemia.3,5 The disorder occurs in about 43% of patients with hypercalcemia but is diagnosed in only 1% to 8% of these patients, who experience longer disease duration and adverse outcomes.8 The overall prevalence in the United States is estimated to be 233 cases per 100,000 women and 85 cases per 100,000 men, and the condition is more common in persons over 40 years old, particularly in postmenopausal women.3,5

Of primary hyperparathyroidism cases, approximately 85% are caused by an isolated parathyroid adenoma, 15% are caused by diffuse parathyroid hyperplasia, and <1% are caused by parathyroid carcinoma.3,5 Normocalcemic primary hyperparathyroidism is characterized by in-range calcium levels (normocalcemic) and occurs in 0.1% to 17% of cases, although the diagnostic criteria are not well defined.4,9

Approximately 10% of cases of primary hyperparathyroidism are due to genetic variants, including known variants of 10 genes: MEN, RET, CDKN1B, CDKN1A, CDKN2B, CDKN2C, CDC73, CASR, GNA11, AP2S1.5 Genetic causes of hyperparathyroidism include familial hypocalciuric hypercalcemia (FHH) and multiple endocrine neoplasia (MEN) syndromes.5 Both FHH and MEN syndromes have an autosomal dominant inheritance pattern. FHH is due to variants in the surface calcium-sensing receptor (CASR) gene, which result in an abnormal calcium sensor and normal or slightly elevated PTH and calcium levels; FHH is benign and does not require treatment.3,5 MEN syndromes are characterized by tumors of multiple endocrine glands, which can be malignant (eg, thyroid medullary carcinoma).10–12 MEN1, MEN2A, MEN2B, and MEN4 syndromes are associated with hyperparathyroidism, and are due to variants of the MEN1 gene (MEN1), RET gene (MEN2A, 2B), or CDNK1B gene (MEN4).10–12

Clinical manifestations and symptoms

The clinical manifestations of primary hyperparathyroidism (Table 1) depend on the duration and severity of the disease.5,8,13

Table 1. Classical Signs, Symptoms, and Manifestations of Hyperparathyroidism and/or Hypercalcemiaa [return to contents]

The 3 clinical phenotypes include asymptomatic, symptomatic hypercalcemic, and normocalcemic hyperparathyroidism. Importantly, the severity of symptoms does not always correlate with calcium level, and bone mass loss occurs with all forms of hyperparathyroidism, including normocalcemic hyperparathyroidism.5,14,15

Asymptomatic hyperparathyroidism is the most common phenotype as it is identified after routine laboratory testing.5,14,15 The phenotype presents with typical biochemical abnormalities (eg, elevated PTH and serum calcium levels) but without overt symptoms or signs; however, nephrolithiasis, nephrocalcinosis, osteoporosis, and silent vertebral fractures may be identified during the workup.5,14,15

Symptomatic hypercalcemic hyperparathyroidism presents with overt skeletal and/or renal complications (Table 1).3–5 Manifestations may also involve other systems, such as gastrointestinal (eg, constipation, peptic ulcer disease, and pancreatitis), neurologic (eg, lethargy, poor concentration, and depression), and cardiovascular (see below), especially in advanced disease.5,15

Normocalcemic hyperparathyroidism—in which PTH levels are persistently elevated and serum calcium levels are normal (or PTH is inappropriately normal in the presence of low calcium)4,9,16—usually presents with osteoporosis (fragility fractures) or nephrolithiasis (in approximately one-third of patients).4,9 Although most patients remain normocalcemic, about 20% to 40% of patients eventually develop hypercalcemia.4 Notably, patients with normocalcemic hyperparathyroidism have increased rates of cardiovascular complications, hypertension, and hyperglycemia due to insulin resistance.4,9 The condition may represent an early stage of symptomatic hyperparathyroidism.4,9,17

Disease course, recommendations, and treatment

The classical, severe course of primary hyperparathyroidism is associated with increased mortality; however, it is not clear if milder forms of hyperparathyroidism have the same association.3,5 Studies have also suggested that primary hyperparathyroidism is associated with cardiovascular risk factors, such as hypertension and atherosclerosis,18 and metabolic syndrome.19 However, consensus has not been reached on the association of hyperparathyroidism and cardiovascular disease (CVD) or on whether to include a CVD risk assessment in the workup for primary hyperparathyroidism. For example, CVD risk assessment is not recommended by the Fifth International Workshop for the Evaluation and Management of Primary Hyperparathyroidism, which concluded that there is insufficient evidence to warrant testing.3,5 On the other hand, CVD risk testing is recommended by the National Institute for Health and Care Excellence (NICE, United Kingdom) for all patients with hyperparathyroidism at diagnosis.20

Treatment of hyperparathyroidism depends on the clinical phenotype. Parathyroidectomy is the recommended treatment for patients with symptomatic primary hyperparathyroidism and for patients with asymptomatic primary hyperparathyroidism who meet certain criteria (see Monitoring treatment: Hyperparathyroidism).3–5,9 No surgical recommendations are available for patients with normocalcemic hyperparathyroidism due to lack of data.5 Nonsurgical medical management recommendations are available for patients with primary hyperparathyroidism; however, there is no consensus regarding the most appropriate medical treatment.4,5,9

Secondary hyperparathyroidism

Secondary hyperparathyroidism is a compensatory increase in the secretion of PTH by the parathyroid glands due to hypocalcemia or peripheral resistance to PTH.2,21,22 Persistently low serum levels of calcium or vitamin D result in the continuous release of PTH from the parathyroid glands.2,21,22 The condition is most commonly seen in patients with chronic kidney disease (CKD) and those with vitamin D deficiency.2,21,22 Vitamin D deficiency can be due to inadequate dietary intake, inadequate exposure to the sun, inability of the kidneys to process vitamin D to its most active form (common in patients with advanced CKD), and vitamin D resistance.2,21,22 Calcium and phosphate levels vary depending on the etiology, and treating the underlying cause can reverse secondary hyperparathyroidism.2,21,22

Tertiary hyperparathyroidism

Tertiary hyperparathyroidism is the persistent, increased secretion of PTH despite correction of the underlying abnormality identified as a cause of secondary hyperparathyroidism.23 Tertiary hyperparathyroidism is commonly seen in patients with end-stage renal disease (ESRD). These patients first develop chronic hypocalcemia, due to decreased renal adsorption of calcium, and then hyperplasia of the parathyroid glands, which no longer respond to serum calcium levels. The patients eventually develop severe hyperparathyroidism and hypercalcemia.23 After renal transplantation, calcium levels may normalize with restoration of kidney function, but PTH levels will remain elevated due to parathyroid gland hyperplasia.23

Hypoparathyroidism

Epidemiology and causes

Hypoparathyroidism is a rare condition, and the prevalence of chronic hypoparathyroidism has been reported to range from 6.4 to 37 cases per 100,000 population.6,7,24 Most cases of hypoparathyroidism (approximately 75%) occur after thyroidectomy; about 15% of cases are idiopathic, and around 10% have genetic causes.6,7,24 In many instances, postsurgical hypoparathyroidism is transient.6,7,24

Autoimmune disease resulting in damage to the parathyroid glands is an uncommon, but important cause of hypoparathyroidism.7,24 Autoimmune hypoparathyroidism may be isolated or associated with autoimmune polyglandular syndrome type I, which is also associated with chronic mucocutaneous candidiasis, adrenal insufficiency, pernicious anemia, and other autoimmune conditions.7,24 Parathyroid antibody is the most common autoantibody associated with hypoparathyroidism.25,26 CASR autoantibodies are extremely rare. Activating mutations of CASR, which are also very rare, result in hereditary hypoparathyroidism characterized by very high urine calcium levels and marked hypercalciuria.25,26

Hungry bone syndrome is the development of severe hypocalcemia after parathyroidectomy in patients with severe primary or secondary hyperparathyroidism, typically in the presence of ESRD.27 The condition is the result of prolonged exposure to elevated PTH levels resulting in a high bone turnover rate with net bone resorption. Hypocalcemia is the result of a rapid shift towards osteoblastic activity after the marked decrease in PTH level. Hungry bone syndrome can also occur in men with metastatic prostate cancer and increased osteoblastic activity and excess bone formation.27

Pseudohypoparathyroidism is a rare inherited disorder characterized by target organ resistance or unresponsiveness to PTH.24,28 The syndrome mimics hypoparathyroidism, with patients experiencing hypocalcemia and hyperphosphatemia. However, instead of low PTH levels, elevated levels of PTH are present in serum.24,28 Another rare cause of hypoparathyroidism is DiGeorge syndrome, the congenital absence or hypoplasia of the parathyroid glands.24

Clinical manifestations and symptoms

Most patients with hypoparathyroidism are asymptomatic, and hypocalcemia is identified as an incidental finding during laboratory testing for other indications.7,24 Similarly, most patients with chronic hypocalcemia are asymptomatic.1,7 Subtle manifestations of hypocalcemia include muscle weakness, tingling of skin, paresthesias, perioral numbness, cramps, fatigue, confusion, depression, anxiety, and memory loss.1,7 Overt manifestations of marked hypocalcemia include seizures, tetany, laryngospasm, and QT interval prolongation (Table 2).1,7

Table 2. Common Signs, Symptoms, and Manifestations of Hypoparathyroidism and/or Hypocalcemiaa [return to contents]

Diagnosis of hyperparathyroidism or hypoparathyroidism begins with establishing both PTH and calcium levels in blood, which are needed for the differential diagnosis of parathyroid dysfunction (Tables 4 and 5). In individuals with parathyroid dysfunction, serum phosphate levels (test code 718), which usually correlate with serum calcium levels in healthy individuals, may be discordant and levels of total and active forms of vitamin D may be affected. Urine calcium, PTH-related protein (PTH-rP), and other measures are also important in the differential diagnosis as discussed below and in the following sections.

Table 4. Biochemical Test Results for Selected Causes of Parathyroid Dysfunction [return to contents]

Table 5. Reference Ranges for Tests Used to Assess Parathyroid Dysfunction in Patients ≥17 Years of Age [return to contents]

PTH and PTH-rP testing

The Quest intact PTH assay (test codes 8837 and 35020) is a second-generation assay that achieves molecular specificity using antibodies directed separately against the N-terminal and C-terminal portions of the intact PTH peptide in an immunochemiluminometric "sandwich" assay (ICMA). The assay is not affected by large C-terminal or mid-truncated fragments of PTH that also circulate in blood, representing about 15% to 30% of the total PTH in healthy individuals and 70% to 80% in patients with CKD.45,46 The assay is also not affected by most drugs or supplements, including biotin.47 However, heterophilic antibodies in patient specimens may interfere with test results.47 PTH assays are not standardized (ie, traceable to approved, extensively characterized reference materials).45,46 Consequently, results from different laboratories should not be compared.45,46

PTH-related protein (PTH-rP) is secreted by, and has a physiological role in, many tissues including the stomach, lungs, bone, and those in the cardiovascular system.48 However, PTH-rP is increased in many malignancies including hepatocellular carcinoma, small cell and non-small cell lung cancers, and leukemia.48 Notably, elevated PTH-rP is present in about 80% of patients with hypercalcemia of malignancy, and as such it is useful in the differential diagnosis of hypercalcemia after hyperparathyroidism and other causes of hypercalcemia have been ruled out.

The PTH-rP assay (test code 34478) is a radioimmune assay (RIA) in which radioactive and non-radioactive antigens compete for a fixed number of antibody binding sites. Because PTH-rP shares a similar N-terminal structure to PTH, the assay achieves selectivity for PTH-rP by targeting the C-terminal region and helps identify patients with hypercalcemia caused by hyperparathyroidism vs malignancy. However, because the assay targets the C-terminal region of the protein, elevated results may also be seen in patients with CKD and eGFR <20 mL/min, reflecting cross-reactive C-terminal fragments of PTH.48

Calcium testing

Quest offers 2 methods of measuring calcium in serum. The first is a common spectrophotometric assay (test code 303) for total calcium. Because about 40% to 50% of calcium in circulation is bound to albumin,1,3 serum calcium level should be corrected for albumin level (test code 223) to calculate the albumin-adjusted or corrected calcium level. Although indicated by guidelines,3,5 some studies have questioned the need for this correction, especially under conditions of hypoalbuminemia.49 As an alternative, ionized calcium (test code 306) measured using an ion-selective electrode represents the bioavailable (free) calcium in circulation, which is less variable and accurately represents a state of hyper- or hypocalcemia.3,49

A 24-hour urine specimen is preferred when measuring calcium excretion for the evaluation of hypercalciuria as it more accurately reflects calcium excretion compared to a random specimen.29,50 Calculation of the urinary calcium clearance/urinary creatinine clearance ratio using serum calcium and creatinine levels and urinary calcium and creatinine levels can help distinguish between primary hyperparathyroidism and FHH.29,34

Vitamin D testing

Quest offers a liquid chromatography-tandem mass spectrometry (LC-MS/MS) test for measuring 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D in serum (test code 16761). In contrast to immunoassays, this test measures total 25(OH)D concentrations as the sum of its individual components, which include 25(OH)D2, 25(OH)D3, concentrations. The LC-MS/MS method has less variability than immunoassays51,52 and is endorsed by experts at the National Institute of Standards and Technology (NIST), the Centers for Disease Control and Prevention (CDC), and the National Institutes of Health.53–56 The total 25(OH)D level is considered the best indicator of vitamin D derived from synthesis in the skin and nutritional intake.37,51,52 The test simultaneously measures 1,25-dihydroxyvitamin D levels, the most active form of vitamin D in circulation, which is derived from conversion of 25(OH)D in the kidneys, and is important in differential diagnosis and management (see below).37 Vitamin D deficiency is not uncommon, and in patients with suspected secondary hyperparathyroidism, correction of a low vitamin D level may result in normalization of PTH level.37