C-type natriuretic peptide forms in adult hyperthyroidism: correlation with thyroid hormones and markers of bone turnover.

CONTEXT: Plasma C-type natriuretic peptide (CNP) forms correlate with linear growth velocity in juveniles. In hyperthyroid children, plasma CNP products fall in parallel with height velocity and thyroid hormones (TH) as euthyroidism is restored. The effect of TH on CNP forms after completion of endochondral growth is unknown. OBJECTIVE: To determine the effect of restoring euthyroidism on plasma CNP forms and bone turnover markers (BTMs) in hyperthyroid adults. DESIGN AND SETTING: We performed a prospective observational study in 20 adults (19 women) with acquired hyperthyroidism before and during carbimazole treatment. INTERVENTION AND MAIN OUTCOMES: Blood levels of CNP, amino-terminal propeptide of CNP (NTproCNP), TH and BTMs - bone-specific alkaline phosphatase, osteocalcin, procollagen type 1 amino-terminal propeptide and type 1 collagen C-telopeptide (CTx) - were measured before and during the first 6 months of carbimazole treatment and correlations determined. RESULTS: Both CNP and NTproCNP were significantly correlated with TH at baseline. As in children, decreases in CNP forms were closely associated with fall in TH. Significant associations were found between CNP forms and CTx. CONCLUSIONS: CNP production from tissues other than endochondral cartilage is responsive to TH. Strong temporal links with markers of bone resorption suggest that CNP may also participate in bone remodelling in the adult skeleton.

Four cases of autosomal dominant hypocalcaemia with hypercalciuria including two with novel mutations in the calcium-sensing receptor gene.

We present four cases with clinical and biochemical hypocalcaemia and evidence supportive of hypoparathyroidism. One case had been previously ascribed a diagnosis of idiopathic hypoparathyroidism. Following the detection of relative hypercalciuria, all cases were found to have autosomal dominant hypocalcaemia with hypercalciuria and mutations of the calcium-sensing receptor gene, of which two were novel. Increased awareness of this condition and access to genotyping enables prompt accurate diagnosis and cascade screening of first-degree relatives.

Central and peripheral forms of C-type natriuretic peptide (CNP): evidence for differential regulation in plasma and cerebrospinal fluid.

Aminoterminal proCNP (NTproCNP), a stable product of CNP gene expression and readily measured in human plasma, provides a new approach to studies of CNP which is rapidly degraded at source. CNP is detectable in human CSF but the presence and proportions of NTproCNP in CSF are unknown. Since CNP is widely expressed throughout the CNS, we hypothesized that the ratio of NTproCNP to CNP in CSF is greatly increased when compared to plasma and that CSF CNP peptides may contribute to their concentrations in the systemic circulation. Concurrent plasma and CSF concentrations of CNP forms were measured in 51 subjects undergoing spinal anesthesia for arranged orthopedic procedures. Elevated concentrations of NTproCNP (1045 ± 359 pmol/L), characterized by HPLC-RIA, were found in CSF and greatly exceeded those of CNP (7.9 ± 3.2 pmol/L). The ratio of NTproCNP to CNP in CSF (145 ± 55) was much higher than in plasma (31 ± 27). A significant inverse relation was found between plasma and CSF CNP concentrations (r = -0.29, p < 0.05). cGMP and neprilysin were unrelated to CNP levels in CSF. We conclude that CNP is differentially regulated across the brain in normal health. Despite markedly elevated levels of NTproCNP in CSF, it is unlikely that these contribute to systemic levels in healthy adults. Identifying NTproCNP as the dominant CNP form in CSF opens up the possibility of its use in future studies exploring CNP regulation within the CNS and possible applications in the diagnosis and monitoring of subjects with central neural disorders.

Subclinical thyrotoxicosis in an outpatient population - predictors of outcome.

OBJECTIVE: Individuals with endogenous subclinical thyrotoxicosis (SCT) may subsequently require treatment for overt disease. We aimed to evaluate the frequency of progression to hyperthyroidism and factors influencing this outcome. DESIGN: This is a retrospective analysis of outcome in 96 consecutive patients (aged 16-91 years) diagnosed with SCT over a 6-year period. Individuals with secondary causes of TSH suppression were excluded. Mean follow-up was 3·8 years. The significance of age, gender, family history of thyrotoxicosis, symptoms at presentation, thyroid nodule(s) on clinical examination, entry TSH level, antithyroid antibody status and (99m) Tc pertechnetate thyroid imaging results on subsequent development of overt thyrotoxicosis was assessed. RESULTS: Progression to overt thyrotoxicosis was seen in 8% at 1 year, 16% at 2 years, 21% at 3 years and 26% at 5 years. Multivariate analysis determined that diagnosis as determined by scintiscan to be the only independent predictor of outcome (P = 0·003) with the cumulative percentage requiring therapy at 5 years being 9% for subclinical Graves' disease, 21% for multinodular goitre and 61% for the autonomous nodule subgroup. CONCLUSIONS: Progression of SCT to overt hyperthyroidism occurred at a rate of 5-8% per year with disease aetiology, as determined by thyroid scintigraphy, significantly influencing risk of progression.

FGF23 elevation and hypophosphatemia after intravenous iron polymaltose: a prospective study.

CONTEXT: Parenteral iron administration has been associated with hypophosphatemia. Fibroblast growth factor 23 (FGF23) has a physiological role in phosphate homeostasis via suppression of 25-hydroxyvitamin D [25(OH)D] activation and promotion of phosphaturia. We recently reported a case of iron-induced hypophosphatemic osteomalacia associated with marked FGF23 elevation. OBJECTIVE: Our objective was to prospectively investigate the effect of parenteral iron polymaltose on phosphate homeostasis and to determine whether any observed change was related to alterations in circulating FGF23. DESIGN, SETTING, AND PARTICIPANTS: Eight medical outpatients prescribed iv iron polymaltose were recruited. Plasma phosphate, 25(OH)D, 1,25-dihydroxyvitamin D [1,25(OH)(2)D], PTH, FGF23, and urinary tubular reabsorption of phosphate were measured prior to iron administration and then weekly for a minimum of 3 wk. RESULTS: Plasma phosphate fell from 3.4 +/- 0.6 mg/dl at baseline to 1.8 +/- 0.6 mg/dl at wk 1 (P < 0.0001) associated with a fall in percentage tubular reabsorption of phosphate (90 +/- 4.8 to 68 +/- 13; P < 0.001) and 1,25(OH)(2)D (54 +/- 25 to 9 +/- 8 pg/ml; P < 0.001). These indices remained significantly suppressed at wk 2 and 3. 25(OH)D levels were unchanged. FGF23 increased significantly from 43.5 pg/ml at baseline to 177 pg/ml at wk 1 (P < 0.001) with levels correlating with both serum phosphate (R = -0.74; P <0.05) and 1,25(OH)(2)D (R = -0.71; P < 0.05). CONCLUSION: Parenteral iron suppresses renal tubular phosphate reabsorption and 1alpha-hydroxylation of vitamin D resulting in hypophosphatemia. Our data suggest that this is mediated by an increase in FGF23.

Iron polymaltose-induced FGF23 elevation complicated by hypophosphataemic osteomalacia.

Iron-induced renal phosphate wasting, hypophosphataemia and osteomalacia have previously been reported in a small number of Japanese patients receiving parenteral iron sucrose. We report the case history of a European male who, as a result of regular intravenous iron polymaltose, developed prolonged hypophosphataemia complicated by widespread insufficiency fractures. The pathogenesis of this complication remains unknown however our novel finding of a marked elevation in fibroblast growth factor 23 (FGF23), which normalized after ceasing parenteral iron, suggests an important and previously unreported effect of iron on FGF23 homeostasis.