Maternal and infant vitamin D status during the first 9 months of infant life-a cohort study.

BACKGROUND/OBJECTIVES: The objective of this study was to assess vitamin D status and possible consequences of low plasma 25-hydroxyvitamin D (25OHD) levels in a population of healthy mothers and their infants. SUBJECTS/METHODS: A total of 107 women aged 24-41 years gave birth to 108 infants. They were followed up three times during 9 months. RESULTS: Cord blood 25OHD level (43.3 ± 20.4 nmol/l) on average was 62 ± 16% of maternal levels (73.3 ± 30.7 nmol/l), measured 1-2 weeks postpartum. Cord blood 25OHD correlated positively with maternal 25OHD levels (r=0.83, P<0.001). At birth, 23% of mothers and 61% of infants had 25OHD <50 nmol/l. Vitamin D deficiency (25OHD<25 nmol/l) was present in 66% of the children born by mothers with 25OHD levels below 50 nmol/l (P<0.01), whereas only one child was born with deficiency among mothers with 25OHD >50 nmol/l. During follow-up, most of the children (>85%) had 25OHD levels >50 nmol/l, which most likely was attributable to the use of supplements, as more than 95% of the children were given daily vitamin D supplements of 10 µg of vitamin D.Cord blood parathyroid hormone levels were very low (median 0.21; interquartile range 0.11-0.33 pmol/l), with increasing levels (P<0.01) reaching 3.08 (2.67-3.92 pmol/l) at the last visit. Vitamin D levels were not associated with anthropometric indices of the newborn infant or their growth during follow-up. CONCLUSIONS: Vitamin D deficiency is widespread in newborn. Maternal 25OHD levels above 50 nmol/l are needed to prevent vitamin D deficiency among newborn.

Protein expression studies of desmoplakin mutations in cardiomyopathy patients reveal different molecular disease mechanisms.

Mutations in the gene for desmoplakin (DSP) may cause arrhythmogenic right ventricular cardiomyopathy (ARVC) and Carvajal syndrome (CS). Desmoplakin is part of all desmosomes, which are abundantly expressed in both myocardial and epidermal tissue and serve as intercellular mechanical junctions. This study aimed to investigate protein expression in myocardial and epidermal tissue of ARVC and CS patients carrying DSP mutations in order to elucidate potential molecular disease mechanisms. Genetic investigations identified three ARVC patients carrying different heterozygous DSP mutations in addition to a homozygous DSP mutation in a CS patient. The protein expression of DSP in mutation carriers was evaluated in biopsies from myocardial and epidermal tissue by immunohistochemistry. Keratinocyte cultures were established from skin biopsies of mutation carriers and characterized by reverse transcriptase polymerase chain reaction, western blotting, and protein mass spectrometry. The results showed that the mutation carriers had abnormal DSP expression in both myocardial and epidermal tissue. The investigations revealed that the disease mechanisms varied accordingly to the specific types of DSP mutation identified and included haploinsufficiency, dominant-negative effects, or a combination hereof. Furthermore, the results suggest that the keratinocytes cultured from patients are a valuable and easily accessible resource to elucidate the effects of desmosomal gene mutations in humans.

Changes in calcitropic hormones, bone markers and insulin-like growth factor I (IGF-I) during pregnancy and postpartum: a controlled cohort study.

UNLABELLED: Pregnancy and lactation cause major changes in calcium homeostasis and bone metabolism. This population-based cohort study presents the physiological changes in biochemical indices of calcium homeostasis and bone metabolism during pregnancy and lactation INTRODUCTION: We describe physiological changes in calcium homeostasis, calcitropic hormones and bone metabolism during pregnancy and lactation. METHODS: We studied 153 women planning pregnancy (n=92 conceived) and 52 non-pregnant, age-matched female controls. Samples were collected prior to pregnancy, once each trimester and 2, 16 and 36 weeks postpartum. The controls were followed in parallel. RESULTS: P-estradiol (E2), prolactin and 1,25-dihydroxyvitamin D (1,25(OH)2D) increased (p<0.001) during pregnancy, whereas plasma levels of parathyroid hormone (P-PTH) and calcitonin decreased (p<0.01). Insulin-like growth factor I (IGF-I) was suppressed (p<0.05) in early pregnancy but peaked in the third trimester. Postpartum, E2 was low (p<0.05); prolactin decreased according to lactation status (p<0.05). 1,25(OH)2D was normal and IGF-I was again reduced (p<0.05). P-PTH and calcitonin increased postpartum. From early pregnancy, markers of bone resorption and formation rose and fall, respectively (p<0.001). From the third trimester, bone formation markers increased in association with IGF-I changes (p<0.01). Postpartum increases in bone turnover markers were associated with lactation status (p<0.001). During lactation, plasma phosphate was increased, whereas calcium levels tended to be decreased which may stimulate PTH levels during and after prolonged lactation. CONCLUSION: The increased calcium requirements in early pregnancy are not completely offset by increased intestinal calcium absorption caused by high 1,25(OH)2D since changes in bone markers indicated a negative bone balance. The rise in bone formation in late pregnancy may be initiated by a spike in IGF-I levels. The high bone turnover in lactating women may be related to high prolactin and PTH levels, low E2 levels and perhaps increased parathyroid hormone-related protein levels.

Effects of 25OHD concentrations on chances of pregnancy and pregnancy outcomes: a cohort study in healthy Danish women.

BACKGROUND/OBJECTIVES: Plasma 25-hydroxyvitamin D (P-25OHD) concentrations may affect pregnancy outcomes. To elucidate this further, we studied the effects of pre-conception P-25OHD concentrations on chances for pregnancy as well as the effects of P-25OHD during pregnancy on the risk of miscarriage, birth weight and length, Apgar score and head circumference. Moreover, we studied whether pregnancy and breastfeeding patterns affect maternal P-25OHD concentrations. SUBJECTS/METHODS: A total of 153 healthy Caucasian women with pregnancy plans were followed with measurements performed before pregnancy, at pregnancy weeks 11±2, 22±1 and 35±2 as well as 15±7, 129±12 and 280±15 days postpartum. Furthermore, 75 non-pregnant, age-matched women were followed in parallel as controls. RESULTS: The 203 women were aged 29 (25-35) years. At baseline, median P-25OHD was 59 nmol/l. Of these women, 31% had P-25OHD <50 nmol/l, whereas 12% had levels above 80 nmol/l. Within ∼6 months after inclusion, 63% conceived. P-25OHD was not associated with chances of conceiving or overall risk of miscarriage. However, women with a miscarriage in their second trimester (n=3) had lower P-25OHD concentrations at measurements performed in the first trimester compared with women without a miscarriage (P=0.03). P-25OHD before or during pregnancy was not associated with gestational length or infant parameters. Adjustments for possible confounders did not change the result. During pregnancy, P-25OHD changed significant over time, but similar changes occurred within the control group, indicating no effect of pregnancy per se (P=0.59). Overall, P-25OHD did not differ according to length of breastfeeding at 2 weeks, and 4 and 9 months postpartum, although women breastfeeding for >9 months had lower P-25OHD levels at the last visit compared with the controls. CONCLUSION: P-25OHD concentrations did not affect fertility or pregnancy outcomes, although low P-25OHD may be associated with an increased risk of late miscarriage.

Bone mineral density in Klinefelter syndrome is reduced and primarily determined by muscle strength and resorptive markers, but not directly by testosterone.

SUMMARY: Klinefelter syndrome (KS) patients have lower bone mineral density (BMD) at the spine, hip and forearm compared to healthy subjects, but frank osteoporosis is not common. Muscle strength and bone markers predicted BMD but KS itself and serum testosterone did not. Low vitamin D and high PTH were frequent among KS. INTRODUCTION: The long-term consequence of KS on bone health is not well described. The objective of this study is to investigate the regional BMD and its determinants in KS. METHODS: This is a cross-sectional study. BMD at the spine, hip and forearm are measured by DXA and correlated to biochemical markers of bone turnover, vitamin D metabolites, PTH, sex hormones, growth factors as well as muscle strength and anthropometric measures. The setting is at a university clinical research centre. The study involves 70 adult KS patients and 71 age-matched healthy subjects. RESULTS: In KS, BMD was universally lowered in all regions. Markers of bone formation or bone resorption were not altered in KS, but 25-OH-Dvitamin was lower (55 vs. 82 nmol/L, p < 0.0001) than in healthy subjects. Significantly more KS patients had low BMD (Z-scores below -2) at the forearm (15 KS vs. two healthy subjects, p = 0.001) but not at the spine or hip. Muscle strength (bicep and quadriceps) was lower among KS patients. Multivariate analysis revealed that muscle strength, treatment with testosterone (ever/never), age at diagnosis, SHBG, bone-specific alkaline phosphatase and 1CTP were all independent predictors of BMD, but androgens was not. CONCLUSIONS: KS patients had lower BMD at the spine, hip and forearm compared to age-matched healthy subjects, but frank osteoporosis was not common. Muscle strength, previous history of testosterone treatment, age at diagnosis and bone markers were predictors of BMD, but testosterone was not. Signs of secondary hyperparathyroidism were present among KS. Dietary intake of vitamin D or sun exposure may be lower in KS patients.

Vitamin D metabolites and skeletal consequences in primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (PHPT) is associated with reduced bone mineral density (BMD) mainly at sites rich in cortical bone. However, successful parathyroidectomy causes an increase in BMD especially at sites rich in trabecular bone. Plasma 25-hydroxyvitamin D (25OHD) levels are typically reduced and plasma 1,25-dihydroxyvitamin D [1,25(OH)(2)D] slightly increased in PHPT. These variations in vitamin D metabolites may influence variations in BMD and fracture risk. AIM: To investigate relations between preoperative vitamin D metabolites and skeletal consequences in patients with untreated PHPT and to appraise the influence of preoperative vitamin D metabolites on postoperative changes in BMD. Design Cross-sectional and cohort study. MATERIALS: Two hundred and forty-six consecutive Caucasian PHPT patients aged 19-91 years. (median 63, 87% females). RESULTS: BMD was reduced at the femoral neck (P < 0.001) and forearm (P < 0.001), but normal at the lumbar spine (P = 0.11). Levels of biochemical bone markers were associated with high plasma PTH, high plasma 1,25(OH)(2)D and low plasma levels of 25OHD. Moreover, low plasma 25OHD was associated with low levels of BMD at the femoral neck (r(p) = 0.23), the forearm (r(p) = 0.19) and the whole body (r(p) = 0.30), whereas plasma 1,25(OH)(2)D was inversely associated with BMD at all regional sites and the whole body. Plasma PTH only showed an inverse association with BMD at the forearm (r(p) = -0.21). No association was observed between biochemical variables and prevalent spinal fractures, all peripheral fractures or osteoporotic peripheral fractures. The annual increase in spinal BMD after surgery was positively associated with preoperative plasma PTH (r(p) = 0.40), whereas the annual increase in whole body BMD was inversely associated with plasma 25OHD (r(p) = -0.32). No change in BMD at the femoral neck and forearm was observed 1 year after surgery. CONCLUSION: Low vitamin D status and high plasma 1,25(OH)(2)D are associated with increased bone turnover and decreased BMD in patients with PHPT.

Plasma 1,25-dihydroxyvitamin D levels in primary hyperparathyroidism depend on sex, body mass index, plasma phosphate and renal function.

BACKGROUND: Primary hyperparathyroidism (PHPT) is characterized by elevated plasma levels of PTH and calcium with reduced plasma phosphate. Physiologically, renal 1alpha,25-dihydroxyvitamin D [1,25(OH)(2)D] production is stimulated by PTH and phosphate deprivation, and inhibited by 1,25(OH)(2)D itself and calcium. AIM: To investigate relations between circulating levels of 1,25(OH)(2)D, 25-dihydroxyvitamin D (25OHD), PTH, calcium, phosphate, renal function and skeletal complications in patients with PHPT. DESIGN: Cross-sectional study. MATERIAL: Two hundred and fifty-two consecutive hypercalcaemic Caucasian patients aged 24-91 (median 65.9) years (85.3% females) with PHPT. RESULTS: In patients with PHPT, plasma 1,25(OH)(2)D was increased by 27%[107 (9-250) pmol/l, median (range)] compared to controls [84 (18-172) pmol/l, P < 0.001]. In univariate models, plasma 1,25(OH)(2)D depended inversely on age (r = -0.23, P < 0.001) and plasma phosphate (r = -0.23, P < 0.001) and positively on plasma calcium (r = 0.14, P < 0.05), plasma 25OHD (r = 0,15, P < 0.05) and creatinine clearance rate (r = 0.32, P < 0.001). In the final multiple regression model, plasma 1,25(OH)(2)D depended positively on renal function (r(p) = 0.43, P < 0.001) and female sex (r(p) = 0.15, P < 0.05) but inversely on body mass index (BMI; r(p) = -0.23, P < 0.005) and plasma phosphate (r(p) = -0.18, P < 0.05). Plasma 1,25(OH)(2)D correlated positively with renal calcium excretion and inversely with lumbar spine bone mineral density (BMD) but was not associated with risk of fractures or renal stones. CONCLUSION: Patients with PHPT have elevated plasma 1,25(OH)(2)D levels but, to a large extent, individual values overlap controls. The increase in plasma 1,25(OH)(2)D depends on renal function, hypophosphataemia and the female sex and is attenuated by high BMI. High plasma 1,25(OH)(2)D is associated with higher plasma calcium levels.

Plasma 25-hydroxyvitamin D and not 1,25-dihydroxyvitamin D is associated with parathyroid adenoma secretion in primary hyperparathyroidism: a cross-sectional study.

BACKGROUND: Primary hyperparathyroidism (PHPT) is associated with reduced plasma 25-hydroxyvitamin D (P-25OHD) and usually increased plasma 1alpha,25-dihydroxyvitamin D (P-1,25(OH)2D). Parathyroid tissue expresses the vitamin D receptor and it is thought that circulating 1,25(OH)2D participate in the regulation of parathyroid cell proliferation, differentiation and secretion. AIM: To investigate the relations between circulating levels of 1,25(OH)2D and 25OHD respectively and parathyroid adenoma weight (AW), plasma-parathyroid hormone (P-PTH) and PTH secretion expressed as P-PTH/AW. DESIGN: Cross-sectional study. MATERIAL: One hundred and seventy-one consecutive hypercalcaemic caucasian patients aged 19-87 years (median 63, 84% females) with surgically proven parathyroid adenoma. RESULTS: A weak positive correlation was found between P-25OHD and P-1,25(OH)2D (r=0.24, P<0.005). AW depended on sex and body mass index. Following adjustment, it was correlated positively to P-PTH, calcium (Ca) and alkaline phosphatase (AP) and inversely to plasma phosphate in a multiple regression model. AW was not associated with vitamin D metabolites. Preoperative P-PTH correlated positively to plasma levels of Ca and AP, but inversely to phosphate and 25OHD (P<0.001) levels. P-PTH was not associated with P-1,25(OH)2D (P=0.65). The P-PTH:AW ratio correlated inversely to P-25OHD (P<0.05), but showed no relations to plasma levels of Ca, phosphate or 1,25(OH)2D (P=0.22). CONCLUSION: In this material, low levels of 25OHD were related to higher levels of P-PTH and higher PTH:AW ratios in patients with PHPT suggesting that vitamin D deficiency increase PTH secretion activity. Neither PTH secretion nor AW was associated with circulating levels of 1,25(OH)2D.

Postpartum vitamin D insufficiency and secondary hyperparathyroidism in healthy Danish women.

OBJECTIVE: To examine vitamin D status and parathyroid function in normal Danish women postpartum. DESIGN: Three cross-sectional measures during follow-up of 89 women postpartum. SUBJECTS AND INTERVENTION: We assessed vitamin D status by measuring plasma 25-hydroxyvitamin D (P-25OHD) and the degree of secondary hyperparathyroidism by measuring plasma parathyroid hormone (P-PTH) in 89 Caucasian women at three consecutive visits: (mean (range)) 23 (10-37) days (spring), 117 (95-140) days (late summer) and 274 (254-323) days (winter) postpartum. RESULTS: P-25OHD showed seasonal variations with higher values in late summer than in the other periods (P < 0.001). At the first visit, 65% received vitamin D supplements. At the following visits, almost 50% were supplemented. Vitamin D insufficiency (P-25OHD < 50 nmol/l) occurred more often during winter (28%) than in spring (14%) (Fisher's exact test, P = 0.02) or late summer (7%) (P = 0.0001). Irrespective of season, vitamin D insufficiency occurred most frequent in women who did not take vitamin D supplements (Fisher's exact test, P < 0.02). Frank vitamin D deficiency (P-25OHD < 25 nmol/l) was observed during winter in 6%. At all three periods, P-25OHD correlated inversely with P-PTH indicating secondary hyperparathyroidism at deficient vitamin D status. During spring, late summer and winter three, one and four females, respectively, had elevated plasma PTH. CONCLUSION: Vitamin D insufficiency with secondary hyperparathyroidism is a frequent finding in healthy Danish women postpartum and especially during winter. Vitamin D supplements reduced the risk of vitamin D insufficiency, especially during winter. Our results support the importance of increased alertness regarding information of pregnant and lactating women about vitamin D supplements. Furthermore, it has to be studied whether the present recommendations of an intake of 5-10 microg vitamin D/day are sufficient, especially during winter months.

Vitamin D and its binding protein Gc: long-term variability in peri- and postmenopausal women with and without hormone replacement therapy.

OBJECTIVE: Measurement of plasma 25-hydroxyvitamin D (25OHD) level is often used to evaluate a patient's vitamin D status. The purpose of this study was to investigate the variability in individual plasma 25OHD- and vitamin D-binding protein- (Gc) levels over a 5-year period in postmenopausal women with and without hormone replacement therapy (HRT). MATERIAL AND METHODS: A total of 187 women were followed-up for 5 years. At baseline, 89 women were allocated to treatment with HRT, given orally. Measurements were performed at baseline and after 1, 2 and 5 years of follow-up. RESULTS: At baseline, 25OHD levels were positively associated with sunbathing and use of vitamin D supplements, and inversely associated with smoking. HRT therapy increased plasma levels of Gc (+8 %) but did not affect 25OHD levels or the free 25OHD index (molar ratio of 25OHD- to Gc levels). Among those classified in the lowest 25OHD tertile at baseline, 40 % remained in the lowest tertile during all subsequent measurement time-points. Similarly, 32 % of those classified in the highest baseline tertile remained in the highest tertile during all subsequent measurements. Use of the free 25OHD index showed similar results. No independent predictors of changes in vitamin D tertiles during follow-up were identified, which suggests that the observed variation was caused by the intra-individual variation in measured parameters. For all participants, the within-patient variability in 25OHD measurements was between 13 % and 19 %. CONCLUSIONS: In healthy postmenopausal women, HRT increases Gc levels. Owing to the high intra-individual variation in plasma 25OHD, it seems questionable to use a single estimate as a predictor of individual vitamin D status.

Vitamin D status, seasonal variations, parathyroid adenoma weight and bone mineral density in primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (PHPT) and vitamin D insufficiency are common conditions that can occur in combination. However, low plasma 25-hydroxyvitamin D (25OHD) may also enhance the risk of PHPT or modify disease severity. AIM: To compare the risk of vitamin D insufficiency and deficiency stratified by age, sex and season between PHPT patients and controls and to assess associations between plasma 25OHD and adenoma weight, biochemical variables, bone mineral density (BMD) and clinical complications. DESIGN: Cross-sectional study. MATERIAL: A total of 289 consecutive Caucasian patients with PHPT aged 65.9 (24-92) years, 289 sex-, age- and season-matched normocalcaemic controls and 187 healthy adult blood donors. PHPT diagnosis was confirmed in 214 by neck exploration. RESULTS: Vitamin D insufficiency (plasma 25OHD < 50 nmol/l) was observed in 81% of PHPT patients compared with 60% of sex- and age-matched controls (P < 0.001) and 35% of blood donors (P < 0.001). During summer, 77%vs. 53% (P < 0.001) and 4% (P < 0.001), respectively, had vitamin D insufficiency. Average plasma 25OHD was 41 (range 9-87) nmol/l among 27 PHPT patients compared with 87 (21-173) nmol/l (P < 0.001) among aged-matched blood donors. During winter, 86%vs. 66% (P < 0.001) and 71% (P < 0.05), respectively, had vitamin D insufficiency. Vitamin D deficiency (plasma 25OHD < 25 nmol/l) was observed in 33% of PHPT patients compared with 20% of age- and sex-matched controls (P < 0.001) and 13% of blood donors (P < 0.001). Both PHPT patients and controls showed seasonal variations in 25OHD related to the average number of sun hours, but values were lower in PHPT patients at all calendar months. In PHPT patients low plasma 25OHD was associated with higher plasma levels of calcium, PTH and alkaline phosphatase and with lower renal calcium excretion, femoral neck and forearm BMD. No association was found between plasma 25OHD and adenoma weight (total or divided into tertiles). There was a trend towards increased risk of osteoporotic fractures (P < 0.08) with low plasma 25OHD. CONCLUSION: Vitamin D insufficiency and deficiency are common findings in PHPT and occur more often than in a sex- and age-matched control group referred from general practice and in normal blood donors irrespective of season. Low plasma 25OHD levels are associated with an aggravated clinical presentation of PHPT but do not affect adenoma size.

Plasma concentrations of 25-hydroxy-vitamin D and 1,25-dihydroxy-vitamin D are related to the phenotype of Gc (vitamin D-binding protein): a cross-sectional study on 595 early postmenopausal women.

The major transporter of vitamin D metabolites in the circulation is the multifunctional plasma protein Gc, also known as group-specific component, Gc globulin, vitamin D-binding protein, or DBP. There are several phenotypes of Gc, and we examined the influence of Gc phenotype and Gc concentration on vitamin D status. By using isoelectric focusing we identified the Gc phenotype of 595 caucasian recent postmenopausal women enrolled into the Danish Osteoporosis Prevention Study (DOPS). We measured plasma concentration of Gc by immunonephelometry (coefficient of variation [CV] < 5%), 25-hydroxy vitamin D (25OHD) by a competitive protein-binding assay (CV 10%), and 1,25-dihydroxy-vitamin D (1,25(OH)(2)D) by a radioimmunoassay (CV 6--14%), and calculated index as the molar ratio of vitamin concentration divided by Gc concentration. Plasma levels of Gc, 25OHD, 25OHD index, and 1,25(OH)(2)D, but not 1,25(OH)(2)D index, differed significantly between women with different Gc phenotype, being highest in Gc1-1, intermediate in Gc1-2, and lowest in Gc2-2. In multiple regression analysis, Gc concentration was an independent predictor of 1,25(OH)(2)D, whereas Gc phenotype was a significant predictor of 25OHD concentration, even after adjustment for the effects of season, sunbathing habits, skin thickness, use of vitamin supplements, smoking, and body mass index (BMI). Plasma parathyroid hormone (PTH) level did not differ between Gc phenotypes. Despite the fact that more than 60% of the women with Gc phenotype Gc2-2 had plasma 25OHD levels of less than 50 nmol/L none of them had plasma PTH higher than reference limits. Bone mineral content (BMC), Bone mineral density (BMD), and bone markers did not differ between Gc phenotypes. In conclusion, plasma 1,25(OH)(2)D, 25OHD, and 25OHD index are related to Gc phenotype, and we speculate that the thresholds for vitamin D sufficiency differ between Gc phenotypes.

Relation between plasma amino-terminal propeptide of procollagen type III and left ventricular longitudinal strain in essential hypertension.

OBJECTIVE: To investigate whether myocardial fibrosis assessed non-invasively is related to left ventricular (LV) longitudinal systolic function in patients with essential hypertension. DESIGN: The study consisted of 30 control subjects and 40 patients with hypertension with normal LV ejection fraction. Tissue Doppler echocardiography was performed to assess LV longitudinal systolic strain from the apical views. Mean strain was calculated from the basal and mid segments. Plasma concentrations of the amino-terminal propeptide of type III procollagen (PIIINP) were measured. RESULTS: In the hypertension group, mean strain was significantly reduced (mean (SD) 13 (6)% v 21 (6)%, p < 0.01) and plasma PIIINP were increased compared with controls (3.0 (0.7) microg/l v 2.1 (0.3) microg/l, p < 0.001). A significant correlation was found between mean strain and PIIINP (r = -0.56, p < 0.001). In patients with abnormal diastolic filling (n = 21) mean strain was reduced compared with patients with normal LV filling (n = 19) (10 (6)% v 15 (6)%, p < 0.01) and the serological marker PIIINP was increased (3.5 (0.6) microg/l v 2.5 (0.5) microg/l, p < 0.001). CONCLUSIONS: There is a significant association between the extent of myocardial fibrosis and reduced LV longitudinal contractility.

NT-proBNP in normoalbuminuric patients with Type 2 diabetes mellitus.

OBJECTIVE: To examine levels of NT-proBNP and its relation to hypertension, as well as diastolic function in normoalbuminuric patients with Type 2 diabetes. RESEARCH DESIGN AND METHODS: The study comprised 60 Type 2 diabetic patients without albuminuria. Thirty patients were normotensive and 30 had hypertension. Exclusion criteria were cardiac symptoms and an ejection fraction < 55%. Thirty age- and sex-matched normal subjects served as controls. Diastolic dysfunction was assessed with echocardiography, by means of mitral inflow and colour M-Mode flow propagation recordings. RESULTS: Overall NT-proBNP was significantly elevated in the Type 2 diabetes group, compared with the controls [54.5 pg/ml (5-162) vs. 32.7 pg/ml (5-74.3) P = 0.02]. NT-proBNP was significantly higher among hypertensive patients compared with both normotensive patients and controls but no difference was found between the normotensive patients and the controls [58.0 pg/ml (8.5-162), P < 0.05 vs. 50.8 pg/ml (5-131) P = 0.4]. Patients with concentric and eccentric hypertrophy had significantly higher NT-proBNP levels compared with the control group [81.0 pg/ml (5-147), P < 0.001 and 66.8 pg/ml (42-128), P < 0.001], whereas patients with left ventricular remodelling (enlarged relative wall diameter but normal left ventricular mass) were comparable with the control group [42.3 pg/ml (8.3-142) P = 0.55]. Patients with left atrial enlargement also had incremental NT-proBNP values. NT-proBNP was only moderately correlated to age (r = 0.33, P < 0.05) and left ventricular diastolic diameter (r = 0.41, P < 0.05), but unrelated to diastolic function. CONCLUSIONS: NT-proBNP is significantly increased in hypertensive, normoalbuminuric patients with Type 2 diabetes. These findings were related to left ventricular hypertrophy and increased left atrial and ventricular diameters.

Effects of long-term treatment with loop diuretics on bone mineral density, calcitropic hormones and bone turnover.

BACKGROUND: Loop diuretics (LD) are widely used in the treatment of cardiovascular diseases and disorders with fluid accumulation. LD are known to increase renal calcium losses and may thereby affect calcium homeostasis and bone metabolism. OBJECTIVE: We studied to what extent long-term treatment with LD affects calcium homeostasis and bone metabolism. DESIGN AND SUBJECTS: In a cross-sectional design we compared 140 postmenopausal women treated with a LD for more than 2 years with 140 age-matched women not in diuretic therapy. RESULTS: Treatment with LD was associated with significantly increased urinary calcium, plasma parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D levels. Per 40 mg day(-1) of furosemide, urinary calcium was increased by 17% (P < 0.05) and plasma PTH levels were increased by 28% (P = 0.04). Users of LD had a 17% higher body weight (P < 0.001) compared with nonusers. This was due to a 32% higher fat mass (P < 0.001) and a 6% higher lean tissue mass (P < 0.001). Moreover, users of LD had a higher bone mineral density (BMD) at the spine (+7.5%, P < 0.001), hip (+4.8%, P = 0.004), forearm (+3.7%, P = 0.01) and whole body (+2.5%, P = 0.06). However, after adjustment for body weight differences, BMD did not differ between groups. Nevertheless, duration of LD treatment was positively associated with BMD at the spine (P = 0.03) and whole body (P < 0.05). BMD at the spine increases by 0.3% per 1 year of treatment. CONCLUSIONS: The increased renal calcium losses in users of LD are compensated for by a PTH-dependent increase in 1,25(OH)(2)D levels. Thereby calcium balance remains neutral without major effects on bone metabolism.

Primary hyperparathyroidism: intraoperative PTH-measurements.

BACKGROUND: With the development of rapid assays and intraoperative measurement of intact parathyroid hormone (PTH), new strategies in the handling of patients with primary hyperparathyroidism (pHPT) have evolved. AIM: The aim of our study was to illustrate the performance of the intraoperative PTH measurement as a predictor of successful cure. MATERIAL AND METHODS: From September 1999 to April 2002 143 patients with pHPT underwent a parathyroid operation (bilateral neck exploration with identification of all parathyroid glands) with intraoperative measurements of plasma PTH (immediately prior to surgery (T0) and 5 minutes after gland excision (T5)). A positive test result was defined as plasma PTH values at T5 below 20% of T0 or a value in the normal range below 7.6 pmol/l. Hence T5 values above 20% of T0 and above 7.6 pmol/l were considered test negative. RESULTS: 122 patients (85%) were test positive and cured, 11 patients (8%) were test negative but cured, and 10 patients (7%) were test negative and not cured by the primary operation. Consequently, the sensitivity of the test was 0.92 and the specificity 1.00. CONCLUSIONS: The rapid PTH test used is a reliable predictor of a successful outcome in pHPT patients undergoing parathyroid surgery.

Quality of lipid-lowering therapy in patients with ischaemic heart disease: a register-based study in 3477 patients.

OBJECTIVE: To develop a method to evaluate routine management practices concerning lipid-lowering treatment in patients with ischaemic heart disease (IHD) in a large geographic area. DESIGN: A register-based study linking information on IHD with cholesterol levels and prescriptions on lipid-lowering medications by personal registration number. Plasma cholesterol levels were collected from the electronic laboratory information system (LIS), and information on IHD from the Danish National Hospital Register (LPR). The extent of treatment was evaluated by information on prescriptions on lipid-lowering medications from the Danish National Health Service. SETTING: Evaluates treatment in both hospitals and primary care. SUBJECTS: Patients with IHD. RESULTS: In total 3477 patients <75 years were identified, and 43.7% had claimed prescriptions on lipid-lowering medications (01.01.2000-31.07.2000). In the whole population, 42% reached the goal for total cholesterol lower than 5 mmol L-1 set by European guidelines. In the 1521 patients treated with lipid-lowering medications 55% reached the goal. CONCLUSION: By use of registers it was possible to develop a method to evaluate and monitor current treatment practice for dyslipidaemia in a large geographic area. The method makes it possible to evaluate the impact of guidelines, changes in treatment procedures and to provide feedback to physicians. The study revealed that lipid-lowering treatment is still not sufficiently implemented in clinical practice even in patients with known IHD, and the used doses of statins are lower than those used in randomized clinical trials.

Vitamin D insufficiency in Greenlanders on a westernized fare: ethnic differences in calcitropic hormones between Greenlanders and Danes.

We studied the influence of age, gender, latitude, season, diet and ethnicity on plasma 25-hydroxyvitamin D 25 OHD, PTH, 1,25-dihydroxyvitamin D, vitamin D-binding protein, bone-specific alkaline phosphatase, and osteocalcin levels in 46 Greenlanders living in Nuuk (64 degrees N) on a traditional fare (group A), 45 Greenlanders living in Nuuk on a westernized fare (group B), 54 Greenlanders (group C), and 43 Danes (Group D) living in Denmark (55 degrees N) on a westernized fare. Blood specimens were drawn both summer and winter. Vitamin D insufficiency (plasma 25 OHD <40 nmol/l) was common in all four study groups during summer (23-74%) and winter (42-81%). Compared to groups A and D, vitamin D insufficiency was significantly more frequent in groups B and C. In all groups, summer levels of 25 OHD were above winter levels. Multiple regression analysis revealed a significant effect of ethnicity. Compared to Danes, Greenlanders had higher 1,25-dihydroxyvitamin D levels, but lower 25 OHD and PTH levels despite relatively low plasma calcium concentrations. In addition to ethnicity, 25(OH)D levels were influenced by age, season (summer > winter), and diet (a traditional Inuit diet>westernized diet). Ethnic differences exist between Greenlanders and Danes. Our results suggest that Greenlanders may have an inherent lower "set-point" for calcium-regulated PTH release or an enhanced renal 1,25(OH)(2)D production. In addition to ethnicity, age, season, and diet were important determinants of vitamin D status. Changes from a traditional to a westernized fare are associated with a reduced vitamin D status in Greenlanders. Vitamin D supplementation should be considered.

Pegvisomant-induced serum insulin-like growth factor-I normalization in patients with acromegaly returns elevated markers of bone turnover to normal.

Active acromegaly is associated with increased biochemical markers of bone turnover. Pegvisomant is a GH receptor antagonist that normalizes serum IGF-I in 97% of patients with active acromegaly. We evaluated the effects of pegvisomant-induced serum IGF-I normalization on biochemical markers of bone and soft tissue turnover, as well as levels of PTH and vitamin D metabolites, in 16 patients (nine males; median age, 52 yr; range, 28-78 yr) with active acromegaly (serum IGF-I at least 30% above upper limit of an age-related reference range). Serum procollagen III amino-terminal propeptide (PIIINP) and type I procollagen amino-terminal propeptide, osteocalcin (OC), bone-related alkaline phosphatase, C-terminal cross-linked telopeptide of type I collagen (CTx), albumin-corrected calcium, intact PTH, 25-hydroxy vitamin D, 1,25-dihydroxy vitamin D [1,25-(OH)(2) vit D], urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio, and urinary calcium (24 h collection) were measured (single-batch analysis) at study entry and after IGF-I normalization, along with sera from 32 age- and sex-matched controls. Compared with controls, PIIINP, OC, and CTx were significantly elevated in patients at baseline. Pegvisomant-induced serum IGF-I normalization (699 +/- 76 to 242 +/- 28 micro g/liter, P < 0.001) was associated with a significant decrease in PIIINP, markers of bone formation (type I procollagen amino-terminal propeptide, OC, and bone-related alkaline phosphatase), and resorption (CTx and urinary type 1 collagen cross-linked N-telopeptide/creatinine ratio). 1,25-(OH)(2) vit D decreased and intact PTH increased significantly, but 25-hydroxy vitamin D was unaffected. A significant decline in calculated calcium clearance was observed. The decrease in serum IGF-I correlated positively with the decrease of serum PIIINP (r = 0.7, P < 0.01). After normalization of serum IGF-I, there was no statistical difference between patients and controls for any parameters for which control data were available. In conclusion, GH excess is associated with increased bone and soft tissue turnover. Pegvisomant-induced normalization of serum IGF-I results in a decrease in markers of bone and soft tissue turnover to levels observed in age-matched controls, and these changes are accompanied by an increase in PTH and a decrease in 1,25-(OH)(2) vit D. These data provide further evidence of the effectiveness of pegvisomant in normalizing the altered biological effects of GH hypersecretion.

Dose-effect relations of loop- and thiazide-diuretics on calcium homeostasis: a randomized, double-blinded Latin-square multiple cross-over study in postmenopausal osteopenic women.

BACKGROUND: Thiazide diuretics (TDs) reduce whereas loop diuretics (LDs) increase urinary calcium. We studied the effects of different doses of a TD and LD on electrolytes, calcitropic hormones and biochemical bone markers. SUBJECTS AND METHODS: In a five-period crossover study, comparing four active doses with placebo, 40 postmenopausal women with osteopenia were treated with different doses of LD bumetanide (n = 20, 0.5-2.0 mg per day) or TD bendroflumethiazide (n = 20, 2.5-10 mg per day). Each treatment period lasted 1 week. RESULTS: Urinary calcium decreased dose-dependently in response to the bendroflumethiazide. The best hypocalciuric effect was achieved by 5 mg day-1 of bendroflumethiazide. Total plasma calcium levels increased, whereas ionised calcium at ambient pH-values decreased because of increased pH-values in response to the bendroflumethiazide. Plasma PTH levels did not change, whereas a slight dose-dependent increase occurred in plasma 1,25(OH)2D levels. As a marker of bone formation, plasma osteocalcin levels increased. Conversely, bumetanide dose-dependently increased renal calcium losses with a concomitant increase in plasma PTH and 1,25(OH)2D levels. Plasma osteocalcin levels increased and bone-specific alkaline phosphatase levels decreased dose-dependently. CONCLUSION: Whether a LD or TD is chosen as diuretic therapy affects calcium homeostasis. The effects of LDs are potentially harmful to bone. Further studies are needed to evaluate whether long-term treatment with LDs causes osteoporosis. Until then, we suggest using, if possible, a TD rather than a LD as diuretic therapy in order not to risk deleterious effects on bone metabolism.