Jean-Hugues Brossard

Overproduction of an amino‐terminal form of PTH distinct from human PTH(1–84) in a case of severe primary hyperparathyroidism: influence of medical treatment and surgery

Objective  Rare patients with severe primary hyperparathyroidism present with large parathyroid tumours, severe hypercalcaemia, very high PTH levels and osteitis fibrosa cystica. Some of these patients display a large amount of C‐PTH fragments in circulation and present with a higher C‐PTH/I‐PTH ratio than seen in less severe cases of primary hyperparathyroidism. We wanted to determine how PTH levels and circulating PTH high‐performance liquid chromatography (HPLC) profiles analysed with PTH assays having different epitopes could be affected by medical and surgical treatment in such patients.

Carboxyl-terminal parathyroid hormone fragments: role in parathyroid hormone physiopathology.

Purpose of reviewCarboxyl-terminal parathyroid hormone (C-PTH) fragments constitute 80% of circulating PTH. Since the first 34 amino acids of the PTH structure are sufficient to explain PTH classical biological effects on the type I PTH/PTHrP receptor and since C-PTH fragments do not bind to this receptor, they have long been considered inactive. Recent data suggest the existence of a C-PTH receptor through which C-PTH fragments exert biological effects opposite to those of human PTH(1–84) on the type I PTH/PTHrP receptor. This is why a lot of attention has been paid to these fragments recently. Recent findingsIn vivo, synthetic C-PTH fragments are able to decrease calcium concentration, to antagonize the calcemic response to human PTH(1–34) and human PTH(1–84) and to decrease the high bone turnover rate induced by human PTH(1–84). In vitro, they inhibit bone resorption, promote osteocyte apoptosis and exert a variety of effects on bone and cartilaginous cells. These effects are opposite to those of human PTH(1–84) on the PTH/PTHrP type I receptor. This suggests that the molecular forms of circulating PTH may control bone participation in calcium homeostasis via two different receptors. Clinically, the accumulation of C-PTH fragments in renal failure patients may cause PTH resistance and may be associated with adynamic bone disease. Rare parathyroid tumors, without a set point error, overproduce C-PTH fragments. The implication of C-PTH fragments in osteoporosis is still to be explored. SummaryC-PTH fragments represent a new field of investigation in PTH biology. More studies are necessary to disclose their real importance in calcium and bone homeostasis in health and disease.

PTH Metabolites in Renal Failure: Bioactivity and Clinical Implications

Non‐(1‐84) parathyroid hormones (PTHs) are large circulating carboxyl‐terminal PTH (C‐PTH) fragments with a partially preserved amino‐terminal structure. They were discovered during high‐performance liquid chromatography (HPLC) analysis of circulating PTH molecular forms detected by an intact PTH (I‐PTH) assay. Like other C‐PTH fragments, they accumulate in blood in renal failure and account for up to 50% of I‐PTH. They are secreted by the parathyroid glands in humans, and are generated by the peripheral metabolism of hPTH(1‐84) in rats. The exact structure of non‐(1‐84)PTH fragments is not known. To study the possible role of non‐(1‐84) in PTH biology, hPTH(7‐84) has been used as a surrogate, being the only large C fragment available on the market. In anesthetized, thyroparathyroidectomized rats, hPTH(7‐84) caused hypocalcemia beyond that induced by surgery. It also blocked the calcemic response to hPTH(1‐84) or hPTH(1‐34). Other smaller C‐PTH fragments, such as hPTH(39‐84) and hPTH(53‐84), were synergistic to hPTH(7‐84) effects. hPTH(7‐84) did not bind to the PTH/PTHrP receptor, but only to the C‐PTH receptor in ROS 17/2.8 clonal cells, and did not stimulate cyclic adenosine monophosphate (cAMP) production by the same cells, suggesting that its hypocalcemic action was mediated via a receptor different from the PTH/PTHrP receptor, and that the calcium concentration resulted from the sum of the positive effect of hPTH(1‐84) on the PTH/PTHrP receptor and of the negative effect of hPTH(7‐84) and of C‐PTH fragments on the C‐PTH receptor. These data will change our understanding of circulating calcium regulation, which must now be viewed as the end result of opposite actions on two PTH receptors. PTH immunoheterogeneity, a highly regulated phenomenon, contributes to this dual biological effect, generating an agonist for the two different receptors. Clinically these results could have some implications in our knowledge of the PTH resistance of renal failure, of renal osteodystrophy, and of certain aspects of the uremic syndrome.

Normal Parathyroid Function with Decreased Bone Mineral Density in Treated Celiac Disease

Decreased bone mineral density (BMD) has been reported in patients with celiac disease in association with secondary hyperparathyroidism. The present study investigated whether basal parathyroid hormone (PTH) remained elevated and whether abnormalities of parathyroid function were still present in celiac disease patients treated with a gluten-free diet. Basal seric measurements of calcium and phosphate homeostasis and BMD were obtained in 17 biopsy-proven patients under treatment for a mean period of 5.7+/-3.7 years (range 1.1 to 15.9). In addition, parathyroid function was studied with calcium chloride and sodium citrate infusions in seven patients. Basal measurements of patients were compared with those of 26 normal individuals, while parathyroid function results were compared with those of seven sex- and age-matched controls. Basal results were similar in patients and controls except for intact PTH (I-PTH) (3.77+/-0.88 pmol/L versus 2.28+/-0.63 pmol/L, P<0.001), which was higher in the former group but still within normal limits. Mean 25-hydroxy vitamin D and 1,25-dihydroxy vitamin D values were normal in patients. Parathyroid function results were also found to be similar in both groups. Compared with a reference population of the same age (Z score), patients had significantly lower BMDs of the hip (-0.60+/-0.96 SDs, P<0.05) and lumbar spine (-0.76+/-1.15 SDs, P<0.05). T scores were also decreased for the hip (-1.3+/-0.9 SDs, P<0.0001) and lumbar spine (-1.4+/-1.35 SDs, P<0.0001), with two to three patients being osteoporotic (T score less than -2.5 SDs) and seven to eight osteopenic (T score less than -1 SDs but greater than or equal to -2.5 SDs) in at least one site. Height and weight were the only important determinants of BMD values by multivariate or logistical regression analysis in these patients. The results show higher basal I-PTH values with normal parathyroid function in treated celiac disease. Height and weight values are, but I-PTH values are not, an important determinant of the actual bone mass of patients. Normal parathyroid function in treated patients suggests a lack of previous severe secondary hyperparathyroidism and/or complete adaptation to prior changes in parathyroid function.

Functional evidence for two types of parathyroid adenoma

The carboxyterminal parathyroid hormone (C‐PTH)/intact (I‐) PTH ratio is influenced by serum calcium concentrations in man, increasing to a maximum value in hypercalcaemia and decreasing to a minimum value in hypocalcaemia. We decided to use this ratio to screen for parathyroid tumour with a normal sensitivity to calcium, symptomatic mainly through a mass effect.

Primary and Secondary Hyperparathyroidism Testing and Assays

Once considered rare disorders, primary (p) and secondary (s) hyperparathyroidism (HPT), are now frequently seen in all parts of the world in relation to the development of routine total calcium measurement and the availability of accurate parathyroid hormone (PTH) and 25-hydroxy-vitamin D (25(OH)D) assays. Both conditions can present with a very different biochemical profile, but normocalcemic primary HPT (pHPT) can also be very difficult to distinguish from mild sHPT. In the following chapter, we analyze which biochemical tests are best suited to investigate and diagnose these disorders.