Variants of primary hyperparathyroidism (pHPT), described as normocalcemic (NC) and normohormonal (NH), can confuse the diagnosis of classic pHPT.
Data Sources
A MEDLINE search was performed for variants of pHPT using the PubMed database (last queried October 2019).
Review Methods
The search was restricted to articles published after 1960 that were specific to humans. Studies were included in our analysis if laboratory values and incidence of end-organ involvement were reported for NCpHPT and NHpHPT variants. The search returned 189 articles; 27 additional studies were identified and included for a total of 216. Non-English-language studies were excluded. Abstracts were screened, full-text articles were then assessed, and 82 articles were excluded. Data were pooled using a random-effects model in studies that compared NC or NH pHPT to classic pHPT. Comparative laboratory values are presented.
Conclusion
This analysis compares NCpHPT and NHpHPT to classic pHPT. Nephrolithiasis was 21.7% (NCpHPT), 15.9% (classic pHPT), and 25.4% (NHpHPT). Decreased bone mineral density was 49.7% (NCpHPT), 39.7% (classic pHPT), and 40.3% (NHpHPT). Fractures in the NCpHPT group were not significantly different from the classic pHPT. Hypertension in the NCpHPT group was significantly less than classic pHPT (odds ratio, 0.59; 95% CI, 0.40-0.88).
Implications for Clinical Practice
This information may serve to inform clinicians of the laboratory subtleties of these variants that are being seen with greater frequency in contemporary practice.
InsognaKL. Primary Hyperparathyroidism. N Engl J Med. 2018; 379(11):1050-1059.
2.
EastellRBrandiMLCostaAG, et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the fourth international workshop. J Clin Endocrinol Metab. 2014;99(10):3570-3579.
3.
SilverbergSJClarkeBLPeacockM, et al. Current issues in the presentation of asymptomatic primary hyperparathyroidism: proceedings of the fourth international workshop. J Clin Endocrinol Metab. 2014;99(10):3580-9354.
4.
StephenAEMannstadtMHodinRA. Indications for surgical management of hyperparathyroidism: a review. JAMA Surg. 2017;152(9):878-882.
5.
CusanoNECiprianiCBilezikianJP. Management of normocalcemic primary hyperparathyroidism. Best Pract Res Clin Endocrinol Metab. 2018;32(6):837-845.
6.
TrainiEBellantoneRTemperaSE, et al. Is parathyroidectomy safe and effective in patients with normocalcemic primary hyperparathyroidism?Langenbecks Arch Surg. 2018;403(3):317-323.
7.
ApplewhiteMKWhiteMGTsengJ, et al. Normohormonal primary hyperparathyroidism is a distinct form of primary hyperparathyroidism. Surgery. 2017;161(1):62-69.
8.
MajidHKhanAHRiazMKarimiHTalatiJ. Identifying parathyroid hormone disorders and their phenotypes through a bone health screening panel: its not simple vitamin D deficiency!Endocr Pract. 2016;22(7):814-821.
9.
KoumakisESouberbielleJ-CSarfatiE, et al. Bone mineral density evolution after successful parathyroidectomy in patients with normocalcemic primary hyperparathyroidism. J Clin Endocrinol Metabol. 2013;98(8):3213-3220.
10.
KoumakisESouberbielleJCPayetJ, et al. Individual site-specific bone mineral density gain in normocalcemic primary hyperparathyroidism. Osteoporos Int. 2014;25(7):1963-1968.
11.
LimJYHermanMCBubisL, et al. Differences in single gland and multigland disease are seen in low biochemical profile primary hyperparathyroidism. Surgery. 2017;161(1):70-77.
12.
NicholsGJrFlanaganB. Normocalcemic hyperparathyroidism. Trans Assoc Am Physicians. 1967;80:314-322.
13.
EastellRArnoldABrandiML, et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab. 2009;94(2) 340-350.
14.
MarquesTFVasconcelosRDinizE, et al. Normocalcemic primary hyperparathyroidism in clinical practice: an indolent condition or a silent threat?Arquivos Brasileiros Endocrinol Metabol. 2011;55(5):314-317.
15.
MesquitaPNDornelas Leao LeiteAPChagas CrisostomoSDVeras FilhoEda Cunha XavierLBandeiraF. Evaluation of coronary calcium score in patients with normocalcemic primary hyperparathyroidism. Vasc Health Risk Manag. 2017;13:225-229.
16.
PepeJCiprianiCSonatoCRaimoOBiamonteFMinisolaS. Cardiovascular manifestations of primary hyperparathyroidism: a narrative review. Eur J Endocrinol. 2017;177(6):R297-R308.
17.
TrinhGNoureldineSIRussellJO, et al. Characterizing the operative findings and utility of intraoperative parathyroid hormone (IOPTH) monitoring in patients with normal baseline IOPTH and normohormonal primary hyperparathyroidism. Surgery. 2017;161(1):78-86.
18.
JovanovicMDZivaljevicVRDiklicADRovcaninBRV ZoricGPaunovicIR. Surgical treatment of concomitant thyroid and parathyroid disorders: analysis of 4882 cases. Eur Arch Otorhinolaryngol. 2017;274(2):997-1004.
19.
Yener OzturkFErolSCanatMM, et al. Patients with normocalcemic primary hyperparathyroidism may have similar metabolic profile as hypercalcemic patients. Endocr J. 2016;63(2):111-118.
20.
SiprovaHFrysakZSoucekM. Primary hyperparathyroidism, with a focus on management of the normocalcemic form: to treat or not to treat?Endocr Pract. 2016;22(3):294-301.
21.
Diaz-SotoGRomeroECastrillonJLJaureguiOIde Luis RomanD. Clinical expression of calcium sensing receptor polymorphism (A986S) in normocalcemic and asymptomatic hyperparathyroidism. Horm Metab Res. 2016;48(3):163-168.
22.
TunaMMCalıskanMUnalM, et al. Normocalcemic hyperparathyroidism is associated with complications similar to those of hypercalcemic hyperparathyroidism. J Bone Miner Metab. 2016;34(3):331-335.
23.
KontogeorgosGTrimpouPLaineCMOlerodGLindahlALandin-WilhelmsenK. Normocalcaemic, vitamin D-sufficient hyperparathyroidism—high prevalence and low morbidity in the general population: a long-term follow-up study, the WHO MONICA project, Gothenburg, Sweden. Clin Endocrinol (Oxf). 2015;83(2):277-284.
24.
ChenGXueYZhangQ. Is normocalcemic primary hyperparathyroidism harmful or harmless?J Clin Endocrinol Metab. 2015;100(6):2420-2424.
25.
CesareoRDi StasioEVesciniF, et al. Effects of alendronate and vitamin D in patients with normocalcemic primary hyperparathyroidism. Osteoporos Int. 2015;26(4):1295-1302.
26.
TemizkanSKocakOAydinK, et al. Normocalcemic hyperparathyroidism and insulin resistance. Endocr Pract. 2015;21(1):23-29.
27.
SchneiderDFBurkeJFOjomoKA, et al. Multigland disease and slower decline in intraoperative PTH characterize mild primary hyperparathyroidism. Ann Surg Oncol. 2013;20(13):4205-4211.
28.
CusanoNEMaaloufNMWangPY, et al. Normocalcemic hyperparathyroidism and hypoparathyroidism in two community-based nonreferral populations. J Clin Endocrinol Metab. 2013;98(7):2734-2741.
29.
RejnmarkLAmstrupAKMollerupCLHeickendorffLMosekildeL. Further insights into the pathogenesis of primary hyperparathyroidism: a nested case-control study. J Clin Endocrinol Metab. 2013;98(1):87-96.
30.
InvernizziMCardaSRighiniVBaricichACisariCBevilacquaM. Different PTH response to oral peptone load and oral calcium load in patients with normocalcemic primary hyperparathyroidism, primary hyperparathyroidism, and healthy subjects. Eur J Endocrinol. 2012;167(4):491-497.
31.
Garcia-MartinAReyes-GarciaRMunoz-TorresM. Normocalcemic primary hyperparathyroidism: one-year follow-up in one hundred postmenopausal women. Endocrine. 2012;42(3):764-766.
32.
PipiliCSekeciogluNOreopoulosDG. Normocalcemic hyperparathyroidism in patients with recurrent kidney stones: a disease entity or vitamin D deficiency?Clin Nephrol. 2012;77(5):352-357.
33.
WadeTJYenTWAminALWangTS. Surgical management of normocalcemic primary hyperparathyroidism. World J Surg. 2012;36(4):761-766.
34.
WallaceLBParikhRTRossLV, et al. The phenotype of primary hyperparathyroidism with normal parathyroid hormone levels: how low can parathyroid hormone go?Surgery. 2011;150(6):1102-1112.
35.
NormanJGoodmanAPolitzD. Calcium, parathyroid hormone, and vitamin D in patients with primary hyperparathyroidism: normograms developed from 10,000 cases. Endocr Pract. 2011;17(3):384-394.
36.
TordjmanKMYaronMIzkhakovE, et al. Cardiovascular risk factors and arterial rigidity are similar in asymptomatic normocalcemic and hypercalcemic primary hyperparathyroidism. Eur J Endocrinol. 2010;162(5):925-933.
37.
Carneiro-PlaDMIrvinGLIIIChenH. Consequences of parathyroidectomy in patients with “mild” sporadic primary hyperparathyroidism [published correction appears in: Surgery. 2008;143(2):301]. Surgery. 2007;142(6):795-799.
38.
LoweHMcMahonDJRubinMRBilezikianJPSilverbergSJ. Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype. J Clin Endocrinol Metab. 2007;92(8):3001-3305.
39.
HagstromELundgrenERastadJHellmanP. Metabolic abnormalities in patients with normocalcemic hyperparathyroidism detected at a population-based screening. Eur J Endocrinol. 2006;155(1):33-39.
40.
YangAHHsuCWChenJYTsengLMWonGSLeeCH. Normocalcemic primary hyperparathyroidism in patients with recurrent kidney stones: pathological analysis of parathyroid glands. Virchows Arch. 2006;449(1):62-68.
41.
TordjmanKMGreenmanYOsherEShenkermanGSternN. Characterization of normocalcemic primary hyperparathyroidism. Am J Med. 2004;117(11):861-863.
42.
MaruaniGHertigAPaillardMHouillierP. Normocalcemic primary hyperparathyroidism: evidence for a generalized target-tissue resistance to parathyroid hormone. J Clin Endocrinol Metab. 2003;88(10):4641-4648.
43.
GardinJPPaillardM. Normocalcemic primary hyperparathyroidism: resistance to PTH effect on tubular reabsorption of calcium. Miner Electrolyte Metab. 1984;10(5):301-308.
44.
KiriakopoulosAPetraliasALinosD. Classic primary hyperparathyroidism versus normocalcemic and normohormonal variants: do they really differ?World J Surg. 2018;42:992-997.
45.
AmaralLMQueirozDCMarquesTFMendesMBandeiraF. Normocalcemic versus hypercalcemic primary hyperparathyroidism: more stone than bone?J Osteoporos. 2012;2012:128352.
46.
YanHCalcateraNMoo-YoungTAPrinzRAWinchesterDJ. Degree of hypercalcemia correlates with parathyroidectomy but not with symptoms. Am J Surg. 2019;217(3):437-440.
47.
TrebouetEBanniniSWargnyM, et al. Mild sporadic primary hyperparathyroidism: high rate of multiglandular disease associated with lower surgical cure rate. Langenbecks Arch Surg. 2019;404(4):431-438.
48.
ShoSKuoEJChenACLiNYehMWLivhitsMJ. Biochemical and skeletal outcomes of parathyroidectomy for normocalcemic (incipient) primary hyperparathyroidism. Ann Surg Oncol. 2019;26(2):539-546.
49.
BeyselSCaliskanMKizilgulM, et al. Parathyroidectomy improves cardiovascular risk factors in normocalcemic and hypercalcemic primary hyperparathyroidism. BMC Cardiovasc Disord. 2019;19(1):106.
50.
RosarioPWCalsolariMR. Normocalcemic primary hyperparathyroidism in adults without a history of nephrolithiasis or fractures: a prospective study. Horm Metab Res. 2019;51(4):243-247.
51.
PierreuxJBravenboerBVelkeniersBUnuaneDAndreescuCEVanhoeijM. Normocalcemic Primary hyperparathyroidism: a comparison with the hypercalcemic form in a tertiary referral population. Horm Metab Res. 2018;50(11):797-802.
52.
BossertIChytirisSHodolicM, et al. PETC/CT with 18F-choline localizes hyperfunctioning parathyroid adenomas equally well in normocalcemic hyperparathyroidism as in overt hyperparathyroidism. J Endocrinol Invest. 2019;42(4):419-426.
53.
TrinhGRettigENoureldineSI, et al. Surgical management of normocalcemic primary hyperparathyroidism and the impact of intraoperative parathyroid hormone testing on outcome. Otolaryngol Head Neck Surg. 2018;159(4):630-637.
54.
LeeDWalkerMDChenHYChabotJALeeJAKuoJH. Bone mineral density changes after parathyroidectomy are dependent on biochemical profile. Surgery. 2019;165(1):107-113.
55.
Cunha-BezerraPVieiraRAmaralF, et al. Better performance of four-dimension computed tomography as a localization procedure in normocalcemic primary hyperparathyroidism [published online April15, 2018]. J Med Imaging Radiat Oncol.
56.
VignaliECetaniFChiavistelliS, et al. Normocalcemic primary hyperparathyroidism: a survey in a small village of southern Italy. Endocr Connect. 2015;4(3):172-178.
57.
WangQLiXChenH, et al. The chloride/phosphate ratio combined with alkaline phosphatase as a valuable predictive marker for primary hyperparathyroidism in Chinese individuals. Sci Rep. 2017;7(1):4868.
58.
BannaniSChristouNGuérinC, et al. Effect of parathyroidectomy on quality of life and non-specific symptoms in normocalcaemic primary hyperparathyroidism. Br J Surg. 2018;105(3):223-229.
59.
AminALWangTSWadeTJ, et al. Normal PTH levels in primary hyperparathyroidism: still the same disease?Ann Surg Oncol. 2011;18(12):3437-3442.
60.
BilezikianJPKhanAAPottsJTJr; Third International Workshop on the Management of Asymptomatic Primary Hyperthyroidism. Guidelines for the management of asymptomatic primary hyperparathyroidism: summary statement from the third international workshop. J Clin Endocrinol Metab. 2009;94(2):335-339.
61.
EastellRArnoldABrandiML, et al. Diagnosis of asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab. 2009;94(2):340-350.
62.
UdelsmanRPasiekaJLSturgeonCYoungJEClarkOH. Surgery for asymptomatic primary hyperparathyroidism: proceedings of the third international workshop. J Clin Endocrinol Metab. 2009;94(2):366-372.
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