Elevated serum vitamin B12 in cystic fibrosis

In 62 patients with cystic fibrosis the serum vitamin B12 concentration ranged from 160-2600 pmol/l with a mean of 1 105 pmol/l. Both vitamin B12-binding proteins in the serum, transcobalamin II and R-binders, carried increased amounts of vitamin B12, but showed relatively normal levels of unsaturated vitamin B12-binding capacity. This combination is rather typical for hepatic dysfunction, although the recurrent pulmonary infections might exert an upward effect on plasma R-binder concentration through increased turnover of myeloid cells. A significant positive correlation between transcobalamin II-vitamin B12 and serum alkaline phosphatase suggests that transcobalamin II-bound vitamin B12 might be an early indicator of focal biliary cirrhosis, which is known to occur in these patients.     

Serum vitamin B12-binding proteins in a case of eosinophilic leukemia.

A patient with subacute eosinophilic leukemia is presented, with full recognition of the controversy surrounding that entity. Serum vitamin B12 and B12-binding protein studies and simultaneous complete blood counts were done before and during 6 months of high-dose, intermittent combination chemotherapy. The patient presented with extremely high levels of serum vitamin B12, unsaturated B12-binding capacity, and transcobalamin I, all of which resembled the highest values seen in chronic myelogenous leukemia. Serial studies, during and after remission induction, showed a precipitous fall of serum vitamin B12 and unsaturated B12-binding capacity to normal levels. The data show that transcobalamin I levels, which eventually reached low-normal range, correlate best with the level of circulating and bone marrow eosinophils. Transcobalamin II and serum third binder appeared to be normal throughout the patient's course. The B12-binding protein abnormalities are not considered diagnostic of eosinophilic leukemia.     

Vitamin B12 absorption in cystic fibrosis

Vitamin B12 absorption was measured in 30 patients with cystic fibrosis by means of the urinary excretion method and found to be impaired, i.e. less than 10%, in 25. The mean urinary excretion amounted to 4.7 +/- 0.8%. In all patients vitamin B12 absorption improved by the addition of trypsin (18.9 +/- 2.1%). Addition of the vitamin B12 analogue cobinamide, which prevents vitamin B12-binding by R-binders, raised the vitamin B12 absorption to 15.0 +/- 2.2%. A further improvement was obtained by the simultaneous addition of cobinamide and trypsin, 18.2 +/- 2.6%, the same value as with trypsin alone. Assuming that cobinamide addition was effective in suppressing all R-binder activity, the additional effect of trypsin suggests a second, stimulatory function of trypsin on vitamin B12 absorption, separate from R-binder-inactivation. In 5 patients only marginal improvement of vitamin B12 absorption was gained by the addition of either trypsin or cobinamide. The deficient serum vitamin B12 (110 pmol/l) in one of them indicates that the normal pancreas-substitution therapy not always implies sufficient restoration of vitamin B12 absorption.     

Serum vitamin B12-binding proteins in a case of eosinophilic leukemia

A patient with subacute eosinophilic leukemia is presented, with full recognition of the controversy surrounding that entity. Serum vitamin B₁₂ and B₁₂ -binding protein studies and simultaneous complete blood counts were done before and during 6 months of high-dose, intermittent combination chemotherapy. The patient presented with extremely high levels of serum vitamin B₁₂, unsaturated B₁₂-binding capacity, and transcobalamin I, all of which resembled the highest values seen in chronic myelogenous leukemia. Serial studies, during and after remission induction, showed a precipitous fall of serum vitamin B₁₂ and unsaturated B₁₂-binding capacity to normal levels. The data show that transcobalamin I levels, which eventually reached low-normal range, correlate best with the level of circulating and bone marrow eosinophils. Transcobalamin II and serum third binder appeared to be normal throughout the patient's course. The B₁₂-binding protein abnormalities are not considered diagnostic of eosinophilic leukemia.     

Vitamin B12 Absorption in Cystic Fibrosis

Vitamin B12 absorption was measured in 30 patients with cystic fibrosis by means of the urinary excretion method and found to be impaired, i.e. less than 10%, in 25. The mean urinary excretion amounted to 4.7 ± 0.8 %. In all patients vitamin B12 absorption improved by the addition of trypsin (18.9 ± 2.1 %). Addition of the vitamin B12 analogue cobinamide, which prevents vitamin B12-binding by R-binders, raised the vitamin B12 absorption to 15.0 ± 2.2 %. A further improvement was obtained by the simultaneous addition of cobinamide and trypsin, 18.2 ± 2.6 %, the same value as with trypsin alone. Assuming that cobinamide addition was effective in suppressing all R-binder activity, the additional effect of trypsin suggests a second, stimulatory function of trypsin on vitamin B12 absorption, separate from R-binder-inactivation. In 5 patients only marginal improvement of vitamin B12 absorption was gained by the addition of either trypsin or cobinamide. The deficient serum vitamin B12 (110 pmol/I) in one of them indicates that the normal pancreas-substitution therapy not always implies sufficient restoration of vitamin B12 absorption.     

Homocysteine and other vascular risk factors in patients with phenylketonuria on a diet

The aim of this study was to investigate the known risk factors, such as lipids, homocysteine and endothelin, for the development of coronary artery disease (CAD) in phenylketonuria (PKU) patients, depending on their diet. The PKU patients (n = 74) were divided into two groups. Group A (n = 34; mean age 6.78 +/- 1.5 y) adhered strictly to a diet and group B (n = 40; mean age 8.0 +/- 3.2 y) did not comply with the diet. The control group comprised 50 healthy non-PKU children. All groups were evaluated for blood levels of homocysteine and vitamin B6 by high-performance liquid chromatography, vitamin B12 and folate in serum by a radioassay, lipids by a routine method, and lipoprotein(a) and endothelin-1 with an immunoassay. Homocysteine levels (28.65 +/- 3.3 micromol l(-1)) were increased in group A compared with group B (6.86 +/- 1.6 micromol l(-1)) and the controls (6.9 +/- 2.0 micromol l(-1)) (p < 0.001). Vitamin B6 (10.7 +/- 10.9 nmol l(-1)), vitamin B12 (98.5 +/- 22.3 pmol l(-1)), folate (2.35 +/- 1.3 nmol l(-1)) and lipids were decreased in group A. The other vascular risk factors, which were not dependent on diet [lipoprotein(a) and endothelin-1], did not differ among the three groups. Conclusion: PKU patients on a strict diet had low vitamin B6, vitamin B12 and folate levels resulting in moderate hyperhomocysteinaemia. The evaluation of these vitamins at short intervals and their supplementation could be an early measure in the prevention of CAD.     

High total and free 1,25-dihydroxyvitamin D concentrations in serum of premature infants

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: 1,750-1,850 g, Study B: 2,100-2,200 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 1,000 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/l, Study B 0.14 +/- 0.03 g/l; means +/- SD) were lower, concentrations of 1,25 (OH)2D (Study A 180 +/- 67 pmol/l, Study B 216 +/- 53 pmol/l) 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.     

Utility of breath ethane as a noninvasive biomarker of vitamin E status in children.

The purpose of our study was to determine if the ethane content of expired air could be a useful index of vitamin E status in children. Eight children with vitamin E deficiency secondary to chronic severe liver disease were studied: six of these children were treated with parenteral vitamin E (2-5 mg/kg/dose every 4-7 d). Measures of vitamin E status pre- and posttherapy were: serum vitamin E, 2 +/- 1 versus 7 +/- 1 micrograms/mL (p less than 0.001); serum vitamin E:total lipids, 0.3 +/- 0.1 versus 1.0 +/- 0.1 mg/g (p less than 0.001); and erythrocyte peroxide hemolysis test, 80 +/- 10 versus 6 +/- 12% (p less than 0.001). Fasting breath ethane in the patients pre- and posttherapy was 78 +/- 10 versus 31 +/- 11 pmol/kg/min (p less than 0.001). Breath ethane correlated negatively with serum vitamin E (p less than 0.042) and serum E:total lipids (p less than 0.004) and positively with the erythrocyte peroxide hemolysis test (p less than 0.003). Values for treated patients did not differ from those for fasted sibling controls (34 +/- 12 pmol/kg/min), postprandial sibling controls (31 +/- 12 pmol/kg/min), and healthy children sampled randomly, in the nonfasted state (21 +/- 14 pmol/kg/min). Breath ethane production in one patient (up to 168 pmol/kg/min) did not normalize after treatment of vitamin E deficiency until her selenium deficiency was corrected as well. We conclude that this noninvasive test can be useful as a screen for vitamin E deficiency in children and for ascertaining response to therapy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Transcobalamin I as a “marker” for fibrolamellar hepatoma

A 12 year old girl with a localised fibrolamellar hepatoma had a raised serum unsaturated vitamin B12 binding capacity (UBBC) and transcobalamin I (TCI) prior to complete resection and chemotherapy. Regular clinical and radiological follow-up detected no recurrence of her disease, but the UBBC and TCI slowly rose. Local recurrence and pulmonary metastases became detectable 2 1/2 years after diagnosis, 18 months after the UBBC and TCI level became elevated. Measurement of UBBC and TCI can help in the early detection of recurrence long before there is clinical or radiological evidence of recurrent fibrolamellar hepatoma.     

Nutrient levels in amniotic fluid from women with normal and neural tube defect pregnancies.

We analyzed nutrient levels in amniotic fluid obtained during the second trimester of normal, uncomplicated pregnancies from 221 women who delivered apparently healthy infants and from 8 with neural tube defect (NTD) pregnancies. Folate was measured by microbiological assay, vitamin B12 by a radiobinding method, and zinc, copper and iron by atomic absorption spectrophotometry. We found that the mean amniotic fluid nutrient levels of normal pregnancies were 24.7 nmol/l for folate, 600 pmol/l for vitamin B12, and 1.7, 1.9, and 9.0 mumol/l for zinc, copper and iron, respectively. Amniotic fluid folate, zinc, copper and iron levels of NTD pregnancies were similar to those found during normal pregnancy, however, vitamin B12 levels were markedly lower than those of normal pregnancies.     

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.     

Transcobalamin I as a "marker" for fibrolamellar hepatoma

A 12 year old girl with a localised fibrolamellar hepatoma had a raised serum unsaturated vitamin B12 binding capacity (UBBC) and transcobalamin I (TCI) prior to complete resection and chemotherapy. Regular clinical and radiological follow-up detected no recurrence of her disease, but the UBBC and TCI slowly rose. Local recurrence and pulmonary metastases became detectable 2 1/2 years after diagnosis, 18 months after the UBBC and TCI level became elevated. Measurement of UBBC and TCI can help in the early detection of recurrence long before there is clinical or radiological evidence of recurrent fibrolamellar hepatoma.     

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.     

Ileal Enterocystoplasty and B12 Deficiency in Pediatric Patients

PurposeVitamin B12 deficiency is a feared complication of enterocystoplasty, but it has never been demonstrated in pediatric patients who have undergone ileal enterocystoplasty. We reviewed our series of over 500 bladder augmentations in an attempt to define the timing and risk of vitamin B12 deficiency in pediatric patients after bladder augmentation.Material and MethodsFrom October 2004 to present, we obtained serum B12 values on patients who had undergone bladder augmentation at our institution. We looked at patients who had an ileal enterocystoplasty and who were 18 years or younger at the time of augmentation. Any B12 value that was obtained while on any form of B12 supplementation was excluded. These criteria resulted in 79 patients with 105 B12 values. B12 values less than 200 pg/mL were considered “low” and values between 201–300 pg/mL were considered “low-normal.”ResultsThere was a statistically significant correlation between follow-up time and serum B12 (p = 0.0001). The probability of “low” B12 increased as follow-up time increased (p = 0.007), as well as the probability of “low-normal” B12 with longer follow-up time (p = 0.005). Starting at 7 years post-operatively, 6 of 29 patients (21%) had low B12 values, while 12 of 29 patients (41%) had low-normal values.ConclusionsPediatric patients who have undergone ileal enterocystoplasty are at risk for developing vitamin B12 deficiency. These patients are at the highest risk beginning at 7 years post-operatively, and their risk increases with time. We recommend an annual serum B12 value beginning at 5 years following bladder augmentation in children.     

Severe hypercalcemia of an infant due to vitamin D toxicity associated with hypercholesterolemia

We report an 11 month-old infant with severe hypercalcemia associated with hyperlipidemia following bolus vitamin D administration. At the time of admission, serum concentration of calcium was 5.5 mmol/l (22 mg/dl); total cholesterol, high density lipoprotein cholesterol (HDL-C), very low density lipoprotein (VLDL), low density lipoprotein cholesterol (LDL-C), and triglyceride levels were respectively: 6.37 mmol/l (246 mg/dl), 0.77 mmol/l (30 mg/dl), 1.37 mmol/l (54 mg/dl), 4.1 mmol/l (162 mg/dl), 3 mmol/l (271 mg/dl). Physical examination revealed dehydration and irritability that was inappropriately mild according to the serum calcium level. On the 16th day of therapy that consisted of intravenous fluids with furosemide (sodium diuresis), steroid, calcitonin, magnesium sulfate, and phosphorus, serum calcium level declined below 3 mmol/l (12 mg/dl). The hyperlipidemia resolved gradually with a concomitant decline in serum calcium. This report is interesting in that hypercalcemia was associated with transient hyperlipidemia that disappeared with normocalcemia, which might suggest protection against hypercalcemic symptoms.     

Hypovitaminosis D among healthy adolescent girls attending an inner city school.

AIMS: To determine the prevalence of hypovitaminosis D among healthy adolescent schoolgirls attending an inner city multiethnic girls' school. METHODS: Fifty one (28%) of 182 girls (14 white, 37 non-white; median age 15.3 years, range 14.7-16.6) took part in the study. Biochemical parameters, dietary vitamin D intake, muscle function parameters, duration of daily sunlight exposure (SE), and percentage of body surface area exposed (%BSA) were measured. RESULTS: Thirty seven (73%) girls were vitamin D deficient (25-hydroxyvitamin D (25OHD) <30 nmol/l) and 9 (17%) were severely deficient (25OHD <12.5 nmol/l). The median (range) 25OHD concentration of white girls (37.3 nmol/l (18.3-73.3)) was higher than that of non-white girls (14.8 nmol/l (5.8-42.8)). The median (range) concentration of parathyroid hormone in white girls (2.8 pmol/l (1.0-3.7)) was lower than that of non-white girls (3.4 pmol/l (1.7-34.2)). Serum Ca, inorganic phosphate, alkaline phosphatase, and 1,25-dihydroxyvitamin D were not different in white and non-white girls. For the whole group, 25OHD concentration was related to the estimated SE and %BSA, but not to estimated intake of vitamin D. In white girls, the estimated SE and %BSA were significantly higher than that of non-white girls. The median times taken to complete the Gower's manoeuvre and grip strength were not different in the two groups; these variables were not related to serum 25OHD. CONCLUSIONS: Hypovitaminosis D is common among healthy adolescent girls; non-white girls are more severely deficient. Reduced sunshine exposure rather than diet explains the difference in vitamin D status of white and non-white girls.     

Imerslund-Grasbeck syndrome associated with recurrent aphthous stomatitis and defective neutrophil function

Vitamin B(12) deficiency is a well-known cause of recurrent aphthous stomatitis (RAS). However, the mechanism by which this deficiency causes the stomatitis is not well understood. Imerslund-Grasbeck syndrome (IGS) causes vitamin B(12) deficiency and proteinuria due to a defect in the vitamin B(12) receptor. We sought to determine whether the RAS observed in IGS patients is associated with neutrophil dysfunction. We report 3 infants with vitamin B(12) deficiency due to IGS, who presented with borderline or normal hemoglobin concentrations, RAS, and a neutrophil function defect. All 3 patients were homozygous for a splice site mutation affecting exon 4 of the AMN gene. A direct correlation was observed between low serum vitamin B12 levels and defective neutrophil function (low chemotaxis and elevated superoxide production) in the patients. Vitamin B(12) therapy led to an immediate resolution of aphthous stomatitis and full correction of neutrophil function. We demonstrated that serum vitamin B(12) deficiency is associated with a neutrophil chemotactic defect and RAS in IGS patients. We suggest that the RAS observed in these patients is due to this defect.     

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.     

Severe hypercalcemic crisis in an infant with idiopathic infantile hypercalcemia caused by mutation in CYP24A1 gene

We report on a male infant presenting at 4 months of age with failure to thrive, dehydration, hypotonia, lethargy, and vomiting. Laboratory and imaging tests revealed severe hypercalcemia (5.8 mmol/l), suppressed parathyroid hormone (0.41 pmol/l), hypercalciuria (8.0 mmol/mmol creatinine), elevated 25-hydroxyvitamin D3 (over 600 nmol/l), and nephrocalcinosis. These symptoms are characteristic of idiopathic infantile hypercalcemia (IIH, MIM 143880). Conservative therapy (parenteral rehydration, diuretics, corticosteroids, bisphosphonates, and vitamin D prophylaxis withdrawal) was not able to improve the symptoms and laboratory values, and acute hemodiafiltration was necessary to normalize hypercalcemia. Clinical symptoms resolved rapidly after normalization of serum calcium levels. Molecular genetic testing revealed a homozygous mutation (R396W) in the CYP24A1 gene (MIM 126065) encoding 25-hydroxyvitamin D3 24-hydroxylase, which is the key enzyme responsible for 1,25-dihydroxyvitamin D3 degradation. The CYP24A1 gene mutation leads to the increased sensitivity of the patients to even prophylactic doses of vitamin D and to the development of severe symptomatic hypercalcemia in patients with IIH. Conclusion: Our patient is only the thirteenth patient with IIH caused by mutation in the CYP24A1 gene and the first one needing acute hemodiafiltration for severe symptomatic hypercalcemic crisis. In all patients with suspected IIH the DNA analysis for CYP24A1 gene mutations should be performed regardless of the type of vitamin D supplementation and serum levels of vitamin D.