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.     

Plasma Concentrations of Vitamin D Metabolites before and during Treatment of Vitamin D Deficiency Rickets in Children

ABSTRACT. Plasma concentrations of 25-hydroxyvitamin D (25-OHD), 1,25-dihydroxyvitamin D (1,25-(OH)₂D), and 24,25-dihydroxyvitamin D (24,25-(OH)₂D) were determined in 17 children with vitamin D deficiency rickets before therapy was started. Thirteen of them also had these tests repeated during treatment. The median 25-OHD concentration was at the lower limit of the reference range before, but increased distinctly within one week of treatment with 1700–4000 IU vitamin D per day (17 vs. 37 nmol/l, p < 0.01). 24,25-(OH)₂D was undetectable in twelve of the patients before therapy. Detectable concentrations were in the range of 1.7 to 3.5 % of the corresponding 25-OHD levels throughout the study, and the two metabolites were closely correlated ( r = 0.84, p < 0.0005). The median l,25-(OH)₂D concentration was near the average of the reference range before, but increased to well above the upper limit of normal within one week of treatment (121 vs. 368 pmol/l, p < 0.01). The levels were largely normal after 10 weeks of therapy, as were the plasma concentrations of calcium, phosphate, and alkaline phosphatase. Parathyroid activity, as judged by serum parathyroid hormone or urinary cyclic AMP concentrations, was stimulated in 11 of 12 children studied prior to treatment. It is concluded that there may be no clear-cut differences between normal nad rachitic values of the different vitamin D metabolites under practical clinical conditions. A low 25-OHD level combined with evidence of a stimulated parathyroid activity, and a rise of l,25-(OH)₂D levels to supernormal values following a few days of vitamin D therapy may be diagnostic clues.     

Serum Concentrations of Vitamin D Metabolites in Exclusively Breast-Fed Infants at 70° North

ABSTRACT. The effect of prolonged breast-feeding on the serum concentrations of vitamin D metabolites, calcium, phosphate, and alkaline phosphatase was studied longitudinally in 7 infants from Northern Norway. They were exclusively breast-fed for a median of 71/2 months. Three of the mothers were supplemented with vitamin D throughout lactation. All but one of the infants had 25-hydroxyvitamin D (25-OHD) levels in the rachitic range (< 20 nmol/l) on at least one occasion. Vitamin D supplementation of the mother had no apparent effect on the infants' 25-OHD levels, but the values increased during summer. The infant who had the lowest 25-OHD levels also had decreased 1,25-dihydroxyvitamin D (1,25-(OH)₂D) concentrations, while the others maintained l,25-(OH)₂D levels within normal limits. 24,25-(OH)₂D concentrations were undetectable when the 25-OHD levels were below 35 nmol/l, but the two metabolites were closely correlated for higher values of 25-OHD. Low 25-OHD levels were associated with decreased phosphate concentrations at 6 months. The calcium levels were normal throughout the study period of one year, as were all but two of the alkaline phospatase values. Although none of the infants had clinical or biochemical evidence of rickets, the results suggest that the vitamin D supply from human milk is inadequate, and that routine vitamin D supplementation is advisable for breast-fed infants who are deprived of sunlight exposure.     

VITAMIN D METABOLISM IN HYPOPHOSPHATASIA

ABSTRACT. A 4-month-old boy with the infantile form of hypophosphatasia was followed for 9 months with measurements of serum calcium, phosphate, alkaline phosphatase and various vitamin D metabolites, together with urinary excretion of cyclic AMP. During the initial hypercalcemic stage the serum concentration of 25-hydroxyvitamin D was normal. Urinary cyclic AMP was low and the serum concentration of the dihydroxymetabolites of vitamin D were appropriate to the high serum calcium with low 1,25(OH)₂D and relatively high 24, 25(OH)₂ and 25, 26(OH)₂D levels. Due to restrictions of the vitamin D intake and lack of exposure to sun he developed vitamin D deficiency rickets at 9 months of age with very low serum concentration of 25-hydroxyvitamin D and markedly increased urinary excretion of cyclic AMP. Following vitamin D treatment the serum level of 1,25(OH)₂D showed a brisk rise to a considerably elevated value. Initially the serum concentration of alkaline phosphatase was well below the normal range, rase markedly during the stage of active rickets and returned to the characteristic low levels of hypophosphatasia with healing of the rickets.     

VITAMIN D METABOLISM IN PRETERM INFANTS

ABSTRACT. In order to evaluate after birth the changes in circulating vitamin D metabolite levels in preterm babies supplemented with vitamin D (2100 I. U./d), the serum concentration of 25-hydroxyvitamin D [25-OHD] and 1 α,25-dihydroxy vitamin D [1, 25(OH)₂D] were measured in 22 infants (31 to 35 weeks of gestation) from birth up to 96 hours of age. Compared to cord blood levels, serum calcium decreased significantly during the first 24 hours of life ( p <0.005) and remained low until day 4. Serum immunoreactive parathyroid hormone (iPTH) levels increased from birth to 24 hours and then plateaued. The 25-OHD levels at birth were 27.5±2.5 nmol/l and increased to 67.5±12.5 nmol/l ( p <0.005) during the four days of the study. During the same period, the 1, 25(OH)₂D serum levels increased steadily from 84<7 to 343<105 pmol/l ( p <0.005). At all times, there was a positive correlation between 25-OHD levels and those of 1, 25(OH)₂D. Our data demonstrate that in preterm infants after 31 weeks of gestation, absorption and activation of vitamin D is present as soon as 24 hours after birth and that early neonatal hypocalcemia is unlikely to be caused by an impairment of either PTH secretion or vitamin D activation.     

Vitamin D metabolism in biliary atresia: intestinal absorptions of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3

In children with biliary atresia, defective intestinal absorption of vitamin D and impaired hepatic uptake and 25-hydroxylation of vitamin D lead to a deficiency of vitamin D and rickets. We recently observed severe rickets in a 3-year-old boy with corrected biliary atresia resulting in jaundice, despite oral treatment with 1 alpha-hydroxyvitamin D3 (1 alpha-OHD3) or 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. He had low 25-hydroxyvitamin D (25-OHD) and high 1,25-(OH)2D serum levels. Intramuscular vitamin D2 administration produced radiological and biochemical evidence of recovery. Oral 1,25-(OH)2D3 (0.1 microgram/kg) and 25-OHD3 (10 micrograms/kg) tolerance tests were done to assess the ability to absorb vitamin D and the effectiveness of using these drugs orally. Eleven children with corrected biliary atresia, aged 9 months to 7 years, were studied. In oral 1,25-(OH)2D3 tolerance tests, the increments above the baseline serum levels of 1,25-(OH)2D were 140.7 +/- 27.4 pg/ml in nonjaundiced patients (n = 5). In jaundiced patients (n = 3), 1,25-(OH)2D3 absorption in two patients with high basal 1,25-(OH)2D values was lower than that of nonjaundiced patients; however, the absorption in the third patient with a low basal value was similar to that of nonjaundiced patients. In oral 25-OHD3 tolerance tests, the mean increase of serum 25-OHD was 48.9 +/- 30.6 ng/ml in nonjaundiced patients (n = 5) and 23.7 +/- 9.5 ng/ml in jaundiced patients (n = 4), the peak serum 25-OHD levels being reached 6-12 h after 25-OHD3 loading.(ABSTRACT TRUNCATED AT 250 WORDS)     

High Total and Free 1,25-Dihydroxyvitamin D Concentrations in Serum of Premature Infants

ABSTRACT. We investigated the relationship between serum total and free 1,25-dihydroxyvitamin D (1,25-OH₂D) and the biochemical regulation of 1,25-OH₂D production in premature infants. We measured 1,25-OH₂D, vitamin D binding protein and related biochemical parameters and calculated the free 1,25-OH₂D index in serum of 17 premature infants (birthweight 810–1700 g; gestational age 31–36 weeks) on two different occasions defined by body weight (Study A: 1750–1850 g, Study B: 2100–2200 g). Dietary calcium (Ca) intake was 1,5 or 2,6 mmol/kg/d, phosphorus (P) intake 1,7 mmol/kg/d and vitamin D intake 1000 IU/d. Biochemical results were similar in infants with different Ca intakes and all were within reference ranges. Concentrations of vitamin D binding protein (Study A 0.15±0.03 g/1, Study B 0.14±0.03 g/1; ± SD) were lower, concentrations of 1,25(OH)₂D (Study A 180±67 pmol/1, Study B 216±53 pmol/1) were higher, and consequently the free 1,25-OH₂D index (Study A 6.6±2.7, Study B 8.8±2.6) was 4 to 6 times higher than in previously studied term infants. 1,25-OH₂D and the free 1,25-OH₂D index increased significantly with age and were not correlated with serum P or parathyroid hormone. The data indicate that in premature infants with normal biochemical parameters of Ca and P metabolism elevated concentrations of 1,25-OH₂D signify an increased fraction of free 1,25-OH₂D and that increased production of 1,25-OH₂D is not due to hypophosphatemia or hyperparathyroidism.     

REDUCED SERUM 1,25-(OH)2 VITAMIN D3 LEVELS IN PREDNISONE-TREATED ADOLESCENTS WITH SYSTEMIC LUPUS ERYTHEMATOSUS

Abstract. The serum levels of 1,25-(OH)₂ vitamin D₃ were assayed in samples from 12 adolescent patients with SLE. Subnormal levels were observed in 7 of these 12 patients. Low levels of the metabolically active polar metabolite of vitamin D₃ may contribute to the development of osteopenia observed in this disease. The cumulative effects of the osteoporotic and anti vitamin D effects of long term steroid therapy in children with SLE may require the cautious administration of supplemental vitamin D.     

LEVELS OF VITAMIN D-METABOLITES IN A CASE OF ACRO-OSTEOLYSIS SYNDROME

ABSTRACT. On the initial examinations of a 17-year-old boy with acro-osteolysis syndrome, the levels of serum 25-hydroxycholecalciferol (25OHD) were low, whereas serum levels of 1,25-dihydroxycholecalciferol (1,25(OH)₂D) were normal. Administration of 1α-hydroxycholecalciferol (1OHD) failed to improve the osteoporosis, although the serum 25OHD level rose to normal. It is unlikely that impaired bone remodeling due to abnormal vitamin D-metabolism was a primary defect in our patient.     

Premature Cranial Synostosis in X-Linked Hypophosphatemic Rickets: Possible Precipitation by 1-alpha-OH-Cholecalciferol Intoxication

ABSTRACT. A child suffering from X-linked hypophosphatemic rickets developed vitamin D intoxication under treatment with 1-alpha-OH-cholecalciferol (1(OH)D₃) and phosphorus. Beside the usual findings in this condition he showed precocious synostosis of the skull with signs of raised intracranial pressure. In view of earlier reports of coincidence of craniostenosis and X-linked hypophosphatemic rickets, we conclude that the possibility exists that intoxication with 1(OH)D₃ has been the precipitating factor. In addition we found hypersensitivity to 1 (OH)D₃ 2 months after cessation of treatment, and normal levels of calcitriol (1,2S(OH)₂D₃) at the same time.     

1,25-Dihydroxyvitamin D3 in childhood hepatic osteodystrophy.

Osteodystrophy frequently accompanies severe childhood hepatobiliary disease. Proposed causes include malabsorption of vitamin D and calcium, and diminished 25-hydroxylation of vitamin D. Two children, ages 23 and 35 months, with radiographic and biochemical evidence of rickets with extrahepatic biliary atresia, were treated with 1,25-dihydroxyvitamin D3. The minimal effective therapeutic dose and efficacy of 1,25-(OH)2D3 in the treatment of rickets associated with severe childhood hepatic disease were determined. Oral 1,25-(OH)2D3 was ineffective at doses of 0.10 microgram/kg/day. Parenteral doses of 0.20 microgram/kg/day effectively produced radiographic, bone mineral (photon absorptiometric), and biochemical evidence of healing. The need for four times the physiologic dose of 1,25-(OH)2D3 by the parenteral route suggested enhanced catabolism of, or end-organ resistance to, 1,25-(OH)2D3 in our patients with severe cholestatic liver disease treated with phenobarbital.     

Low vitamin D status is associated with low cord blood levels of the immunosuppressive cytokine interleukin-10

The cytokine interleukin-10 (IL-10) plays a pivotal regulatory role in tolerizing exogenous antigens. Experimental data indicate that low cellular availability of the vitamin D hormone 1,25-dihydroxyvitamin D [1,25(OH)2D] results in a down-regulation of IL-10 concentrations. The tissue production of an adequate amount of 1,25(OH)2D depends on a high circulating 25-hydroxyvitamin D (25-OHD) level. The present study was thus aimed at evaluating the associations between season of birth, vitamin D status, and the allergy risk markers IL-10 and total immunoglobulin (IgE) in newborns. Cord blood was obtained from 49 infants born during the summer half year (mid-April to mid-October, geographic latitude 51 degrees N) and from 47 infants born during the winter half year (mid-October to mid-April, geographic latitude of 51 degrees N). Serum levels of 25-OHD were 99% higher, and IL-10 levels were 43% higher in the summer half year compared with the winter half year (p < 0.001 and p = 0.018). Moreover, the ratio of IL-10 to total IgE was 124% higher in the summer half year compared with the winter half year (p = 0.039). Serum levels of 25-OHD were correlated with IL-10 levels (r = +0.22; p < 0.05). Mothers' age, gestational ages, birth weights and serum 1,25(OH)2D levels did not differ between study groups. We conclude that the low vitamin D status of infants born in winter may at least in part adversely affect biomarkers of allergy risk.     

THE PLASMA LEVELS OF 25-HYDROXYVITAMIN D IN PATIENTS WITH VARIOUS LIVER DISEASES AND THE RESPONSE OF 25-HYDROXYVITAMIN D TO VITAMIN D TREATMENT

ABSTRACT. 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 <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 <0.05). In patients with congenital biliary atresia, vitamin D treatment did not affect the plasma levels of 25-OH-D.     

Effect of Long-Term Treatment with Massive Doses of 1α-Hydroxyvitamin D3 on Calcium-Phosphate Balance in Patients with Vitamin D-Dependent Rickets Type II

Three patients with vitamin D-dependent rickets type II were given massive doses of 1α-hydroxyvitamin D₃ for 29 to 36 months and their calcium-phosphate balance was studied during treatment and one month after cesation of treatment. During treatment fasting hypercalciuria was observed in patient 1 and an increased rate of calcium excretion after calcium loading in patients 1 and 2. In these patients, calcium excretion was parallel with the serum 24, 25-dihydroxyvitamin D. These findings suggested that the responsiveness to 1,25-dihydroxyvitamin D improved during long-term treatment of these two patients with vitamin D-dependent rickets type II.     

The association between ketoacidosis and 25(OH)-vitamin D levels at presentation in children with type 1 diabetes mellitus

Background:  There is considerable evidence supporting the role of vitamin D deficiency in the pathogenesis of type 1 diabetes mellitus (T1DM). Vitamin D deficiency is also associated with impairment of insulin synthesis and secretion. There have been no formal studies looking at the relationship between 25(OH)-vitamin D₃ and the severity of diabetic ketoacidosis (DKA) in children at presentation with T1DM.
Objective:  To determine the relationship between measured 25(OH)-vitamin D₃ levels and the degree of acidosis in children at diagnosis with T1DM.
Subjects:  Children presenting with new-onset T1DM at a tertiary children's hospital.
Methods:  25(OH)-vitamin D₃ and bicarbonate levels were measured in children at presentation with newly diagnosed T1DM. Those with suboptimal 25(OH)-vitamin D₃ levels (<50 nmol/L) had repeat measurements performed without interim vitamin D supplementation.
Results:  Fourteen of the 64 children had low 25(OH)-vitamin D₃ levels at presentation, and 12 of these had low bicarbonate levels (<18 mmol/L) (p = 0.001). Bicarbonate explained 20% of the variation in vitamin D level at presentation (partial r² = 0.20, p < 0.001) and ethnic background a further 10% (partial r² = 0.10, p = 0.002). The levels of 25(OH)-vitamin D₃ increased in 10 of the 11 children with resolution of the acidosis.
Conclusions:  Acid–base status should be considered when interpreting 25(OH)-vitamin D₃ levels in patients with recently diagnosed T1DM. Acidosis may alter vitamin D metabolism, or alternatively, low vitamin D may contribute to a child's risk of presenting with DKA.     

Nephrocalcinosis, Hypercalciuria and Elevated Serum Levels of 1,25-Dihydroxyvitamin D in Children Possible Link to Vitamin D Toxicity

ABSTRACT. Ten children, age 1 1/2 to 14 years, had bilateral nephrocalcinosis and hypercalciuria, but normal serum calcium (Ca) and phosphate (P) concentrations. Patients with hypercalciuria were divided into absorptive (n=4) and renal (n=6) subgroups, and in the latter four patients had a primary Ca-leak and two had a P-leak. All the children had received intermittent high dose vitamin D prophylaxis during infancy. At the time of investigation all had normal serum levels of 25-hydroxyvitamin D, yet all but one had elevated values of 1, 25-(OH)₂D. Although the hypercalciuria was indistinguishable from the various known forms of idiopathic hypercalciuria, the previous clinical course and the pattern of bone mineral homeostasis suggest that both clinical features, namely nephrocalcinosis and hypercalciuria were related to vitamin D toxicity through various pathogenetic pathways.     

Serum vitamin D metabolites in very low birth weight infants with and without rickets and fractures

Seventy-one very low birth weight (less than or equal to 1500 gm) infants were studied to determine the sequential changes in serum vitamin D metabolite concentrations between infants with and without radiographically documented rickets, fractures, or both (R/F). Usual intake of vitamin D included 20 IU/kg/day from parenteral nutrition or 400 IU/day supplementation with enteral feeding. Radiographs of both forearms and serum samples were obtained at 3, 6, 9, and 12 months. Twenty-two infants had R/F. At 3 months, significantly lower mean (+/- SEM) serum phosphorus levels (4.5 +/- 0.4 vs 6.1 +/- 0.2 mg/dl), higher 1,25-dihydroxyvitamin D (1,25-[OH]2D) concentrations (96 +/- 5 vs 77 +/- 4 pg/ml), and higher free 1,25-(OH)2D index (1,25-[OH]2D:vitamin D binding protein ratio; 5.2 +/- 0.3 x 10(5) vs 4.0 +/- 0.2 x 10(5] were found in the R/F group. These values returned to normal and were similar between groups on subsequent measurements. Serum calcium, magnesium, and 25-hydroxyvitamin D (25-OHD) concentrations were normal and similar between groups. In both groups, serum vitamin D binding concentrations increased initially but remained stable and normal beyond 6 months. We conclude that in very low birth weight infants with R/F, the vitamin D status (as indicated by serum 25-OHD concentrations) is normal, and that lowered serum phosphorus levels, higher serum 1,25-(OH)2D levels, and a higher free 1,25-(OH)2D index support the thesis that mineral deficiency (especially of phosphorus) may be important in the pathogenesis of R/F in small preterm infants.     

Nutritional and metabolic rickets

Nutritional rickets is casued by vitamin D deficiency due to lack of exposure to sunlight. Neonatal rickets occurs only in infants born to mothers with very severe osteomalacia. Calcium deficiency alone does not cause mineralisation defects. It only causes osteoporosis and secondary hyperparathyroidism with raised plasma, 1,25 (OH)₂D and osteocalcin. Low 25-OHD, increased IPTH, increased alkaline phosphatase in plasma and decreased calcium and increased hydroxyproline in urine are diagnostic of rickets. Low or undetectable plasma levels of 25-OHD, in presence of high plasma 1,25(OH)₂D and IPTH are often observed during treatment with vitamin D. Even the marginal intakes of fluoride (> 2.5 mg/day) cause rickets in calcium deficient children. Indian children often need high dose of vitamin D due to severely depleted D stores, high IPTH and severe bone disease (radiologic and histomorphometric) for treatment.     

25-Hydroxycholecalciferol inthe management of rickets associated with extrahepatic biliary atresia.

In children with extrahepatic biliary atresia, impaired hydroxylation and defective intestinal absorption of cholecalciferol may lead to a deficiency of vitamin D and rickets. The data presented herein demonstrate that in such patients serum levels of vitamin D measured as 25-hydroxycalciferol are reduced. A moderate therapeutic oral dose of 25-hydroxycholecalciferol, by circumventing the hepatic conversion of cholecalciferol to 25-hydroxycholecalciferol, will replete vitamin D stores and maintain the serum concentration of 25-hydroxycalciferol required to prevent or heal rickets in these patients.     

EFFECT OF PORCINE CALCITONIN THERAPY ON VITAMIN D METABOLISM AND CLINICAL RESPONSE IN A PATIENT WITH OSTEOGENESIS IMPERFECTA

ABSTRACT. A 1 11/12-year-old girl with osteogenesis imperfecta was treated with porcine calcitonin. Eight bone fractures occurred in the previous 20 months before therapy, but none occurred during eight months of therapy. There was also a significant improvement in linear growth and radiographic bone density. This is the first study of the effect of calcitonin on vitamin D metabolism in a human. The high plasma levels of 1,25 dihydroxy-vitamin D (1,25-(OH)₂-D) and 24,25 dihydroxy-vitamin D (24,25-(OH)₂-D) before calcitonin therapy decreased after therapy. Plasma 25 hydroxy-vitamin D (25-OH-D) concentration, which normal in level before calcitonin therapy, was normal or slightly decreased during administration. It is concluded that calcitonin probably influences vitamin D metabolism in a patient with osteogenesis imperfecta.