OBJECTIVE: Disturbed renal function may play an important role in the clinico-pathological presentation of primary hyperparathyroidism (pHPT). We studied the influence of renal function on the clinico-pathological characteristics of 141 patients (123 women and 18 men) with surgically proven pHPT. METHODS: The 141 patients were assigned to one of two groups based on creatinine clearance (C(cr)) level: a renal insufficiency group (n=37) in which C(cr) of patients was <70 ml/min and a normal renal function group (n=104) in which C(cr) was > or =70 ml/min. Clinical presentation and biochemical indices were evaluated and compared between the two groups. RESULTS: Age, and frequency of hypertension and of diabetes mellitus were significantly (P<0.001, P<0.05 and P<0.05 respectively) higher in the renal insufficiency group than in the normal renal function group. Serum levels of calcium, intact parathyroid hormone and bone Gla protein were significantly (P<0.05) higher and the excised parathyroid weighed significantly more (P<0.05) in the renal insufficiency group than in the normal renal function group; however, serum 1,25-dihydroxyvitamin D (1,25(OH)(2)D) and 24 h urinary calcium excretion were significantly (P<0.001 and P<0.05 respectively) lower in the former than in the latter group. There was a significant inverse correlation between C(cr) level and serum calcium (r=0.315, P<0.001) and a significant positive correlation between C(cr) level, 1,25(OH)(2)D (r=0.315, P<0.001), and 24 h calcium excretion (r=0.458, P<0.0001). CONCLUSIONS: Clinico-pathological features of pHPT were notably influenced by even moderate renal insufficiency. Urinary calcium excretion decreased according to the decrease in glomerular filtration rate. Therefore, endocrinologists need to appraise urinary calcium excretion and renal function of pHPT patients when considering surgery or in discriminating familial hypocalciuric hypercalcemia.
H Yamashita, S Noguchi, S Uchino, S Watanabe, T Murakami, T Ogawa, T Masatsugu, Y Takamatsu, E Miyatake and H Yamashita
H Yamashita, T Yamashita, M Miyamoto, T Shigematsu, JJ Kazama, T Shimada, Y Yamazaki, S Fukumoto, M Fukagaw and S Noguchi
OBJECTIVE: We aimed to determine the serum level of fibroblast growth factor-23 (FGF-23) in patients with primary hyperparathyroidism (pHPT) to understand its physiological role in the disorder. PATIENTS AND METHODS: Ninety-eight patients with pHPT who underwent parathyroidectomy formed the study group. We also measured serum FGF-23 in 11 of these patients on postoperative day 6. RESULTS: Serum FGF-23 levels was significantly higher in pHPT patients than in healthy controls (35.6+/-17.8 ng/l vs 28.9+/-11.2 ng/l (mean+/-s.d.); P<0.001 (Pearson's correlation coefficient)), but there was no significant difference in the serum FGF-23 level between pHPT patients with normal renal function (creatinine clearance (Ccr) of >or=70 ml/min) and healthy controls. Serum FGF-23 correlated positively with serum calcium (P<0.0001) and intact parathyroid hormone (PTH) (P<0.01), and negatively with Ccr (P<0.001), serum phosphate (P<0.05), and serum 1,25-dihydroxyvitamin D (1,25(OH)(2)D) (P<0.05). Multiple linear regression analysis of factors potentially determining serum FGF-23 levels in pHPT patients showed serum calcium (P<0.01) and Ccr (P<0.001) to be significant predictors. The serum levels of FGF-23 did not change after parathyroidectomy despite the normalization of serum calcium values. Multiple linear regression analysis revealed that serum FGF-23 was not a significant predictor of serum phosphate or 1,25(OH)(2)D in pHPT patients. CONCLUSIONS: FGF-23 may not play a significant role in regulating phosphate or 1,25(OH)(2)D in pHPT patients, especially in those with normal renal function. Further studies are warranted to determine the role of FGF-23 in renal insufficiency or failure.
H Yamashita, P Gao, T Cantor, T Futata, T Murakami, S Uchino, S Watanabe, H Kawamoto, M Fukagawa and S Noguchi
OBJECTIVE: It was discovered that an immunoreactive large carboxy-terminal parathyroid hormone (PTH) fragment (large C-PTH), likely 7-84 PTH, is present in the circulation. However, very little is known about the production and metabolism of this large C-PTH. Combining a whole molecule PTH (whole PTH) immunoradiometric assay (IRMA) specifically for 1-84 PTH and an intact PTH (iPTH) IRMA for the sum of 1-84 PTH and large C-PTH, we were able to assess the circulating level of this large C-PTH as well as the glandular secretion and metabolism of this large C-PTH in primary hyperparathyroidism (pHPT). METHODS: This study consisted of two patient groups consisting of 77 pHPT patients with a single adenoma. Of these, 43 comprised the venous sampling study group and 70 comprised the intra-operative PTH study group. (Seven patients belonged only to the former group, 34 patients to only the latter group, and 36 patients to both groups.) Preoperatively, blood samples were drawn from the bilateral internal jugular vein by ultrasonographic guidance and from the peripheral vein (n=43). During surgery, blood samples were drawn after anesthesia (basal level), before excision (pre-excision level) of one enlarged parathyroid gland, and at 5, 10, and 15 min post-excision (n=70). RESULTS: There were 26 patients whose iPTH assay levels differed by more than 10% between the right and left internal jugular. In 24 of the 26 patients, the large C-PTH levels obtained from the adenoma side were significantly higher than those from the contralateral side (117+/-135 vs 43+/-33 pg/ml, P<0.001). The plasma whole PTH values decreased more rapidly than the iPTH values after parathyroidectomy (P<0.001). CONCLUSIONS: Our study has demonstrated that the large C-PTH, likely 7-84 PTH, is directly released from the parathyroid gland in humans. Since the half-life of 1-84 PTH is much shorter than large C-PTH, likely 7-84 PTH, it would be advantageous to use an assay that specifically measures 1-84 PTH for intra-operative monitoring of parathyroidectomy.
S Suzuki, J Mori, M Kobayashi, T Inagaki, H Inaba, A Komatsu, K Yamashita, T Takeda, T Miyamoto, K Ichikawa and K Hashizume
We have previously shown that cytosolic 3,5,3'-triiodo-L-thyronine (T3)-binding protein (CTBP) possesses a high affinity for T3 binding in the presence of nicotinamide adenine dinucleotide phosphate in vitro, and that p38CTBP increases intracellular content of T3, and suppresses T3-mediated transactivity. Screening of mRNA expression in 73 different human tIssues has demonstrated that p38CTBP mRNA is expressed at high levels in brain and heart. We have examined the intracellular localization and tissue-specific distribution of this protein by using a specific antibody against human p38CTBP. Western blotting and immunoprecipitation studies have shown that the antibody recognizes human p38CTBP. Interaction of p38CTBP with the antibody did not affect the T3-binding activity of p38CTBP, and its dimer formation in vitro. Western blotting analysis has shown that p38CTBP is expressed in brain and heart predominantly, similar to the distribution of mRNA. Immunohistochemical studies have demonstrated p38CTBP in neural cells and cardiac muscle cells. p38CTBP localizes in cytoplasm rather than in nuclei in neural cells. The evidence for the presence of tIssue-specific localization of p38CTBP has indicated that p38CTBP has a tIssue-specific function, such as the regulation of T3 delivery from cytoplasm to nuclei.