Hyperparathyroidism Diagnostics

Laboratory Tests







24-hour Urinary Calcium

A 24-hour urinary calcium is not required for the diagnosis of primary hyperparathyroidism but is routinely measured in asymptomatic primary hyperparathyroidism to assess the risk for renal complications. High urinary calcium (>200-300 mg/day) suggests underlying primary hyperparathyroidism and increased risk for renal complications. Familial hypocalciuric hypercalcemia (FHH) or primary hyperparathyroidism with concomitant vitamin D deficiency is possible if urinary calcium is <200 mg/day. Approximately 75% of patients with familial hypocalciuric hypercalcemia have <100 mg/day urinary calcium excretion. 

Total Serum Calcium 

Total serum calcium is used for initial and repeat serum calcium measurements. This is preferably done on a fasted patient with minimal venous occlusion. This may be normal or elevated in primary hyperparathyroidism. This is measured with serum albumin because the latter may influence total serum calcium concentration and is adjusted to reflect any abnormality in albumin.  

To compute for corrected calcium:  

Corrected calcium (mg/dL) = Measured total serum calcium (mg/dL) + 0.8 x (4.0 - serum albumin concentration _(Patient)[g/dL])  
Corrected calcium (mg/dL) = Measured calcium (mg/dL) - measured albumin (g/dL) + 4

Ionized Serum Calcium

Ionized serum calcium is preferred for patients with asymptomatic primary hyperparathyroidism with normal serum albumin concentrations in the absence of acid-base imbalance. This is not affected by albumin levels. This is an adjunct to diagnosis in patients with presumed normocalcemic primary hyperparathyroidism, which is typically seen in the setting of evaluation for low bone mineral density (BMD). There is elevated parathyroid hormone in the absence of hypercalcemia, as demonstrated by consistently normal ionized calcium measurements. 

Serum Parathyroid Hormone (PTH) 

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Serum parathyroid hormone uses either intact parathyroid hormone (second generation parathyroid hormone assay) or PTH 1-84 assays (third generation) and is concomitantly measured with serum calcium to diagnose hyperparathyroidism. This is elevated in 80-90% or in the high end of the normal range in primary hyperparathyroidism patients. If the parathyroid hormone is minimally elevated or within normal range, a 24-hour urinary calcium excretion measurement may be done to help distinguish primary hyperparathyroidism from familial hypocalciuric hypercalcemia. If the parathyroid hormone is below or in the lower end of the normal range, investigate for a non-PTH-mediated cause of hypercalcemia. 

Serum Phosphorus 

Serum phosphorus may be in the lower normal range or decreased in cases of primary hyperparathyroidism. Some patients may present with mild hyperchloremic acidosis. 

Serum 25-hydroxyvitamin D (25[OH]D) 

Serum 25-hydroxyvitamin D (25[OH]D) may be useful to distinguish primary hyperparathyroidism from other conditions. Insufficiency (<20 ng/dL) or frank deficiency (<10 ng/dL) indicates a more active disease. Evidence showed parathyroid hormone level reduction can occur in cases of insufficient correction of 25(OH)D. An increased urinary calcium excretion with vitamin D repletion is seen in mild primary hyperparathyroidism with concomitant vitamin D deficiency, elevated serum parathyroid hormone and calcium with normal or low 24-hour urine calcium excretion. A low 25-hydroxyvitamin D is noted in secondary hyperparathyroidism due to vitamin D deficiency. 

Serum Creatinine 

Serum creatinine is used to assess kidney function together with estimated glomerular filtration rate (eGFR). An eGFR of 60 mL/min is the chronic kidney disease threshold for deciding which asymptomatic primary hyperparathyroidism patient will benefit from early surgical management. 

Bone Turnover Markers 

Examples of bone turnover markers are collagen crosslinks, osteocalcin, and bone-specific alkaline phosphatase. This is at an upper normal value or mildly elevated in asymptomatic primary hyperparathyroidism. Severe cases present with elevated bone markers. 

Genetic Testing 

Genetic testing is not required but may be performed in patients suspected of having a familial form of primary hyperparathyroidism, young patients and those with a family history of primary hyperparathyroidism, multi-gland involvement, and clinical findings suspicious for multiple endocrine neoplasia type 1 (MEN1). Approximately 10% of patients with primary hyperparathyroidism have 1 out of 11 gene mutations. 

Imaging of the parathyroid is primarily used for localization of tumor/adenoma and to identify patients who are candidates for surgery, have persistent or recurrent disease, or had prior cervical exploration requiring preoperative ѕurgеrу. 

Plain Radiography  

Plain radiography can be used to assess bone fractures, nephrocalcinosis, or kidney stones.  

Ultrasonography 

Ultrasonography is recommended as the initial imaging study for primary hyperparathyroidism. This is the most commonly used imaging modality to evaluate for the presence of nephrocalcinosis or kidney stones which demonstrate end-organ damage in hyperparathyroidism and used as criteria for surgical intervention. Vital information for diagnosis can be detected when correlated with scintigraphy findings. 







Cervical ultrasonography is utilized for excellent anatomic information but not for lesion identification. Parathyroid adenoma appears as a homogenous, well-demarcated mass and hypoechoic in contrast to hyperechoic thyroid tissue. Enlarged inferior parathyroid adenomas are found immediately adjacent to the inferior pole of the thyroid lobes, the thyrothymic ligament, or upper cervical portion of the thymus. Enlarged superior parathyroid adenomas are usually found adjacent to the posterior thyroid lobe, which tends to migrate posteriorly and inferiorly. 

Single-proton Emission Computed Tomography (SPECT/CT) 

Single-proton emission computed tomography (SPECT/CT) is a second-line modality in the identification of ectopic glands. This is most valuable in identifying ectopic adenoma (except those located in the lower neck at the level of the shoulders and lesions close to or within the thyroid gland or hyperfunctioning glands) not identified during initial surgery. This is a more successful modality in detecting retrotracheal, retro-esophageal and mediastinal adenoma. The mediastinal view is utilized to locate ectopic glands in the thorax. A jaw view may be used to locate undescended glands. 

Magnetic Resonance Imaging (MRI) 

Magnetic resonance imaging provides anatomic visualization without the use of contrast or radiation. This is indicated in pregnant patients with non-informative ultrasound results and identification of ectopic parathyroid tissue. 

4D Computed Tomography (CT) 

The 4D computed tomography is a powerful modality in identifying missed parathyroid glands and localization of small adenomas and multi-gland disease. This provides anatomic and function (perfusion) information. Axial views from jaw to aortic arch and perfusion studies should be included. This differentiates between perfusion characteristics, hyperfunctioning parathyroid gland, and the status of parathyroid glands and other neck structures are visualized. When used with ultrasound, 4D computed tomography shows 94% sensitivity and 90% specificity in lateralizing hyperfunctioning parathyroid glands and 82% sensitivity in localizing to the correct quadrant of the neck. 

Parathyroid Positron Emission Tomography (PET) 

Parathyroid positron emission tomography can differentiate between parathyroid adenoma and hyperplasia preoperatively based on maximal standardized uptake values. Tracers utilized are 18F-fluorodeoxyglucose, which is used for the identification of pituitary adenomas, and 11C-methionine, which is utilized in cases of problematic identification of parathyroid sites with conventional scintigraphy. 

Double-tracer Parathyroid Scintigraphy 

Double-tracer parathyroid scintigraphy is also known as subtraction scanning. The parathyroid tracers are non-specific and absorbed by the thyroid gland. A comparison with a second tracer is necessary. This is used to detect recurrent and persistent disease in both primary and secondary hyperparathyroidism, in the selection of appropriate surgical management for patients with primary hyperparathyroidism, and in the evaluation after surgery. The parathyroid localization tracers utilized are ^99mTc-sestamibi, which is used for parathyroid localization involving subtraction technique using ¹²³I; however, vitamin D therapy might reduce tracer uptake; and ^99mTc-tetrofosmin is used as an alternative to ^99mTc-sestamibi for parathyroid subtraction scanning.

Bone Mineral Density (BMD) Evaluation 

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The modalities include dual-energy X-ray absorptiometry (DXA), vertebral X-ray, vertebral fracture assessment (VFA) by DXA, trabecular bone score (TBS) by DXA, or high-resolution peripheral quantitative computed tomography (HRpQCT). Patients with hyperparathyroidism may have decreased bone mineral density more often in cortical sites (eg forearm and hip) compared with trabecular sites (eg spine). Determining reductions in bone density in primary hyperparathyroidism patients is not required for the diagnosis but is an essential part of disease management. The degree of bone loss reflects the severity of hуреrраrаthyrοidism and is useful in making recommendations for management (eg parathyroid surgery or observation with monitoring in asymptomatic patients). This aids in confirmation of trabecular involvement in asymptomatic primary hyperparathyroidism. 

Invasive Methods  

Selective Venous Sampling (SVS) 

Selective venous sampling is the most sensitive localization procedure and is highly operator-dependent. Catheterization of the common femoral vein or iliac vein is done to obtain parathyroid hormone baseline values and the internal jugular vein or multiple veins (neck and mediastinum) for lateralization. Venograms should be obtained in two planes to delineate the precise anatomic location of sampled vessels. A two-fold elevation in parathyroid hormone value compared to baseline denotes a positive localization study. This is limited by procedure cost and risk of adverse reactions (ie renal failure and anaphylactic reaction to contrast medium) and operative complications (ie bleeding, infection, pseudoaneurysm, AV fistula).  

Ultrasound-guided Fine Needle Aspiration (FNA)/Biopsy 

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Cytologic confirmation and parathyroid hormone biochemical assay should be done on samples. Ultrasound-guided fine needle aspiration confirms the presence of parathyroid hormone and differentiates it from other structures. A positive parathyroid hormone FNA warrants surgical exploration. This is useful in the differential diagnosis of intrathyroidal parathyroid adenoma from a thyroid nodule. Preoperative FNA of parathyroid glands should not be done due to the theoretical risk of parathyroid cell seeding.