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== Overview ==
== Overview ==
* The diagnosis is usually first suspected because of the incidental finding of an elevated serum calcium concentration on biochemical screening tests.
* If hypercalcemia is confirmed, intact parathyroid hormone (PTH) should be measured concomitantly with the serum calcium.
* Parathyroid adenoma 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, Parathyroid adenoma remains the most likely diagnosis.
* Patients with Parathyroid adenoma 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 particular, all secondary causes for Parathyroid adenoma, and ionized calcium levels should be normal.


== Diagnostic Study of Choice ==
== Diagnostic Study of Choice ==
=== Study of choice ===


==Serum calcium==  
==Serum calcium==  
* A single elevated serum calcium concentration should be repeated to confirm the presence of hypercalcemia.  
* 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.  
* 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 [6].
* 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<ref name="pmid8964825">{{cite journal |vauthors=Silverberg SJ, Bilezikian JP |title=Evaluation and management of primary hyperparathyroidism |journal=J. Clin. Endocrinol. Metab. |volume=81 |issue=6 |pages=2036–40 |date=June 1996 |pmid=8964825 |doi=10.1210/jcem.81.6.8964825 |url=}}</ref>.
 
* Ionized calcium measurements are an important adjunct to diagnosis is in patients with presumed normocalcemic PHPT.  
* Ionized calcium measurements are an important adjunct to diagnosis is in patients with presumed normocalcemic PHPT.  
* Ionized calcium levels should be normal. [7].
* Ionized calcium levels should be normal<ref name="pmid9612524">{{cite journal |vauthors=Glendenning P, Gutteridge DH, Retallack RW, Stuckey BG, Kermode DG, Kent GN |title=High prevalence of normal total calcium and intact PTH in 60 patients with proven primary hyperparathyroidism: a challenge to current diagnostic criteria |journal=Aust N Z J Med |volume=28 |issue=2 |pages=173–8 |date=April 1998 |pmid=9612524 |doi= |url=}}</ref>.


==Serum PTH==  
==Serum PTH==  
* Parathyroid hormone (PTH) or PTH 1-84 assays (third-generation) should be measured concomitantly with the serum calcium level to diagnose hyperparathyroidism [8].  
* Parathyroid hormone (PTH) or PTH 1-84 assays (third-generation) should be measured concomitantly with the serum calcium level to diagnose hyperparathyroidism<ref name="pmid25162666">{{cite journal |vauthors=Eastell R, Brandi ML, Costa AG, D'Amour P, Shoback DM, Thakker RV |title=Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop |journal=J. Clin. Endocrinol. Metab. |volume=99 |issue=10 |pages=3570–9 |date=October 2014 |pmid=25162666 |doi=10.1210/jc.2014-1414 |url=}}</ref>.  
* 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 [10,11].  
* 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<ref name="pmid14718396">{{cite journal |vauthors=Carnevale V, Dionisi S, Nofroni I, Romagnoli E, Paglia F, De Geronimo S, Pepe J, Clemente G, Tonnarini G, Minisola S |title=Potential clinical utility of a new IRMA for parathyroid hormone in postmenopausal patients with primary hyperparathyroidism |journal=Clin. Chem. |volume=50 |issue=3 |pages=626–31 |date=March 2004 |pmid=14718396 |doi=10.1373/clinchem.2003.026328 |url=}}</ref>.
 
==PTH elevated==  
 
* PHPT have serum PTH concentrations above the normal range for the assay [12,13].  
* Parathyroid cancer and secondary hyperparathyroidism associated with renal failure, often in the range of twice the upper limit of normal.
 


==24-hour urinary calcium==  
==24-hour urinary calcium==  
* Measurement of 24-hour urinary calcium excretion is not always required for the diagnosis of PHPT,
* Measurement of 24-hour urinary calcium excretion is not always required for the diagnosis of Parathyroid adenoma.
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.  
* It is routinely measured in patients with asymptomatic Parathyroid adenoma in order to assess the risk of renal complications (when urine calcium is high) and thus determine subsequent management.  
* Hypercalcemia and PTH that is only minimally elevated or inappropriately normal given the patient's hypercalcemia, the 24-hour urinary calcium also helps to distinguish PHPT from FHH.
* Hypercalcemia and PTH that is only minimally elevated or inappropriately normal given the patient's hypercalcemia, the 24-hour urinary calcium also helps to distinguish PHPT from FHH<ref name="pmid2393037">{{cite journal |vauthors=Silverberg SJ, Shane E, Jacobs TP, Siris ES, Gartenberg F, Seldin D, Clemens TL, Bilezikian JP |title=Nephrolithiasis and bone involvement in primary hyperparathyroidism |journal=Am. J. Med. |volume=89 |issue=3 |pages=327–34 |date=September 1990 |pmid=2393037 |doi=10.1016/0002-9343(90)90346-f |url=}}</ref>.
 
* The data establishing the value of the Ca/Cr clearance ratio in differentiating FHH from PHPT are based primarily on 24-hour urine collections.  
●Approximately 40 percent of patients with PHPT are hypercalciuric, and most of the remaining patients have normal values [18]. An elevated urinary calcium concentration (>200 to 300 mg/day) essentially excludes FHH.
* There are insufficient data available to prove that Ca/Cr ratios calculated from spot urines are equivalent to those determined from 24-hour urines.
 
●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 1). (See 'Serum 25-hydroxyvitamin D' below.)
 
●Approximately 75 percent of affected persons with FHH excrete less than 100 mg of calcium in urine daily [19]. (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:
 
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). 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 [20-22].
 
Some individuals with PHPT and with FHH have Ca/Cr clearance ratios between 0.01 and 0.02 [19]. 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. [8,19,22,23]. 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. 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 hyperparathyroidism 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 hypercalciuria, 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 [24,25]. 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 and patients with a family history of PHPT, multigland involvement, or clinical findings suspicious for multiple endocrine neoplasia type 1 (MEN1) [8]. Approximately 10 percent of patients with PHPT will have a mutation in 1 of 11 genes [8]. (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'.)
==Serum 25-hydroxyvitamin D==


==References==
==References==

Latest revision as of 20:27, 3 October 2019

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Syed Musadiq Ali M.B.B.S.[2]

Overview

  • The diagnosis is usually first suspected because of the incidental finding of an elevated serum calcium concentration on biochemical screening tests.
  • If hypercalcemia is confirmed, intact parathyroid hormone (PTH) should be measured concomitantly with the serum calcium.
  • Parathyroid adenoma 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, Parathyroid adenoma remains the most likely diagnosis.
  • Patients with Parathyroid adenoma 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 particular, all secondary causes for Parathyroid adenoma, and ionized calcium levels should be normal.

Diagnostic Study of Choice

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[1].
  • Ionized calcium measurements are an important adjunct to diagnosis is in patients with presumed normocalcemic PHPT.
  • Ionized calcium levels should be normal[2].

Serum PTH

  • Parathyroid hormone (PTH) or PTH 1-84 assays (third-generation) should be measured concomitantly with the serum calcium level to diagnose hyperparathyroidism[3].
  • 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[4].

24-hour urinary calcium

  • Measurement of 24-hour urinary calcium excretion is not always required for the diagnosis of Parathyroid adenoma.
  • It is routinely measured in patients with asymptomatic Parathyroid adenoma in order to assess the risk of renal complications (when urine calcium is high) and thus determine subsequent management.
  • Hypercalcemia and PTH that is only minimally elevated or inappropriately normal given the patient's hypercalcemia, the 24-hour urinary calcium also helps to distinguish PHPT from FHH[5].
  • The data establishing the value of the Ca/Cr clearance ratio in differentiating FHH from PHPT are based primarily on 24-hour urine collections.
  • There are insufficient data available to prove that Ca/Cr ratios calculated from spot urines are equivalent to those determined from 24-hour urines.

Serum 25-hydroxyvitamin D

References

  1. ↑ Silverberg SJ, Bilezikian JP (June 1996). "Evaluation and management of primary hyperparathyroidism". J. Clin. Endocrinol. Metab. 81 (6): 2036–40. doi:10.1210/jcem.81.6.8964825. PMID 8964825.
  2. ↑ Glendenning P, Gutteridge DH, Retallack RW, Stuckey BG, Kermode DG, Kent GN (April 1998). "High prevalence of normal total calcium and intact PTH in 60 patients with proven primary hyperparathyroidism: a challenge to current diagnostic criteria". Aust N Z J Med. 28 (2): 173–8. PMID 9612524.
  3. ↑ Eastell R, Brandi ML, Costa AG, D'Amour P, Shoback DM, Thakker RV (October 2014). "Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the Fourth International Workshop". J. Clin. Endocrinol. Metab. 99 (10): 3570–9. doi:10.1210/jc.2014-1414. PMID 25162666.
  4. ↑ Carnevale V, Dionisi S, Nofroni I, Romagnoli E, Paglia F, De Geronimo S, Pepe J, Clemente G, Tonnarini G, Minisola S (March 2004). "Potential clinical utility of a new IRMA for parathyroid hormone in postmenopausal patients with primary hyperparathyroidism". Clin. Chem. 50 (3): 626–31. doi:10.1373/clinchem.2003.026328. PMID 14718396.
  5. ↑ Silverberg SJ, Shane E, Jacobs TP, Siris ES, Gartenberg F, Seldin D, Clemens TL, Bilezikian JP (September 1990). "Nephrolithiasis and bone involvement in primary hyperparathyroidism". Am. J. Med. 89 (3): 327–34. doi:10.1016/0002-9343(90)90346-f. PMID 2393037.

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