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Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation

Primary hyperparathyroidism: Diagnosis, differential diagnosis, and evaluation
Authors:
Ghada El-Hajj Fuleihan, MD, MPH
Shonni J Silverberg, MD
Section Editor:
Clifford J Rosen, MD
Deputy Editor:
Jean E Mulder, MD
Literature review current through: Jun 2022. | This topic last updated: May 24, 2022.

INTRODUCTION — The diagnosis of hyperparathyroidism is usually first suspected because of the finding of an elevated serum calcium concentration. If hypercalcemia is confirmed on a repeat sample, all of its causes should be considered (table 1). (See "Etiology of hypercalcemia".)

The serum parathyroid hormone (PTH) concentration should then be measured using a two-site immunoradiometric sandwich assay. The diagnosis of primary hyperparathyroidism (PHPT) is usually made by finding a PTH concentration that is frankly elevated or within the normal range but inappropriately normal given the patient's hypercalcemia (figure 1).

The diagnosis, differential diagnosis, and evaluation of PHPT will be discussed here. Other aspects of PHPT are reviewed elsewhere.

(See "Primary hyperparathyroidism: Clinical manifestations".)

(See "Primary hyperparathyroidism: Management".)

(See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism".)

(See "Parathyroid exploration for primary hyperparathyroidism".)

(See "Pathogenesis and etiology of primary hyperparathyroidism".)

DIAGNOSIS

Primary hyperparathyroidism (PHPT) – The most common clinical presentation of PHPT is asymptomatic hypercalcemia. The diagnosis is usually first suspected because of the incidental finding of an elevated serum calcium concentration on biochemical screening tests. In addition, PHPT may be suspected in a patient with nephrolithiasis. If hypercalcemia is confirmed, intact parathyroid hormone (PTH) should be measured concomitantly with the serum calcium.

PHPT is diagnosed by finding a frankly elevated PTH concentration in a patient with hypercalcemia. When the PTH is only minimally elevated or within the normal range (but inappropriately normal given the patient's hypercalcemia), PHPT remains the most likely diagnosis, although familial hypocalciuric hypercalcemia (FHH), a rare disorder, is possible (figure 1 and algorithm 1). (See 'Diagnostic evaluation' below.)

Normocalcemic PHPT – Normocalcemic PHPT is a variant of PHPT, first recognized in 2009 by an international panel of experts [1]. Patients with normocalcemic PHPT typically come to medical attention in the setting of an evaluation for low bone mineral density (BMD), during which time PTH levels are drawn and found to be elevated in the absence of hypercalcemia [2-5]. In order to make a diagnosis of normocalcemic PHPT, certain conditions must be met. In particular, ionized calcium levels should be normal, and all secondary causes for hyperparathyroidism (table 2) must be ruled out. Vitamin D deficiency and chronic kidney disease are the most common causes of secondary hyperparathyroidism; however, the precise serum 25-hydroxyvitamin D (25[OH]D) and estimated glomerular filtration rate (eGFR) thresholds for defining them are not well established [6,7]. (See 'Secondary hyperparathyroidism' below.)

DIAGNOSTIC EVALUATION

Serum calcium — A single elevated serum calcium concentration should be repeated to confirm the presence of hypercalcemia. The total serum calcium concentration should be used for both the initial and the repeat serum calcium measurements. If a laboratory known to measure ionized calcium reliably is available, some authorities prefer to measure the ionized calcium, although this usually adds little to the diagnosis of asymptomatic primary hyperparathyroidism (PHPT) in patients with normal serum albumin concentrations and no abnormalities in acid-base balance [8]. (See "Diagnostic approach to hypercalcemia", section on 'Confirm hypercalcemia'.)

One circumstance in which ionized calcium measurements are an important adjunct to diagnosis is in patients with presumed normocalcemic PHPT. In order to make this diagnosis, ionized calcium levels should be measured several times and should be consistently normal [9]. In one series, 12 of 60 patients in whom the diagnosis of normocalcemic PHPT was considered had a raised serum concentration of ionized calcium in the presence of a normal total serum calcium concentration [10].

Previous values for serum calcium should be reviewed, if available. The presence of longstanding asymptomatic hypercalcemia is more suggestive of PHPT and, in young individuals, also raises the possibility of familial hypocalciuric hypercalcemia (FHH).

Serum PTH — Either intact parathyroid hormone (PTH) (second-generation PTH assay) or PTH 1-84 assays (third-generation) should be measured concomitantly with the serum calcium level to diagnose hyperparathyroidism [11]. Although limited data [12] suggest that PTH is increased in a higher proportion of patients with PHPT using the PTH 1-84 assay, several other studies have found no increase in diagnostic utility [13,14]. (See "Parathyroid hormone assays and their clinical use", section on 'Clinical use of PTH assays'.)

PTH elevated – Approximately 80 to 90 percent of patients with PHPT have serum PTH concentrations above the normal range for the assay (figure 1 and algorithm 1) [15,16]. In contrast to parathyroid cancer and secondary hyperparathyroidism associated with renal failure, the extent of elevation in PHPT tends to be modest, often in the range of 1.5 to 2-fold the upper limit of normal.

PTH within normal range – Ten to 20 percent of patients have serum PTH values that are only minimally elevated or normal [1]. These "normal" values in the presence of hypercalcemia are inappropriately high; healthy individuals given calcium intravenously have suppressed serum PTH concentrations (below 10 pg/mL), and patients with nonparathyroid hypercalcemia virtually always have values below 20 to 25 pg/mL (figure 1) [17,18]. When the PTH is minimally elevated or within the normal range (but inappropriately normal given the patient's hypercalcemia), measurement of 24-hour urinary calcium excretion may help distinguish PHPT from FHH (algorithm 2 and algorithm 1) (see '24-hour urinary calcium' below). We do not favor the use of the terms "normohormonal" or "euparathyroid" hyperparathyroidism, as they suggest a clinical distinction based upon a false dichotomy. Anyone with high calcium and a non-suppressed PTH level has an inappropriate excess of PTH and should be considered to have hypercalcemic PHPT.

PTH lower end of normal range – When PTH is below or in the lower end of the normal range, non-PTH-mediated causes of hypercalcemia should be investigated (algorithm 1). Occasionally, a patient with proven PHPT has a serum intact PTH concentration in the lower half of the normal range [19] and, very rarely, one that is undetectable [20]. In the latter report, the patient had a biologically active PTH fragment, which was undetectable with the intact PTH assay. (See "Parathyroid hormone assays and their clinical use", section on 'PTH fragments'.)

24-hour urinary calcium — Measurement of 24-hour urinary calcium excretion is not always required for the diagnosis of PHPT, but it is routinely measured in patients with asymptomatic PHPT in order to assess the risk of renal complications (when urine calcium is high) and thus determine subsequent management (see 'Additional evaluation to determine management' below). For patients with hypercalcemia and PTH that is only minimally elevated or inappropriately normal given the patient's hypercalcemia, the 24-hour urinary calcium may also help to distinguish PHPT from FHH (algorithm 2).

Approximately 40 percent of patients with PHPT are hypercalciuric, and most of the remaining patients have normal values [21]. An elevated urinary calcium concentration (>200 to 300 mg/day) essentially excludes FHH.

If calcium excretion is <200 mg/day (5.0 mmol/day), FHH or PHPT with concomitant vitamin D deficiency are possibilities. Lower urinary calcium values may also be seen in patients with PHPT whose calcium intake is extremely low (algorithm 2). (See 'Serum 25-hydroxyvitamin D' below.)

Approximately 75 percent of affected persons with FHH excrete less than 100 mg of calcium in urine daily [22]. (See 'Familial hypocalciuric hypercalcemia' below.)

A calcium/creatinine (Ca/Cr) clearance ratio, which is equivalent to the fractional excretion of calcium, may also be helpful. This ratio is calculated from 24-hour urinary calcium and creatinine and total serum calcium and creatinine concentrations using the following formula:

 Ca/Cr clearance ratio  =  [24-hour urine Ca  x  serum Cr]  ÷  [serum Ca  x  24-hour urine Cr]

The data establishing the value of the Ca/Cr clearance ratio in differentiating FHH from PHPT are based primarily on 24-hour urine collections. While there are insufficient data available to prove that Ca/Cr ratios calculated from spot urines are equivalent to those determined from 24-hour urines, in principle, the two should reflect renal calcium handling similarly.

A value below 0.01 in a vitamin D-replete individual is highly suggestive of FHH rather than PHPT (ratio usually >0.02). However, up to 10 percent of individuals with FHH can have Ca/Cr clearance ratios >0.02, and up to 20 percent of those with PHPT can have ratios <0.01 [22]. In an analysis of five large studies combining 165 patients with FHH and 197 patients with PHPT, a Ca/Cr clearance ratio <0.01 had a sensitivity for FHH of 85 percent, a specificity of 88 percent, and a positive predictive value of 85 percent; a value >0.02 essentially excluded FHH [23-25]. In a subsequent case-control study of 250 patients with surgically proven PHPT and 19 patients with genetically proven FHH, the median Ca/Cr clearance ratios were 0.02 and 0.01, respectively [26]. Using a threshold of <0.02, the specificity for FHH was 93 percent.

Many individuals (approximately 40 percent) with PHPT and with FHH have Ca/Cr clearance ratios between 0.01 and 0.02 [22,26-29]. Due to the difficulty of differentiating FHH from vitamin D-replete PHPT when the Ca/Cr clearance ratio is between 0.01 and 0.02, some have suggested genetic testing for FHH, where available, for such individuals. [11,22,25,30]. Genetic testing for FHH is reviewed separately. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Distinction from primary hyperparathyroidism'.)

The role of genetic testing in hereditary PHPT is reviewed below. (See 'Role of genetic testing' below.)

Serum 25-hydroxyvitamin D — Measurement of vitamin D metabolites may be useful to distinguish PHPT from other conditions in the following circumstances:

Differentiation of FHH from mild PHPT with concomitant vitamin D deficiency in individuals with concomitantly elevated serum PTH and calcium but with normal or low 24-hour urinary calcium excretion (algorithm 2). To do so, we typically measure 25-hydroxyvitamin D (25[OH]D). In the latter patients, urinary calcium excretion increases with vitamin D repletion, thereby distinguishing it from FHH. (See "Primary hyperparathyroidism: Management", section on 'Concomitant vitamin D deficiency'.)

Differentiation of secondary hyperparathyroidism due to vitamin D deficiency from normocalcemic PHPT in patients with elevated PTH and normal serum calcium concentrations. To do so, we typically measure 25(OH)D, which is low in the former and normal in the latter.

Sometimes patients with presumed secondary hyperparathyroidism actually have PHPT with concomitant vitamin D deficiency. In these patients, the diagnosis of mild PHPT is obscured by vitamin D deficiency due to poor dietary intake of vitamin D or sunlight exposure and may not be recognized until vitamin D is repleted and hypercalcemia and/or hypercalciuria develop. PHPT with coexisting vitamin D deficiency may be suspected when serum calcium concentrations are in the upper half of the normal range and urinary calcium concentration is normal, despite vitamin D deficiency.

Individuals with normocalcemic PHPT and low 25(OH)D concentrations may be repleted with vitamin D. However, vitamin D replacement should be provided cautiously in those with suspected concurrent PHPT, in particular in those with a urinary calcium that is in the high-normal range, as worsening hypercalcemia and hypercalciuria may develop. In contrast, serum and urinary calcium remain normal and PTH normalizes after vitamin D repletion in individuals with vitamin D deficiency-induced secondary hyperparathyroidism. (See "Primary hyperparathyroidism: Management", section on 'Concomitant vitamin D deficiency' and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Coexisting primary hyperparathyroidism'.)

Patients with PHPT convert more 25(OH)D (calcidiol) to 1,25 dihydroxyvitamin D (calcitriol) than normal individuals. Serum concentrations of 1,25 dihydroxyvitamin D may therefore be at upper limits of normal or elevated [31,32]. An elevated value is not specific for diagnosis, and measurement of 1,25-dihydroxyvitamin D is not generally needed to confirm the diagnosis.

Role of genetic testing — The majority of patients with PHPT do not require genetic testing. Due to the difficulty of differentiating FHH from vitamin D-replete PHPT when the Ca/Cr clearance ratio is between 0.01 and 0.02, some experts have suggested calcium-sensing receptor (CaSR) mutation analysis for such individuals. (See 'Familial hypocalciuric hypercalcemia' below and "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Distinction from primary hyperparathyroidism'.)

Genetic testing, where available, can also be performed in selected patients in whom a familial form of PHPT is suspected, including young patients (<30 years) and patients with a family history of PHPT, multigland involvement, atypical parathyroid adenoma, or clinical findings suspicious for syndromic PHPT, such as multiple endocrine neoplasia (MEN) type 1, MEN2A, or hyperparathyroidism jaw tumor syndrome [11]. Approximately 10 percent of patients with PHPT will have a mutation in 1 of 11 genes [11,33,34]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'MEN1 mutational analysis'.)

Abnormalities in key growth-controlling genes, protooncogenes, or tumor suppressor genes underlie the development of parathyroid tumors, which may occur sporadically or in familial patterns. The underlying genetic abnormalities include gain-of-function changes in genes such as cyclin D1/PRAD1 for sporadic tumors and RET for familial tumors, or loss-of-function mutations in genes such as MEN1 or HRPT2 for sporadic and familial tumors. (See "Pathogenesis and etiology of primary hyperparathyroidism", section on 'Genetic or chromosomal defects'.)

DIFFERENTIAL DIAGNOSIS — Although the most common clinical presentation of primary hyperparathyroidism (PHPT) is asymptomatic hypercalcemia with an elevated or high-normal intact parathyroid hormone (PTH) concentration, the presentation may be atypical. Atypical presentations include a spectrum of disturbances in calcium homeostasis, ranging from symptomatic severe hypercalcemia (parathyroid crisis) to normocalcemic PHPT. Laboratory testing often can distinguish atypical presentations of PHPT from other diseases, such as malignancy, familial hypocalciuric hypercalcemia (FHH), and secondary hyperparathyroidism (table 3).

In PHPT and FHH, the calcium and PTH levels are usually simultaneously elevated. Nonparathyroid-mediated causes of hypercalcemia (table 3), including milk-alkali syndrome, granulomatous disease, and hypervitaminosis D, are associated with suppressed rather than elevated PTH concentrations. They are discussed in more detail elsewhere. (See "Etiology of hypercalcemia" and "Diagnostic approach to hypercalcemia".)

Malignancy — PHPT and malignancy are the most common causes of hypercalcemia, accounting for more than 90 percent of cases (table 1). It is usually not difficult to differentiate between them. Malignancy is often evident clinically by the time it causes hypercalcemia, and patients with hypercalcemia of malignancy have higher calcium concentrations and are more symptomatic from hypercalcemia than individuals with PHPT. (See "Hypercalcemia of malignancy: Mechanisms".)

However, it may be difficult to differentiate the two problems clinically when the presentation is less typical. As an example, some patients with occult malignancy may present with mild hypercalcemia. Alternatively, patients with hyperparathyroidism can occasionally have acute onset of severe, symptomatic hypercalcemia (parathyroid crisis). In these cases, measurement of intact PTH will usually distinguish the two diseases. Intact PTH concentrations are generally undetectable or very low in hypercalcemia of malignancy and are elevated or high-normal in PHPT (table 3). It is uncommon for patients with hypercalcemia of malignancy to have elevated PTH levels, but this finding may occur rarely in individuals with hypercalcemia of malignancy and concomitant PHPT or in individuals with PTH-secreting tumors, which are also rare. (See "Hypercalcemia of malignancy: Mechanisms", section on 'Coexisting primary hyperparathyroidism' and "Hypercalcemia of malignancy: Mechanisms", section on 'Ectopic PTH secretion'.)

Patients with parathyroid carcinomas have severe hypercalcemia and PTH levels in the hundreds to thousands pg/mL range. (See "Parathyroid carcinoma".)

Familial hypocalciuric hypercalcemia — FHH is an autosomal dominant disorder characterized by longstanding, mild hypercalcemia; normal or mildly elevated PTH levels; and low urinary calcium excretion. In most cases, it is due to an inactivating mutation in the calcium-sensing receptor in the parathyroid glands and the kidneys; this form of FHH is now called FHH1 [23]. A family history of hypercalcemia, especially in young children, and the absence of symptoms and signs of hypercalcemia are characteristic of this disorder. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Familial hypocalciuric hypercalcemia'.)

Fifteen to 20 percent of patients with FHH may have a mildly elevated PTH concentration [23,24,35,36]. In these individuals, it may be difficult to distinguish asymptomatic PHPT from FHH. It is important to make this distinction, however, because FHH is a benign inherited condition that typically does not require parathyroidectomy and will not be cured by it (algorithm 2).

The major feature that distinguishes FHH from PHPT is a low urine calcium excretion and calcium/creatinine (Ca/Cr) clearance ratio (table 3). In contrast, in the absence of hypovitaminosis D, most patients with PHPT have either normal or elevated urinary calcium excretion (see '24-hour urinary calcium' above). Because the calcium-sensing receptor is a cation receptor, urinary magnesium excretion parallels calcium excretion and is therefore low in FHH, in contrast with PHPT. Measurement of urinary magnesium is not, however, recommended in the evaluation of PHPT or FHH. (See "Disorders of the calcium-sensing receptor: Familial hypocalciuric hypercalcemia and autosomal dominant hypocalcemia", section on 'Distinction from primary hyperparathyroidism'.)

Drugs — Two drugs deserve special consideration when evaluating a patient for hyperparathyroidism: thiazide diuretics and lithium.

Thiazide diuretics, including chlorthalidone, reduce urinary calcium excretion and therefore can cause mild hypercalcemia (up to 11.5 mg/dL [2.9 mmol/L]) (see "Etiology of hypercalcemia"). In addition, some patients with hyperparathyroidism may be prescribed thiazides, which may elevate the serum calcium further and thereby unmask the hyperparathyroidism. Following discontinuation of the drug, these individuals remain hypercalcemic, although perhaps less so, and are found to have surgically proven hyperparathyroidism. Thus, if a patient taking a thiazide is found to be hypercalcemic, the drug should be withdrawn, if possible, and calcium and PTH assessed three months later. Persistent hypercalcemia (with elevated or high-normal PTH) after drug withdrawal suggests that the thiazide has unmasked PHPT. (See "Pathogenesis and etiology of primary hyperparathyroidism", section on 'Thiazide therapy'.)

Lithium decreases parathyroid gland sensitivity to calcium, shifting the calcium-PTH curve to the right (figure 2). Lithium may also reduce urinary calcium excretion. Lithium is thought to affect calcium-PTH dynamics through an action downstream of the calcium-sensing receptor, but the exact locus is still unknown. Some patients taking lithium develop hypercalcemia and hypocalciuria, and a subset of these individuals have high serum PTH concentrations. If the lithium can be stopped without exacerbating the psychiatric condition, the hypercalcemia may resolve. Following discontinuation, the serum calcium concentration is more likely to normalize if the duration of lithium use had been relatively short (eg, less than a few years), but less likely if it had been longer (eg, more than 10 years). (See "Pathogenesis and etiology of primary hyperparathyroidism", section on 'Lithium therapy' and "Parathyroid hormone secretion and action", section on 'Lithium and PTH secretion'.)

Secondary hyperparathyroidism — Occasionally, patients with PHPT have consistently normal total and ionized calcium concentrations (normocalcemic PHPT). These patients typically come to medical attention in the setting of an evaluation for low bone mineral density (BMD). In these cases, it may be difficult to distinguish secondary hyperparathyroidism from early PHPT because the biochemical findings may be similar.

Secondary hyperparathyroidism occurs when the parathyroid gland appropriately responds to a reduced level of extracellular calcium. PTH concentrations rise, and calcium is mobilized by increasing intestinal absorption (via increase in calcitriol) and by increasing bone resorption. Thus, it is characterized biochemically by elevated PTH and normal or low serum calcium concentrations. (See "Management of secondary hyperparathyroidism in adult dialysis patients".)

Secondary hyperparathyroidism may occur in patients with renal insufficiency or failure and impaired calcitriol (1,25 dihydroxyvitamin D) production, as well as in individuals with inadequate calcium intake or absorption, as can occur with vitamin D deficiency or with gastrointestinal diseases causing malabsorption (table 2). Assessment of renal function (serum creatinine), vitamin D status (25-hydroxyvitamin D [25(OH)D]), and calcium sufficiency (urinary calcium excretion) may help differentiate normocalcemic primary and secondary hyperparathyroidism. Further assessment and work-up for specific gastrointestinal disorders is generally undertaken only when the clinical suspicion is high. It is important to rule out causes of secondary hyperparathyroidism before making the diagnosis of normocalcemic PHPT.

Some patients may have more than one condition leading to increased PTH secretion. Co-existing PHPT and vitamin D deficiency is not uncommon. When this occurs, the serum calcium level in the primary hyperparathyroid patient may be reduced (into the normal range in some cases) due to vitamin D deficiency. Repletion of vitamin D in these patients will unmask their hypercalcemia. (See 'Serum vitamin D' below and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Coexisting primary hyperparathyroidism'.)

ADDITIONAL EVALUATION TO DETERMINE MANAGEMENT — For patients diagnosed with asymptomatic primary hyperparathyroidism (PHPT), additional evaluation is necessary to make subsequent management decisions. (See "Primary hyperparathyroidism: Management".)

Although patients with symptomatic PHPT should have parathyroid surgery, the widespread identification of asymptomatic individuals raises the question of need for and timing of surgical intervention in this population. In order to make management recommendations for patients with asymptomatic PHPT, we measure:

Urinary calcium excretion (if not previously measured)

Serum 25-hydroxyvitamin D (25[OH]D) (if not previously measured)

Serum creatinine and estimated glomerular filtration rate (eGFR) to assess for renal compromise

Bone density to determine if it is low

Given data demonstrating subclinical manifestations of PHPT in bone and kidney, further imaging can indicate the presence of involvement of these important target organs. This includes renal imaging (plain radiographs or ultrasound) to determine if the patient has a clinically silent kidney stone (present in up to 22 percent of seemingly asymptomatic PHPT patients [37-40]) and vertebral imaging (spine radiograph or vertebral fracture assessment [VFA] of dual-energy x-ray absorptiometry [DXA] image) for subclinical vertebral fracture [41]. Urinary stone risk profile is also recommended in patients with hypercalciuria who are unsure about parathyroid surgery. While these tests are more expensive and may not be readily available to all clinicians, they may be helpful for making management recommendations for patients with asymptomatic PHPT. (See "Primary hyperparathyroidism: Management", section on 'Candidates for surgery'.)

Urinary calcium excretion — In asymptomatic patients, the urinary calcium excretion is helpful to assess the risk of renal complications (when urine calcium is high) and thus determine subsequent management. While the Fourth International Workshop on Asymptomatic Primary Hyperparathyroidism guidelines recommended surgical intervention as opposed to observation in asymptomatic patients who have a 24-hour urinary calcium excretion >400 mg/day (>10 mmol/day), urinary calcium levels are considered to be elevated at a significantly lower level of excretion (250 mg/24 hours in women and 300 mg/24 hours in men), and there are no specific data assessing the cutpoint of 400 mg calcium excretion daily. In those with nephrolithiasis but without hypercalciuria, a stone risk profile is helpful since many factors in addition to the urinary excretion of calcium contribute to stone formation. (See "Primary hyperparathyroidism: Management", section on 'Candidates for surgery'.)

Serum vitamin D — We measure serum 25(OH)D in all patients with suspected or diagnosed PHPT. Measurement of 25(OH)D is important to identify patients with PHPT and vitamin D deficiency, who require vitamin D repletion. (See "Primary hyperparathyroidism: Management", section on 'Concomitant vitamin D deficiency' and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Coexisting primary hyperparathyroidism'.)

Due to the significant prevalence of vitamin D insufficiency in individuals with PHPT, the Fourth International Workshop on Asymptomatic Primary Hyperparathyroidism recommended measuring 25(OH)D in all patients with the disease and repleting those with low levels (defined as ≤20 ng/mL [50 nmol/L]) prior to making any management decisions [11]. In some cases, the decision regarding surgery will be clear despite the low vitamin D level. In such patients, it is still advisable to replete vitamin D if this can be done safely, in order to mitigate postoperative hypocalcemia.

Serum creatinine — The serum creatinine concentration provides information about renal function, which can be diminished by hypercalcemia. Rather than using serum creatinine alone, the eGFR can be estimated in patients with a stable serum creatinine concentration. (See "Clinical manifestations of hypercalcemia" and "Assessment of kidney function", section on 'Estimation of GFR'.)

An eGFR of 60 mL/min is the threshold of chronic kidney disease for deciding which asymptomatic individuals with PHPT may benefit from early surgical treatment [41]. (See "Primary hyperparathyroidism: Management", section on 'Candidates for surgery'.)

Renal imaging — In several studies, clinically silent kidney stones were reported in 7 to 22 percent of patients with asymptomatic PHPT [37-40]. Patients with undiagnosed (subclinical) nephrocalcinosis or calcium kidney stones are regarded as having symptomatic disease, regardless of the absence of symptoms. Thus, these patients meet criteria for surgical intervention [41]. For patients who do not have other overt indications for surgery, some UpToDate authors and editors obtain renal imaging (ultrasound, computed tomography [CT], or abdominal radiograph) to look for nephrocalcinosis or asymptomatic nephrolithiasis at the time of the original evaluation for PHPT [3]. Ultrasound is typically the imaging modality used.

Bone mineral density — Patients with hyperparathyroidism may have decreased bone mineral density (BMD), in particular at more cortical sites (forearm and hip) as compared with more trabecular (cancellous) sites (spine). Although measurement of BMD is not required for the diagnosis of PHPT, it is an essential part of the management of the disease, and BMD must be measured at the spine, hip, and distal one-third forearm sites. The degree of bone loss is reflective of the severity of hyperparathyroidism and is useful for making recommendations for parathyroid surgery or observation with monitoring in asymptomatic patients. (See "Primary hyperparathyroidism: Management", section on 'Asymptomatic' and "Primary hyperparathyroidism: Management", section on 'Subclinical bone disease'.)

Assessment for vertebral fracture — Patients with subclinical, idiopathic vertebral compression fractures are regarded as having osteoporosis, independent of BMD findings. Vertebral compression fractures are underdiagnosed in all populations, and many studies have demonstrated an increased risk of asymptomatic vertebral fractures in patients with PHPT. (See "Primary hyperparathyroidism: Clinical manifestations", section on 'Skeletal'.)

In order to diagnose asymptomatic vertebral compression fractures, the Fourth International Workshop guidelines recommended imaging to assess for vertebral fracture in asymptomatic patients who do not have osteoporosis on BMD testing (patients with clinical osteoporotic fractures or with BMD in the osteoporosis range already meet criteria for surgery) [41]. If a vertebral fracture is present by VFA or radiograph, parathyroidectomy is recommended. Vertebral assessment can be performed with plain radiographs or with VFA by DXA. The latter can be done at the time of BMD testing, at greater patient convenience, less cost, and lower radiation exposure than conventional radiography of the spine. (See "Overview of dual-energy x-ray absorptiometry", section on 'Vertebral fracture assessment' and "Primary hyperparathyroidism: Management", section on 'Candidates for surgery'.)

Other tests — Other tests that may provide useful clinical information include the following:

Biochemical renal stone prediction — For asymptomatic patients with hypercalciuria (>400 mg/day [10 mmol/day]), the Fourth International Workshop Guidelines on the Management of Asymptomatic Primary Hyperparathyroidism recommended assessment of the urine composition to identify patients at highest risk for nephrolithiasis [41]. There are no specific data to suggest that urine stone risk profiling can predict risk of nephrolithiasis in patients with PHPT [42]. Some experts believe that urinary calcium excretion >400 mg/day alone raises sufficient enough concern about long-term renal complications to warrant a recommendation for parathyroidectomy. Since many factors other than urinary calcium contribute to stone risk, some experts favor using a stone risk profile to provide useful information for making a decision about surgery in PHPT patients with a renal stone history in the absence of hypercalciuria. (See "Kidney stones in adults: Evaluation of the patient with established stone disease", section on '24-hour urine collections'.)

Serum phosphorus — The serum phosphorus concentration may be decreased but typically is in the lower range of normal. Some patients have mild hyperchloremic acidosis. (See "Primary hyperparathyroidism: Clinical manifestations".)

Markers of bone turnover — Biochemical markers of bone turnover (collagen crosslinks, osteocalcin, bone-specific alkaline phosphatase) are often at the upper end of normal or mildly elevated in asymptomatic PHPT (see "Bone physiology and biochemical markers of bone turnover"). In those with more severe disease, they are typically high. They are only occasionally helpful in the management of hyperparathyroidism and should not be routinely measured [8].

Localization studies — The diagnosis of PHPT is established by appropriate biochemical testing. Localization studies with ultrasonography, technetium-99m sestamibi, CT, or magnetic resonance imaging (MRI) scanning should not be used to establish the diagnosis of PHPT or to determine management. Localization studies should be performed only after a decision for surgery has been made. Their utility is questionable when bilateral neck exploration is planned. However, they are commonly used now, along with intraoperative parathyroid hormone (PTH) monitoring, to facilitate unilateral exploration and minimally invasive surgery in those with probable single gland disease. (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary hyperparathyroidism".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Primary hyperparathyroidism (The Basics)")

Beyond the Basics topic (see "Patient education: Primary hyperparathyroidism (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Diagnosis

Primary hyperparathyroidism (PHPT) – The diagnosis of PHPT is usually first suspected because of the incidental finding of an elevated serum calcium concentration on biochemical screening tests. In addition, PHPT may be suspected in a patient with nephrolithiasis. PHPT is diagnosed by finding a frankly elevated parathyroid hormone (PTH) concentration in a patient with hypercalcemia. When the PTH is only minimally elevated, or within the normal range (but inappropriately normal given the patient's hypercalcemia), PHPT remains the most likely diagnosis, although familial hypocalciuric hypercalcemia (FHH), a rare disorder, is possible (algorithm 1). (See 'Diagnosis' above.)

Normocalcemic primary hyperparathyroidism – Normocalcemic PHPT is a variant of PHPT. Patients with normocalcemic PHPT typically come to medical attention in the setting of an evaluation for low bone mineral density (BMD), during which time PTH levels are drawn and found to be elevated in the absence of hypercalcemia. In such cases, BMD at cortical sites may be preferentially affected. In order to make this diagnosis, all secondary causes for hyperparathyroidism (table 2) must be ruled out, and ionized calcium levels should be normal. (See 'Diagnosis' above and 'Bone mineral density' above.)

Diagnostic evaluation – For patients with hypercalcemia and PTH that is only minimally elevated or inappropriately normal given the patient's hypercalcemia, further evaluation is necessary to confirm the diagnosis. We measure urinary calcium excretion and 25-hydroxyvitamin D (25[OH]D) in all patients with suspected PHPT (algorithm 2). Measurement of 24-hour urine calcium excretion is helpful for distinguishing PHPT from FHH. Measurement of 25(OH)D is not only important to distinguish PHPT from other conditions, but also to identify patients with both PHPT and vitamin D deficiency, who require vitamin D repletion. (See '24-hour urinary calcium' above and 'Serum 25-hydroxyvitamin D' above.)

Differential diagnosis – Although the most common clinical presentation of PHPT is asymptomatic hypercalcemia with an elevated or high-normal intact PTH concentration, the presentation may be atypical. Atypical presentations include a spectrum of disturbances in calcium homeostasis, ranging from symptomatic severe hypercalcemia (parathyroid crisis) to normocalcemic PHPT. Laboratory testing often can distinguish atypical presentations of PHPT from other diseases, such as malignancy, FHH, and secondary hyperparathyroidism (table 3). (See 'Differential diagnosis' above.)

Additional evaluation to determine management – For patients diagnosed with asymptomatic PHPT, additional evaluation is necessary to make subsequent management decisions. (See 'Additional evaluation to determine management' above and "Primary hyperparathyroidism: Management", section on 'Surgery versus nonsurgical management'.)

Although patients with symptomatic PHPT should have parathyroid surgery, the widespread identification of asymptomatic individuals raises the question of the need for and timing of surgical intervention in this population. In order to make management recommendations for patients with asymptomatic PHPT, we measure urinary calcium excretion and serum 25(OH)D (if both have not been previously measured), assess kidney function by estimated glomerular filtration rate (eGFR), and obtain a BMD test. Imaging of the kidneys and spine to assess for occult kidney stones and asymptomatic vertebral compression fracture, respectively, may be helpful for making management recommendations for patients with asymptomatic PHPT. (See 'Additional evaluation to determine management' above.)

Other tests – Localization studies with ultrasonography, technetium-99m sestamibi, computed tomography (CT), or magnetic resonance imaging (MRI) scanning should not be used to establish the diagnosis of PHPT or to determine management. If localization studies are performed, they should be done after a decision for surgery has been made. (See "Preoperative localization for parathyroid surgery in patients with primary hyperparathyroidism".)

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