The phenotype of primary hyperparathyroidism with normal parathyroid hormone levels: How low can parathyroid hormone go?


      While normocalcemic hyperparathyroidism is well recognized in primary hyperparathyroidism (PHP), less is known about patients with high calcium but normal intact parathyroid hormone (iPTH). We aimed to describe this entity and designated it normohormonal primary hyperparathyroidism (NHPHP).


      From a prospectively maintained database of patients undergoing bilateral parathyroid exploration for PHP, we identified and compared those with preoperative iPTH levels below (NHPHP) and above (typical PHP) normal reference peak (60 pg/mL).


      NHPHP occurred in 46 of 843 patients (5.5%) undergoing initial parathyroidectomy for PHP. All had hypercalcemia (11.1 mg/dL). Regarding preoperative iPTH, 7 patients (15%) had values <40 pg/mL, 19 (41%) had values <60 pg/mL; and 20 (44%) had intermittent values >60 pg/mL. Unlike patients with elevated iPTH, nearly all NHPHP patients had additional testing delaying the operation. Imaging correctly localized NHPHP parathyroid disease in 80%. At the time of operation, 74% of NHPHP patients had single adenomas. Intraoperatively postmobilization, using the same assay that was used preoperatively, 82% had PTH levels >60 pg/mL (mean, 279 pg/mL). During the follow-up period, iPTH levels remained lower among NHPHP patients (21 pg/mL) compared to 41 pg/mL for patients with preoperative iPTH 60 to 100 pg/mL and 56 pg/mL for patients with preoperative iPTH 100 to 200 pg/mL (P < .0001).


      Lower PTH set points may exist in some patients with otherwise typical PHP features. Although high normal iPTH is inappropriate for hypercalcemia and should suggest PHP, this disorder may occur with iPTH levels as low as 5 pg/mL. Awareness of the unusual phenotype of NHPHP may facilitate earlier diagnosis and surgery.
      To read this article in full you will need to make a payment
      Subscribe to Surgery
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • AACE/AAES Task Force on Primary Hyperparathyroidism
        The American Association of Clinical Endocrinologists and the American Association of Endocrine Surgeons position statement on the diagnosis and management of primary hyperparathyroidism.
        Endocr Pract. 2005; 11: 50-54
        • Siperstein A.E.
        • Shen W.
        • Chan A.K.
        • et al.
        Normocalcemic hyperparathyroidism. Biochemical and symptom profiles before and after surgery.
        Arch Surg. 1992; 127: 1157-1163
        • Lowe H.
        • McMahon D.J.
        • Rubin M.R.
        • et al.
        Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype.
        J Clin Endocrinol Metab. 2007; 92: 3001-3005
        • Ljunghall S.
        • Larsson K.
        • Lindh E.
        • et al.
        Disturbance of basal and stimulated serum levels of intact parathyroid hormone in primary hyperparathyroidism.
        Surgery. 1991; 110: 47-53
        • Hollenberg A.N.
        • Arnold A.
        Hypercalcemia with low-normal serum intact PTH: a novel presentation of primary hyperparathyroidism.
        Am J Med. 1991; 91: 547-548
        • Glendenning P.
        • Gutteridge D.H.
        • Retallack R.W.
        • et al.
        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. 1998; 28: 173-178
        • Mischis-Troussard C.
        • Goudet P.
        • Verges B.
        • et al.
        Primary hyperparathyroidism with normal serum intact parathyroid hormone levels.
        QJM. 2000; 93: 365-367
        • Perez J.B.
        • Pazianos A.G.
        Unusual presentation of primary hyperparathyroidism with osteoporosis, hypercalcemia, and normal parathyroid hormone level.
        South Med J. 2001; 94: 339-341
        • Bergenfelz A.
        • Lindblom P.
        • Lindergard B.
        • et al.
        Preoperative normal level of parathyroid hormone signifies an early and mild form of primary hyperparathyroidism.
        World J Surg. 2003; 27: 481-485
        • Lafferty F.W.
        • Hamlin C.R.
        • Corrado K.R.
        • et al.
        Primary hyperparathyroidism with a low-normal, atypical serum parathyroid hormone as shown by discordant immunoassay curves.
        J Clin Endocrinol Metab. 2006; 91: 3826-3829
        • Norman J.
        • Goodman A.
        • Politz D.
        Calcium, parathyroid hormone, and vitamin D in patients with primary hyperparathyroidism: normograms developed from 10,000 cases.
        Endocr Pract. 2010; 17: 384-394
        • Berber E.
        • Parikh R.T.
        • Ballem N.
        • et al.
        Factors contributing to negative parathyroid localization: an analysis of 1000 patients.
        Surgery. 2008; 144: 74-79
        • Ballem N.
        • Greene A.B.
        • Parikh R.T.
        • et al.
        Appreciation of osteoporosis among men with hyperparathyroidism.
        Endocr Pract. 2008; 14: 820-831
        • Mazzaglia P.J.
        • Berber E.
        • Kovach A.
        • et al.
        The changing presentation of hyperparathyroidism over 3 decades.
        Arch Surg. 2008; 143: 260-266
        • Harvey A.
        • Barbosa G.
        • Walks N.
        • et al.
        Parathyroid tumor burden: is a critical mass of parathyroid tissue necessary for manifestations of primary hyperparathyroidism?.
        Proc Ann Cancer Symposium Soc Surg Oncol. 2009; ([abstract P117]. Available from:–events/annual-cancer-symposium/past-programs/2009-posters-(all).aspx)
        • Siperstein A.
        • Berber E.
        • Barbosa G.
        • et al.
        Predicting the success of limited exploration for primary hyperparathyroidism using ultrasound, sestamibi, and intraoperative parathyroid hormone: analysis of 1158 cases.
        Ann Surg. 2008; 248: 420-428
        • Gurrado A.
        • Marzullo A.
        • Lissidini G.
        • et al.
        Substernal oxyphil parathyroid adenoma producing PTHrp with hypercalcemia and normal PTH level.
        World J Surg Oncol. 2008; 6: 1-5