Louise Rousseau

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.

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.

Nontruncated amino-terminal parathyroid hormone overproduction in two patients with parathyroid carcinoma: a possible link to HRPT2 gene inactivation

Objective  Some patients with parathyroid carcinoma present with an over‐production of nontruncated amino‐terminal (NT‐N) parathyroid hormone (PTH), a post‐transcriptionally modified form of PTH(1‐84). This is usually picked up on an elevated whole (W) PTH (third‐generation)/total (T) (second‐generation) PTH assay ratio (N > 0·8).

Rat parathyroid hormone (rPTH) ELISAs specific for regions (2-7), (22-34) and (40-60) of the rat PTH structure: influence of sex and age.

Rat (r) PTH ELISAs were used to study the influence of age and sex on rPTH levels and circulating PTH molecular forms separated by HPLC. Standard curves and saturation analysis were undertaken to define epitopes. Rats were sacrificed at approximately 27, 47 and 75days. Relevant biochemical parameters and 25(OH) vitamin D were measured. Differences between sexes were analyzed by Kruskal-Wallis ANOVA, followed by Dunns test. Epitopes were localized in regions 2-7, 22-34 and 40-60 of rPTH structure for whole (W), total (T) and carboxyl (C) rPTH ELISAs. The W-rPTH assay only detected rPTH(1-84) and N-PTH in circulation while the T-PTH assay further detected large C-rPTH fragments. The C-rPTH assay detected all circulating rPTH molecular forms including smaller C-rPTH fragments. In both sexes, weight (p<0.001), ionized calcium, creatinine, albumin and 25(OH)D values (p<0.001) increased with age, while phosphate and alkaline phosphatase decreased (p<0.001). In male rats, W-rPTH remained unchanged, while T-rPTH rose slightly (p<0.05) and C-rPTH declined by half with time (p<0.001). In female rats, W-rPTH (p<0.05), T-rPTH (p<0.001) and C-rPTH (p<0.01) all increased in older animals. In both sexes, C-rPTH/W-rPTH and C-rPTH/T-rPTH ratios decreased between 25 and 47 days, to rise again between 47 and 75 days. The initial decrease may represent an adaptation to weaning and a change of diet between 25 and 47 days while the rise corresponds to higher calcium and 25(OH)D levels between 47 and 75 days. These changes were more pronounced in female rats, indicating an influence of sex on PTH molecular form secretion or metabolism.

Influence of Secondary Hyperparathyroidism Induced by Low Dietary Calcium, Vitamin D Deficiency, and Renal Failure on Circulating Rat PTH Molecular Forms

Rats(r) with secondary hyperparathyroidism were studied to define the relationship between vitamin D metabolites and rPTH levels measured by 3 different rat ELISAs. Controls and renal failure (RF) rats were on a normal diet, while 2 groups on a low-calcium (-Ca) or a vitamin D-deficient (-D) diet. RF was induced surgically. Mild RF rats had normal calcium and 25(OH)D but reduced 1,25(OH)2D levels (P < .001) with a 2.5-fold increased in rPTH (P < .001). Severe RF rats and those on a -Ca or -D diet had reduced calcium (P < .01) and 25(OH)D levels (P < .05), with rPTH increased by 2 (-Ca diet; P < .05), 4 (-D diet; P < .001), and 20-folds (RF; P < .001) while 1,25(OH)2D was high (-Ca diet: P < .001) or low (-D diet, RF: P < .001). 25(OH)D and 1,25(OH)2D were positively and negatively related on the -Ca and -D diets, respectively. rPTH molecular forms behaved as expected in RF and on -Ca diet, but not on -D diet with more C-rPTH fragments when less were expected. This may be related to the short-time course of this study compared to prior studies.

Nontruncated amino-terminal parathyroid hormone overproduction in two patients with parathyroid carcinoma: a possible link to HRPT2 gene inactivation: Third/second-generation PTH ratio in parathyroid cancer

Objective  Some patients with parathyroid carcinoma present with an over‐production of nontruncated amino‐terminal (NT‐N) parathyroid hormone (PTH), a post‐transcriptionally modified form of PTH(1‐84). This is usually picked up on an elevated whole (W) PTH (third‐generation)/total (T) (second‐generation) PTH assay ratio (N > 0·8).

Non-Truncated Amino-Terminal PTH Overproduction in Two Patients with Parathyroid Carcinoma: A Possible Link to HRPT2 Gene Inactivation

Objective  Some patients with parathyroid carcinoma present with an over‐production of nontruncated amino‐terminal (NT‐N) parathyroid hormone (PTH), a post‐transcriptionally modified form of PTH(1‐84). This is usually picked up on an elevated whole (W) PTH (third‐generation)/total (T) (second‐generation) PTH assay ratio (N > 0·8).