Parathyroid Disorders. Группа авторов

The fetal loss rate increased directly with increasing maternal serum calcium levels and was most evident when measured levels were above 11.4 mg/dL. Because pregnancy is normally associated with a decrease in serum calcium and suppression of PTH, an increased serum calcium level with detectable PTH during this time indicates maternal PHPT. Mild hypercalcemia in gestational PHPT is generally not associated with an increased risk of obstetrical complications [44]. The study lacked NPHPT, therefore data about an increased risk of preeclampsia due to hyperparathyroidism in NPHPT are not available.

      Parathyroid Gland Tumors

NPHPT has been reported to be associated with a high incidence of multi-gland disease compared with HPHPT (45 vs. 37%) [45]. The high prevalence of multi-gland involvement may represent a challenge for successful surgery and should be considered in the evaluation for parathyroidectomy. Notably, a case of NPHPT sustained by a histologically diagnosed parathyroid carcinoma has been reported [46].

      Natural History

Data relating to NPHPT natural history are scanty. It is thought that years prior to a clinical diagnosis of PHPT, calcium homeostasis shows signs of perturbations. Latent PHPT may be characterized by either NPHPT or normoparathyroid hypercalcemia. Such patients should be offered long-term follow-up to ascertain whether their biochemical profile represents an early state of PHPT. Rejnmark et al. [47] found that the time from inclusion until a diagnosis of PHPT was a median of 5.6 years. Parathyroidectomy was performed in 97%. At the cohort inclusion, undiagnosed PHPT was present in 63% of the cases. Among those without HPHPT at inclusion (n = 43), 55% had NPHPT and 31% had normoparathyroid hypercalcemia. Overall, 25(OH)D levels were lower in the cases. Compared with their matched controls, 25(OH)D levels were lower in NPHPT but not in normoparathyroid hypercalcemia. An adenoma was removed from 78% of the cases with NPHPT, whereas 39% of the cases with normoparathyroid hypercalcemia had parathyroid hyperplasia [47].

      Therapeutic Management

      Effects of Parathyroidectomy

      Considering that surgery is the only potentially curable option for patients with PHPT, there is universal agreement that all symptomatic as well as asymptomatic patients with significant kidney and bone signs of the disease, have clear indications to surgical treatment. Less certain are patients who do not meet the criteria and, in particular, do not experience hypercalcemia. The Fourth International Workshop on the management of symptomatic PHPT [25] proposed an algorithm for the management of NPHPT patients; the panel of experts suggested, based on the monitoring of serum calcium and PTH annually and bone density by DXA (dual-energy X-ray absorptiometry) every 1–2 years, to consider surgery in the following conditions:

      •Progression to HPHPT: indication to parathyroidectomy according to the guidelines;

      •Progression of the disease, that means worsening of BMD or occurrence of an osteoporotic fracture and/or diagnosis of kidney stones or nephrocalcinosis.

Successful parathyroidectomy has been reported to be followed at 1 year by a significant individual BMD gain in nearly half of NPHPT patients with osteoporosis. Elevated alkaline phosphatase levels above the median could contribute to the therapeutic decision in this context [48, 49].

From a surgical point of view, it should be considered that 63% of PHPT patients with preoperative normal ionized calcium had an adenoma involving a single gland, which was correctly identified by preoperative imaging in 60% of cases. Intraoperative PTH assay identified the cure in 75% of PHPT patients with normal ionized calcium [50].

      Effects of Medical Treatment

Medical treatment is recognized as an option for patients who have contraindications to surgery, or are unwilling to undergo parathyroidectomy [51]. In general, the consensus derived from the Fourth Workshop does not recommend dietary calcium restriction in patients with asymptomatic PHPT, while it expresses a favorable indication for vitamin D repletion, though suggesting monitoring of serum and urinary calcium excretion [51]. Supplemental doses of 600–1,000 IU cholecalciferol were considered a more prudent dosage regimen to follow than large doses. The goal of cautiously administered repletion regimens should be to increase the serum 25(OH)D levels to >50 and up to 75 nmol/L (20–30 ng/mL).

Just one study has investigated vitamin D repletion and alendronate treatment in NPHPT patients. In a prospective open label randomized trial, Cesareo et al. [52] investigated 15 postmenopausal women with NPHPT, treated with oral alendronate plus cholecalciferol (treated group) compared with 15 NPHPT treated only with cholecalciferol (control group). After 1 year of treatment, BMD increased significantly at the lumbar, femoral neck, and hip level in the treated group, but not in the control group. No differences were found between or within groups in serum calcium, PTH, and urinary calcium levels. The authors concluded that alendronate/cholecalciferol could increase BMD in postmenopausal women with NPHPT, while alendronate/cholecalciferol or vitamin D alone does not affect serum or urinary calcium. The administration of vitamin D was safe and it did not induce any cases of hypercalcemia or hypercalciuria and PTH was unaffected by the treatments [52]. Among antiresorptive drugs used to increase BMD, denosumab is a relatively new option. Its safe profile on kidney function makes it a good option for the treatment of osteoporosis in CKD; in patients with CKD, it should be cautiously managed as hypocalcemia may occur. There are no reports on the use of denosumab in patients with PHPT except for a recently published paper describing the occurrence of severe symptomatic hypophosphatemia 1 month after the administration of 60 mg denosumab subcutaneously in a patient with NPHPT and CKD stage IIIa [53].

      Finally, another medical option for PHPT patients is represented by cinacalcet HCl. It is a potent CASR agonist, which normalizes serum calcium levels, reducing circulating PTH levels without normalization. Cinacalcet is recommended in those PHPT patients who need to manage hypercalcemia [51]; based on this consideration, the use of cinacalcet in NPHPT patients is not reasonable. Moreover, no data are available about cinacalcet effects in NPHPT patients.

      Conclusions

      Emerging data suggest that NPHPT may not be an isolated biochemical alteration but it may affect the health of patients. It appears as a disease with some clinical features overlapping those of the HPHPT and others peculiar to NPHPT. Therefore, attention should be paid to identifying PTH-related diseases involving bone, kidney, and the cardiovascular system, and, when present, therapeutic options should be considered and discussed with the patients. Alternatively, long-term follow-up should be scheduled with the patients to detect the potential progression.

      References

1Silverberg SJ, Lewiecki EM, Mosekilde L, Peacock M, Ribin MR: Presentation of asymptomatic primary hyperparathyroidism: proceedings of the third