New Directions in the treatment of Hypoparathyroidism

Hypoparathyroidism is a rare endocrine disorder with an estimated prevalence in the USA of 37 cases per 100,000 population. In Europe, an estimated total of 110,000 persons are affected by the disease [1]. The condition is characterized by hypocalcemia with concomitant hyperphosphatemia, a low or inappropriate level of parathyroid hormone (PTH) and hypercalciuria [2]. In the vast majority of cases it is caused by a defect in PTH secretion, while occasionally it is due to PTH resistance.

The most frequent cause (75% of cases) is postoperative hypothyroiditis in adults who have undergone surgery to the neck (thyroid or parathyroid surgery) [3]. In this situation, transient hypoparathyroidism is reported to occur in between 7 to 46% of patients, depending on the published series [4], and hypoparathyroidism becomes chronic in only 0.9 to 1.6% of surgical cases [5].

Other causes of hypoparathyroidism are represented by autoimmune hypoparathyroidism, which may be isolated or occur as part of a pathological syndrome, such as autoimmune polyglandular syndrome type 1 (APS-1) [6]. In younger patients, anti-parathyroid and to a lesser extent anti-calcium sensing receptor (CaSR) antibodies are most frequently detected [7]. Genetic causes can be the result of mutations in single genes (e.g., PTH, GCMB, CASR, SOX3), associated with syndromes (e.g., DiGeorge syndrome), or mitochondrial diseases. Lastly, hypoparathyroidism can be acquired, aside from a postoperative etiology, through hypomagnesemia, ß-thalassemia or hemochromatosis [8], [9]. However, the cause of hypoparathyroidism remains unknown in 15% of patients. The causes of hypoparathyroidism are listed in Table 1.

Resistance to PTH is rare (between 0.34 and 1.1 cases per 100,000 population) and is observed in pseudohypoparathyroidism. The clinical chemistry profile is distinguishable from common hypoparathyroidism by the presence of high levels of PTH [10].

Parathyroid hormone is an 84 amino acid peptide with its biologically-active PTH receptor binding site at the N-terminal. It is a hormone that raises plasma calcium and which regulates calcium and phosphate homeostasis. Secretion of PTH is pulsatile and follows a circadian rhythm with troughs occurring in the late morning and late afternoon [11]. Its secretion from the parathyroid glands is regulated via CaSR, a ubiquitous G-protein-coupled receptor. PTH acts, via its receptor PTH1R (a receptor with 7 transmembrane-spanning domains), on bone remodeling, digestive calcium absorption via renal production of alpha-1 hydroxylase, and renal tubular calcium reabsorption. These actions therefore, explain its effects on body biochemistry (Fig. 1). The PTH signalling pathway is mediated via cyclic AMP and protein kinase A (cAMP/PKA).

The clinical manifestations of hypoparathyroidism are the main reason for alteration in patient quality of life. Typically these include paresthesia in the extremities and peri-oral areas (in 75% of cases), increased muscle tone with cramps and stiffness. Severe hypocalcemia can sometimes be associated with bronchial and/or laryngeal spasms [12]. Cognitive impairment is observed in a third of patients, mainly manifested as alterations of higher functions, chronic asthenia and instability of mood [13]. Epileptic seizures are seen in 4 to 8% of cases and motor function impairment (extrapyramidal effects, bradykinesia) in 4 to 12% of patients [14]. These symptoms are related to basal ganglia calcification.

Calcifications, due to precipitation of calcium and phosphorus, are found not only in the basal ganglia but in other soft tissues as well. Phosphocalcic deposits are found in all types of tissue and can cause deformities or chronic joint pain. Ophthalmological effects are observed in 50% of cases, most commonly cataracts on the posterior side of the lens. Dental effects, mainly due to diminished dental enamel, have been described in 20 to 80% of cases.

Hypocalcemia can cause cardiac impacts, mainly irregular heart rhythm due to prolonged QT interval. Cases of left ventricular dysfunction have also been reported [15].

However, it is the impacts on kidney and bone that present the principal problems posed by hypoparathyroidism. Indeed, the hypercalciuria present in almost half of the affected patients exposes them to an increased risk of nephrolithiasis (kidney stones), altered renal function and nephrocalcinosis. Bone mineralisation is also altered, with increased bone resorption and reduced osteogenesis, however studies to date have not demonstrated significant excess risk of fractures in patients with hypoparathyroidism, compared to control populations [16], [17].