Vitamin D metabolites (25-hydroxyvitamin D, 24,25-dihydroxyvitamin D and 1,25-dihydroxyvitamin D) and osteocalcin in β-thalassaemia

Serum levels of the vitamin D metabolites 25-hydroxyvitamin D, 24,25-dihydroxyvitamin D, and 1,25-dihydroxyvitamin D. and of osteocalcin. C-tenninal parathyroid hormone and other biochemical indices related to bone metabolism, were determined in two groups of patients with β-thalassaemia aged 5–10 years (summer 7.8 ± 0.4 years, mean ± SEM. and winter 7.7 ± 0.4 years, group A, n= 15) and 11–23 years (16.6 ± 0.9 and 15.7 ± 0.9 years in summer and winter, respectively, group B, n= 22). Emphasis was given to populations of school and adolescent ages and to the seasons of summer and winter when vitamin D status demonstrates the widest extremes. The mean serum levels of 25-hydroxyvitamin D in patients aged 5–10 years did not differ from those of controls during both seasons studied. In contrast, in the age group 11–23 years these levels were found to be lower in patients than in controls both in winter (10.6 ± 0.9ng/ml vs 15.0 ± 2.0ng/ml, p < 0.05) and summer (20.2 ± 2.1 ng/ml vs 27.1 ± 2.0ng/ml, p < 0.05). The serum concentrations of 24,25-dihydroxyvitamin D were lower in the thalassaemic patients than in controls in both age groups and both seasons. In the patients under 10 years of age the mean values of this metabolite in winter were 1.06 ± 0.17 ng/ml vs 1.68 ± 0.20 ng/ml in the respective controls (p < 0.05), and in summer 1.44 ± 0.11 ng/ml vs 2.35 ± 0.36 ng/ml in controls (p < 0.05). In the group of patients aged 11–23 years, the mean levels of 24,25-dihydroxyvitamin D were in winter 0.65 ± 0.12 ng/ml vs 1.12 ± 0.19 ng/ml (p < 0.05) in controls and in summer 1.34 ± 0.12 ng/ml vs 1.84 ± 0.20 ng/ml (p < 0.05). The 1,25-dihydroxyvitamin D concentrations in both thalassaemic patient groups were significantly no different from those in the respective control groups. Serum osteocalcin, C-terminal parathyroid hormone, calcium, inorganic phosphate and alkaline phosphatase levels in the patients studied were not significantly different from those in controls, except for calcium and phosphate in the older group. In the older group of thalassaemic patients, serum calcium was lower than in the controls (2.26 ± 0.03 vs 2.37 ± 0.03 mmol/1, p < 0.05) in summer and serum phosphate higher than in the controls in winter (1.47 ± 0.05 mmol/1 vs 1.27 ± 0.06 mmol/1. p < 0.05).     

Bone density and 25-hydroxyvitamin D level in extrahepatic biliary atresia

Biliary atresia (BA) represents a common cholestatic affliction of the gastrointestinal tract affecting infants and children. The objective of the present study was to evaluate 42 patients (20 with and 22 without jaundice) diagnosed with extrahepatic BA for bone mineral content and serum 25-hydroxyvitamin D (HVD) levels. Physical examination and anthropometric nutritional assessment were performed. The investigation included liver function tests and serum calcium (Ca), phosphate (P), magnesium (Mg), and 25-HVD levels. Dual-energy X-ray absorptiometry was used to measure the bone mineral density (BMD) of the lumbar spine (L₁–L₄). Our results showed that 16 jaundiced␣patients (80%) and only 3 nonjaundiced patients (13.6%) showed osteoporosis (P< 0.05). All patients had normal serum Ca and P levels. Only 1 nonjaundiced patient had a low serum Mg level. Serum 25-HVD levels (mean ± SD) were 20.71 ± 8.24, 16.12 ± 4.3, and 9.18 ± 5.84 ng/ml, respectively, in subjects with normal bone density (n=7), osteopenia (n=3), and osteoporosis (n=11). Bone disease represents a well-known complication among long-term survivors of BA. To date, the pathogenesis has remained unexplained. Since, as demonstrated in the present study, jaundiced patients develop osteoporosis more frequently than nonjaundiced patients, hyperbilirubinemia may have an influence. Bone-mineral deficiency can be detected earlier by means of BMD measurement (non-invasive method) than by measuring serum Ca, P, and Mg levels in these patients. Accepted: 27 November 2000     

Vitamin D metabolism in pre-operative extrahepatic biliary atresia

In order to clarify the pathogenesis of rickets in preoperative patients with extrahepatic biliary atresia, we evaluated baseline serum 25-OHD and 1,25(OH)2D levels and correlated serum 25-OHD levels with increase in age and season of birth in 16 preoperative patients. Further, parenteral vitamin D2 tolerance tests were performed in 5 cases. Serum 25-OHD and 1,25(OH)2D levels were significantly lower than those in 15 normal controls. There was a negative correlation between the serum 25-OHD levels and increase in age. The patients born during the winter had lower serum 25-OHD concentrations than those born in summer. The mean value of increased 25-OHD levels after the parenteral vitamin D2 tolerance tests did not differ from that of 6 controls. Since there was no impairment of vitamin D 25-hydroxylation, the reduction in serum 25-OHD may therefore be mainly due to disturbed intestinal vitamin D absorption. It was also concluded that season of birth and increase in age are pathogenic factors in the etiology of rickets in preoperative patients with extrahepatic biliary atresia.     

Vitamin D dependent rickets: Decreased sensitivity to 1,25-dihydroxyvitamin D

A patient with vitamin D dependent rickets with decreased sensitivity to 1,25-Dihydroxyvitamin D was observed. She suffered from bone pain of two years duration beginning at 12 years of age and was found to be suffering from hypocalcemia, secondary hyperparathyroidism and osteomalacia. Laboratory findings revealed normal serum 25-hydroxyvitamin D (27 ng/ml) and markedly elevated serum 1,25-dihydroxyvitamin D (131.9 pg/ml). The hypocalcemia was refractory in spite of administration of 25,000 units of vitamin D₂, but therapy with high doses of oral 1-hydroxyvitamin D₃ resulted in significant elevation of the serum calcium level. The clinical findings and course of the patient's disease were quite different from those of other patients with vitamin D dependent rickets reported by other authors.     

Calcium and phosphate metabolism in children with idiopathic hypoparathyroidism or pseudohypoparathyroidism: effects of 1,25-dihydroxyvitamin D3

Two children with congenital hypoparathyroidism and two children with pseudohypoparathyroidism were given maintenance doses of 15 to 45 ng/kg/day 1,25-dihydroxyvitamin D3 for a total of 255 months. The urinary calcium excretion showed an upward elevation after the first 2 years of treatment but was not significantly higher than that in 10 normal control subjects. The renal threshold for phosphate excretion stayed within the normal ranges compared with control values. Two hypercalcemic and two hypocalcemic episodes occurred during this period of treatment. Hypercalcemia was reversed within 1 week after withdrawal of 1,25-dihydroxyvitamin D3. Hypocalcemia was countered by increasing the dose of 1,25-dihydroxyvitamin D3. Renal functions were not adversely affected, as estimated by creatinine clearance and reciprocals of serum creatinine concentrations. The mean serum calcium concentration during 1,25-dihydroxyvitamin D3 treatment was significantly higher (P = 0.001) compared with that obtained during vitamin D2 treatment at a dose of 500 to 3000 IU/kg/day. These data provide additional support for the long-term use of 1,25-dihydroxyvitamin D3 in idiopathic hypoparathyroidism and pseudohypoparathyroidism.     

1,25-二羟维生素D3在慢性肾疾病中的作用

1,25-二羟维生素D3[1,25-(OH)2D3]是维生素D的活性代谢产物,除有促进钙磷吸收及免疫调节作用外,还能负向调节肾素-血管紧张素系统的活性,减少肾小球硬化,抑制转化生长因子-β1诱导肾小管上皮细胞向间质细胞转化,减轻肾小管间质纤维化;而且参与滤过屏障的维持,恢复裂孔隔膜蛋白的表达,减少足细胞的损伤脱落,降低慢性肾疾病蛋白尿.其肾保护作用为临床治疗慢性肾疾病提供了可供选择的药物之一.该文综述1,25-(OH)2D3在慢性肾疾病中的积极作用.     

活性维生素D及其类似物对足细胞的保护作用

1,25(OH)2D3产生不足是慢性肾脏病(CKD)的主要特征之一,不仅导致钙磷代谢异常及骨矿化障碍,而且加速肾疾病的进展。1,25(OH)2D3及其类似物可减轻CKD患者的蛋白尿,减轻动物模型足细胞的损伤、凋亡和脱落,促进裂孔隔膜蛋白的表达,维持肾小球滤过屏障的完整性。1,25(OH)2D3保护足细胞机制与抑制足细胞肾素-血管紧张素系统、阻断Wnt/β-Catenin和转化生长因子(TGF)-β1信号通路有关。     

Hypophosphatemic rickets: effect of 1 alpha, 25-dihydroxyvitamin D3 on growth and mineral metabolism.

Growth retardation nearly invariably accompanies hypophosphatemic rickets. Studies were conducted in an adolescent male with this disorder as follows. Protocol I: age, 6 to 16 years; treatment per day, 5,000 to 80,000 units vitamin D2, 1,760 to 2,200 mg phosphorus, orally as buffered phosphate; growth velocity, 5 to 6 cm/year. Protocol II: age 16 to 17 years; treatment per day, 1 alpha,25-dihydroxyvitamin D3, 1 microgram; 2,200 mg of phosphorus, orally as buffered phosphate; growth velocity, 14 cm/year. The height improved from less than third percentile for the decade during study protocol I to the 25th percentile during protocol II. Mineral balance studies showed a reduction of urinary and stool phosphorus during treatment protocol II, while the patient was receiving metabolic diet. The serum phosphorus improved from 2.2 to 4.3 mg/dl and radiologic healing of rickets was documented. No hypercalcemic episode was encountered. The data support the contention that 1 alpha,25-dihydroxyvitamin D3 is the treatment of choice for hypophosphatemic rickets.     

Renal hypophosphatemic rickets. Growth and mineral metabolism after treatment with calcitriol (1,25-dihydroxyvitamin D3) and phosphate supplementation

To delineate the mineral metabolism of renal hypophosphatemic rickets and to update progress in linear growth after calcitriol (1,25-dihydroxyvitamin D3) therapy, the medical records of 19 patients were examined retrospectively from January 1978 through December 1985. With a mean (+/- SD) follow-up period of 42.0 +/- 5.4 months after calcitriol had been administered for at least 12 months, the growth measurements were as follows: the percentile weight (mean +/- SD) remained unchanged, with the initial being 12.3% +/- 17.3% and the final being 15.3% +/- 18.6%, and the length/height percentiles were -2.7% +/- 5.9% and -2.4% +/- 4.4%. The growth velocity index showed a significant improvement from mean values of 61.7% (at age 2 years) to mean values of 101.2% (at age 11.2 years). Serum phosphate concentrations rose from the initial value of 2.9 +/- 0.6 to 3.5 +/- 0.8 mg/dL (0.9 +/- 0.2 to 1.1 +/- 0.3 mmol/L). The effects of calcitriol on renal function were tested by creatinine clearance values, which were 127 +/- 22 mL/min/1.73 m2 (2.12 +/- 0.37 mL/s/1.73 m2) at the conclusion of the study, compared with 128 +/- 25 mL/min/1.73 m2 (2.13 +/- 0.41 mL/s/1.73 m2) obtained at the initiation of calcitriol therapy. We conclude that calcitriol treatment of renal hypophosphatemic rickets in children results in improvement of growth velocity and serum phosphate concentration without deterioration of renal function.     

1 alpha-hydroxyvitamin D3 treatment of three patients with 1,25-dihydroxyvitamin D-receptor-defect rickets and alopecia

Three patients with clinically different severities of vitamin D-dependent rickets, type II, with alopecia, which is 1,25-dihydroxyvitamin D-receptor-defect rickets and is particularly resistant to treatment with calciferol analogues, were treated with large doses of 1 alpha-hydroxyvitamin D3 (1 alpha-(OH)D3) and 2 g of calcium lactate. Except for the alopecia, all of the abnormalities of patients 1 and 2 were reversed by treatment with 3 micrograms/kg/d of 1 alpha-(OH)D3, and those of patient 3, who had the severest manifestations, were reversed by treatment with 6 micrograms/kg/d. The serum 24,25-dihydroxyvitamin D concentrations of the three patients were low before treatment and those of patients 1 and 2 increased during treatment. These findings suggest that in patients 1 and 2, 25-hydroxyvitamin D-24-hydroxylase was stimulated via a 1,25-dihydroxyvitamin D-receptor-mediated system by treatment with 1 alpha-(OH)D3.     

Serum 25-hydroxyvitamin D in infantile rickets.

In small children with nutritional vitamin D deficiency, the serum concentration of 25-hydroxyvitamin D (25-OH-D), the major circulating metabolite of vitamin D, was correlated with the stage of clinical disease. It was low (16 to 20 ng/ml) but within the normal range in the earliest (hypocalcemic) stage of the deficiency syndrome and decreased (less than 15 ng/ml) in the more advanced stages. In patients with familial hypophosphatemia (X-linked dominant), mean serum 25-OH-D concentration was the same as in age-matched normal controls. Evidence is presented that endogenous parathyroid hormone may have a role in the depletion of serum 25-OH0D in deficiency states.     

Serum 25-hydroxyvitamin D levels in thalassaemia.

Serum 25-hydroxyvitamin D levels were measured in 36 thalassaemic children and 27 controls aged 5-15 years. Blood specimens were collected from the beginning of April until the end of October 1976. We considered as the winter period the first 3 months and the summer period the last 4 months. We found that (a) thalassaemic children had lower levels of serum 25-hydroxyvitamin D than controls: (b) there was a seasonal variation of serum 25-hydroxyvitamin D in both groups; and (c) the thalassaemic children had malabsorption of vitamin D. We suggest that the bone lesions in thalassaemic children are related to vitamin D deficiency.     

The plasma levels of 25-hydroxyvitamin D in patients with various liver diseases and the response of 25-hydroxyvitamin D to vitamin D treatment.

The mean plasma levels of 25-hydroxyvitamin D (25-OH-D) were measured before and after the administration of 2000 units of daily oral vitamin D2 for a period of 2 weeks in 9 normal infants and children, 7 infants with neonatal hepatitis and persistent neonatal hepatitis, and 4 infants with congenital biliary atresia. The mean plasma level of 25-OH-D increased significantly from 19.5 +/- 3.7 (S.E.) ng/ml to 34.0 +/- 6.8 (S.E.) ng/ml after administration of vitamin D2 in controls (p less than 0.05). The mean plasma level of 25-OH-D also increased from 8.0 +/- 2.1 (S.E.) ng/ml to 22.1 +/- 2.6 (S.E.) ng/ml after vitamin D treatment in hepatitis group (p less than 0.05). In patients with congenital biliary atresia, vitamin D treatment did not affect eh plasma levels of 25-OH-D.