scholarly journals Detectable Unmetabolized Folic Acid, and Sufficient Folate and Vitamin B12 Concentrations Are Evident in Canadian Children with Sickle Cell Disease

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1100-1100
Author(s):  
Brock Williams ◽  
Heather McCartney ◽  
Yvonne Lamers ◽  
Suzanne Vercauteren ◽  
John Wu ◽  
...  
Keyword(s):  
Folic Acid ◽  
Sickle Cell Disease ◽  
Vitamin B12 ◽  
Sickle Cell ◽  
Vitamin B6 ◽  
Serum Folate ◽  
High Dose ◽  
Cell Disease ◽  
Median Serum ◽  
B Vitamin

Abstract Objectives Canadian children with sickle cell disease (SCD) are routinely supplemented with high-dose folic acid (1 mg/d), synthetic folate, due to increased erythrocyte production and turn-over in the disease. Folate also plays a vital role in one-carbon metabolism. Impairments in this folate-dependent mechanism can also occur due to secondary B-vitamin (vitamin B2, B6 and B12) deficiencies. The study objective was to determine B-vitamin status in Canadian children with SCD. Methods Serum and plasma samples from children diagnosed with SCD were obtained from BC Children's Hospital BioBank (Vancouver, Canada). Samples were analyzed for folate, vitamin B6, and related metabolites using electrospray ionization-liquid chromatography-tandem mass spectrometry. Vitamin B12 concentrations were analyzed using chemiluminescent immunoassay. World Health Organization cut-offs were used to determine deficiencies of folate (<10 nmol/L) and vitamin B12 (<150 pmol/L), and European Food Safety Authority Panel cut-offs were used for vitamin B6 (<30 nmol/L pyridoxal 5’-phosphate; PLP). Medians with interquartile ranges (IQR) are presented. Results Six individuals (50% male; SCD type: Hgb SS n = 3, Hgb SC n = 2, HbSβ,0-Thal n = 1) were included. Median age of participants was 15 (9, 18) years. Half (50%) of participants were prescribed hydroxyurea (median dose: 21(14, 30) mg/kg/d), and all participants were prescribed 1 mg/d folic acid (adherence data not available). Median serum folate was 55.4 (43.1, 71.9) nmol/L, with levels 3 to 15 times above the cut-off for deficiency. Unmetabolized folic acid (UMFA), unused folic acid in circulation, was detected in all six participants. All participants were vitamin B12 sufficient, with median plasma vitamin B12 of 325 (288, 411) nmol/L. The majority (n = 5; 83%) had sufficient B6 status, with median serum PLP of 39 (36.9, 44.2) nmol/L. Conclusions In this pilot project, there was limited evidence of B-vitamin deficiencies among Canadian children with SCD. Serum folate levels exceeded the cut-off for deficiency by 3 to 15 times, with all participants having detectable levels of UMFA. A randomized clinical trial re-assessing the routine practice of high-dose folic acid supplementation in children with SCD is warranted. Funding Sources Thrasher Research Fund and Rare Disease Foundation.

Optimization of folic acid, vitamin B12, and vitamin B6 supplements in pediatric patients with sickle cell disease

2002 ◽  
Vol 69 (4) ◽  
pp. 239-246 ◽  
Author(s):  
Fey P.L. van der Dijs ◽  
M. Rebecca Fokkema ◽  
D.A. Janneke Dijck-Brouwer ◽  
Bram Niessink ◽  
Thaliet I.C. van der Wal ◽  
...  
Keyword(s):  
Folic Acid ◽  
Sickle Cell Disease ◽  
Vitamin B12 ◽  
Sickle Cell ◽  
Vitamin B6 ◽  
Pediatric Patients ◽  
Cell Disease

scholarly journals Detectable Unmetabolized Folic Acid and Elevated Folate Concentrations in Folic Acid-Supplemented Canadian Children With Sickle Cell Disease

2021 ◽  
Vol 8 ◽  
Author(s):  
Brock A. Williams ◽  
Cara Mayer ◽  
Heather McCartney ◽  
Angela M. Devlin ◽  
Yvonne Lamers ◽  
...  
Keyword(s):  
Folic Acid ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Routine Practice ◽  
Cell Disease ◽  
Gene Encoding ◽  
Vitamin Deficiencies ◽  
Vitamin Status ◽  
Vitamin B 12 ◽  
B Vitamin

Sickle cell disease (SCD) is an inherited hemoglobinopathy caused by a variant (rs344) in the HBB gene encoding the β-globin subunit of hemoglobin. Chronic hemolytic anemia and increased erythropoiesis and RBC turnover in individuals with SCD can result in increased needs for folate and other B-vitamins. We assessed B-vitamin status, and the distribution of folate forms, including unmetabolized folic acid (UMFA), in Canadian children with SCD supplemented with 1 mg/d folic acid (current routine practice). Non-fasted serum and plasma samples were analyzed for concentrations of folate, and vitamins B-2, B-6, and B-12. Eleven individuals (45% male; SCD type: HbSS n = 8, HbSC n = 2, HbSβ0-Thal n = 1), with a median (IQR) age of 14 (7, 18) years, were included. Total folate concentrations were 3–27 times above the deficiency cut-off (10 nmol/L), and 64% of children had elevated folate levels (>45.3 nmol/L). UMFA (>0.23 nmol/L) was detected in all children, and 36% of participants had elevated levels of UMFA (>5.4 nmol/L). All children were vitamin B-12 sufficient (>150 pmol/L), and the majority (55%) had sufficient B-6 status (>30 nmol/L). Among this sample of Canadian children with SCD, there was limited evidence of B-vitamin deficiencies, but UMFA was detectable in all children.

scholarly journals Folic Acid Supplementation in Children with Sickle Cell Disease: Study Protocol for a Double-Blind Randomized Cross-Over Trial

2020 ◽  
Author(s):  
Brock A Williams ◽  
Heather McCartney ◽  
Erin Adams ◽  
Angela M Devlin ◽  
Joel Singer ◽  
...  
Keyword(s):  
Folic Acid ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Biological Effects ◽  
Genetic Disorder ◽  
Folic Acid Supplementation ◽  
High Dose ◽  
Cell Disease ◽  
Double Blind ◽  
Acid Supplementation

Abstract • Background: Sickle cell disease (SCD) is a genetic disorder which causes dysfunctional red blood cells (RBC) and is thought to increase requirements for folate, an essential B-vitamin, due to increased RBC production and turn-over in the disease. High-dose supplementation with 1-5mg/d folic acid, synthetic folate, has been the standard recommendation for children with SCD. There is concern about whether children with SCD need such high doses of folic acid, following mandatory folic acid fortification of enriched grains in Canada, and advancements in medical therapies which extend the average lifespan of RBCs. In animal and human studies, high folic acid intakes (1 mg/d)have been associated with accelerated growth of some cancers, and the biological effects of circulating unmetabolized folic acid (UMFA), which can occur with doses of folic acid ≥0.2mg/d, are not fully understood. The objective of this study is to determine efficacy and alterations in folate metabolism of high-dose folic acid in children with SCD during periods of folic acid supplementation versus no supplementation• Methods: In this double-blind randomized controlled cross-over trial, children with SCD (n=36, aged 2-19 y)will be randomized to either receive 1 mg/d folic acid, the current standard of care, or a placebo for 12-weeks. After a 12-week washout period, treatments will be reversed. Total folate concentrations (serum and RBC), different folate forms (including UMFA), folate-related metabolites, and clinical outcomes will be measured at baseline and after treatment periods. The sum of the values measured in the two periods will be calculated for each subject and compared across the two sequence groups by means of a test for independent samples for the primary (RBC folate concentrations) and secondary (UMFA) outcomes. Dietary intake will be measured at the beginning of each study period. • Discussion:As the first rigorously designed clinical trial in children with SCD, this trial will inform and assess current clinical practice, with the ultimate goal of improving nutritional status of children with SCD.• Trial registration: This trial was registered July 8, 2019 at clinicaltrials.gov: NCT04011345. https://clinicaltrials.gov/ct2/show/NCT04011345

Red Blood Cell Folate and Serum Vitamin B12 Status in Children With Sickle Cell Disease

2001 ◽  
Vol 23 (3) ◽  
pp. 165-169 ◽  
Author(s):  
Tay S. Kennedy ◽  
Ellen B. Fung ◽  
Deborah A. Kawchak ◽  
Babette S. Zemel ◽  
Kwaku Ohene-Frempong ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Blood Cell ◽  
Vitamin B12 ◽  
Sickle Cell ◽  
Red Blood Cell ◽  
Serum Vitamin ◽  
Cell Disease

Effect of homocysteine and folic acid on vaso-occlusive crisis in children with sickle cell disease

2018 ◽  
Vol 43 (3) ◽  
pp. 115 ◽  
Author(s):  
AhmedM Badr ◽  
AhmedA Raouf ◽  
MonaM Hamdy ◽  
Osama Shalaan ◽  
Moustafa Sakr ◽  
...  
Keyword(s):  
Folic Acid ◽  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Cell Disease

scholarly journals Plasma Vitamin B6 Vitamers before and after Oral Vitamin B6 Treatment: A Randomized Placebo-controlled Study

2003 ◽  
Vol 49 (1) ◽  
pp. 155-161 ◽  
Author(s):  
Mustafa Vakur Bor ◽  
Helga Refsum ◽  
Marianne R Bisp ◽  
Øyvind Bleie ◽  
Jorn Schneede ◽  
...  
Keyword(s):  
Folic Acid ◽  
Vitamin B12 ◽  
Vitamin B6 ◽  
Oral Treatment ◽  
Prolonged Treatment ◽  
Controlled Study ◽  
Plasma Vitamin ◽  
Additional Increase ◽  
Before And After ◽  
B Vitamin

Abstract Background: Vitamin B6 has attracted renewed interest because of its role in homocysteine metabolism and its possible relation to cardiovascular risk. We examined the plasma B6 vitamers, pyridoxal 5′-phosphate (PLP), pyridoxal (PL), pyridoxine (PN), and 4-pyridoxic acid (4-PA) before and after vitamin B6 supplementation. Methods: Patients (n = 90; age range, 38–80 years) undergoing coronary angiography (part of the homocysteine-lowering Western Norway B-Vitamin Intervention Trial) were allocated to the following daily oral treatment groups: (A), vitamin B12 (0.4 mg), folic acid (0.8 mg), and vitamin B6 (40 mg); (B), vitamin B12 and folic acid; (C), vitamin B6; or (D), placebo. EDTA blood was obtained before treatment and 3, 14, 28, and 84 days thereafter. Results: Before treatment, PLP (range, 5–111 nmol/L) and 4-PA (6–93 nmol/L) were the predominant B6 vitamers identified in plasma. During the 84-day study period, the intraindividual variation (CV) in patients not treated with vitamin B6 (groups B and D) was 45% for PLP and 67% for 4-PA. Three days after the start of treatment, the increases in concentration were ∼10-, 50-, and 100-fold for PLP, 4-PA, and PL, respectively. No significant additional increase was observed at the later time points. The PLP concentration correlated to the concentrations of 4-PA and PL before treatment, but not after treatment. The PL concentration correlated with 4-PA before and after treatment. Conclusions: Vitamin B6 treatment has an immediate effect on the concentrations and the forms of B6 vitamers present in plasma, and the changes remain the same during prolonged treatment. Our results suggest that the B6 vitamers in plasma reflect vitamin B6 intake.

Vitamin B6 Status of Children With Sickle Cell Disease

2002 ◽  
Vol 24 (6) ◽  
pp. 463-469 ◽  
Author(s):  
Melissa C. Nelson ◽  
Babette S. Zemel ◽  
Deborah A. Kawchak ◽  
Elizabeth M. Barden ◽  
Edward A. Frongillo ◽  
...  
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Vitamin B6 ◽  
Cell Disease

Folic Acid Supplementation and Twin Pregnancy in Patients with Sickle Cell Disease.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3744-3744
Author(s):  
Samir K. Ballas ◽  
Jason Baxter ◽  
Gaye Riddick
Keyword(s):  
Folic Acid ◽  
Sickle Cell Disease ◽  
Pregnant Women ◽  
Sickle Cell ◽  
Folic Acid Supplementation ◽  
Multiple Births ◽  
Cell Disease ◽  
Folate Supplementation ◽  
Acid Supplementation ◽  
Twin Pregnancies

Abstract Patients with sickle cell disease (SCD) usually take 1mg of folic acid daily. The rationale for this approach is to maintain effective erythropoiesis with a stable hemoglobin level. Other potential advantages of folate therapy in patients with SCD include the prevention of hyperhomocysteinemia that may predispose to thrombotic events, which, in turn, may lead to painful episodes. Moreover, folate supplementation during pregnancy is known to prevent neural tube defects in infants. The major disadvantage of folate supplementation in patients with SCD is that it may mask vitamin B12 deficiency. Another controversial effect of folic acid supplementation pertains to its potential effect on the number of twins coming to term. We reviewed our database on patients with SCD to determine the effect, if any, of folic acid supplementation on twin pregnancies. The data were collected prospectively since 1981. All patients routinely took 1.0 mg of folic acid orally on a daily basis. Random testing of the level of folic acid in the steady state in women with SCD including those who became pregnant showed increased levels to > 20ng/ml (Normal range: 3.0–18.0 ng/ml) in most patients. Pregnant patients also took additional perinatal vitamins that also contained folic acid. We selected those pregnant patients in whom the outcome of pregnancy was either a liveborn or stillborn at or after 20 weeks’ gestation. We found that 46 patients with SCD became pregnant 60 times between 1981 and 2002 and who met the defined criteria mentioned above. The average maternal age at delivery was 26 years. Fifty-six pregnancies (93%) ended in liveborn and the remaining four (7%) in intrauterine fetal death. Five pregnancies (8.3%) resulted in the delivery of twins. This is a significantly higher rate of multiple births compared to other pregnant women. The reported rate of multiple births is between 0.34 and 1.1% both in Black and Caucasian women respectively. All twin births were dizygotic in nature. Patients with SCD take higher amounts of folic acid on a regular basis for a longer period of time before and after pregnancy than other pregnant women. This may explain why twin pregnancies are higher in these patients. The reason why folate therapy is associated with twinning is unknown at the present. Further studies may clarify the pathogenetic pathway of this phenomenon.

Tetrahydrobiopterin (6R-BH4): Novel Therapy for Endothelial Dysfunction in Sickle Cell Disease

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. lba-5-lba-5 ◽  
Author(s):  
Lewis Hsu ◽  
Kenneth I Ataga ◽  
Victor R. Gordeuk ◽  
Paul S. Swerdlow ◽  
Abdullah Kutlar ◽  
...  
Keyword(s):  
Folic Acid ◽  
Endothelial Dysfunction ◽  
Sickle Cell Disease ◽  
Endothelial Function ◽  
Sickle Cell ◽  
No Production ◽  
Central Feature ◽  
Cell Transplant ◽  
Cell Disease ◽  
Dose Dependent

Abstract Dysregulated nitric oxide (NO) homeostasis, a consequence of hemolysis, is a central feature of endothelial dysfunction (ED) in Sickle Cell disease (SCD). In addition to ED, scavenging of NO by free heme leads to increased cell adhesion and inflammation. Vascular inflammation and the production of superoxide may decrease BH4, an essential cofactor for NO production, thus creating an acquired BH4 deficiency. Restoring BH4 levels could potentially improve ED thereby favorably impacting complications of SCD. We assessed the safety and efficacy of 6R-BH4 on endothelial function in a Phase 2a, open-label, dose escalation study in SCD subjects using a non-invasive, operatorindependent technique of peripheral arterial tonometry (Endo-PAT; Itamar, Israel). Endo-PAT (PAT) scores were quantitatively determined as the ratio between the arterial pulse wave amplitude following a 5 min arterial occlusion in the forearm to the pre-occlusion value. A value of ≤1.67 represents an impaired response or endothelial dysfunction. Only patients with HbSS and HbSC disease and at least 15 years of age were enrolled. Patients were excluded if they: were on chronic hypertransfusion; had sickle cell crisis within 30 days of screening; had a history of bone marrow or stem cell transplant or were on hydroxyurea (HU) therapy during the 3 months prior to screening. Thirty-two African-American subjects, mean age 29 years (41% male) were sequentially treated for 4 weeks each with 6R-BH4 at 2.5, 5, 10, and 20 mg/kg/day at 12 US sites. Nine subjects discontinued therapy for various reasons including loss of follow up and pregnancy. Twenty-seven subjects had baseline PAT scores and the number of subjects with PAT scores varied at each treatment dose. There were no deaths and only one subject had a drug related adverse effect resulting in discontinuation. Overall, 6R-BH4 is safe and well-tolerated in subjects with SCD. The mean PAT scores for all participants at baseline was 1.58 ± 0.43 (mean ± SD). Mean PAT scores at baseline were 1.33 ± 0.17 in 18 patients with abnormal PAT scores and 2.09 ± 0.31 (p=<0.001) in 9 patients with normal PAT scores. Mean PAT score for all subjects demonstrated significant improvement at 5mg/kg/day and 10mg/kg/day (dose, N, mean change +/− SD, mean % change and p value) (5 mg/kg/day, N=24, 1.79 ± 0.64, 22.4%, p= 0.042; 10 mg/kg/day, N=24, 1.95 ± 0.46, 28.2%, p=0.003). Eighteen of the 27 (67%) subjects who had abnormal PAT scores at baseline had statistically significant dose-dependent improvements over the 16 weeks of therapy with 6R-BH4 (2.5 mg/kg, N=15, 1.63 ± 0.37, 24.7%, p=0.012; 5mg/kg, N=14, 1.69 ± 0.56, 31.2%, p=0.025; 10mg/kg, N=15, 1.84 ± 0.47, 39.9%, p<0.001; 20mg/kg, N=15, 2.01 ± 0.76, 56.6%, p=0.005). Consistent with the mechanism of action of 6R-BH4 subjects with normal Endo-PAT scores at baseline demonstrated no improvement with therapy. HbSS subjects appear to have more ED based on PAT scores compared with HbSC subjects, although the difference was not statistically significant 1.52 ± 0.45 vs 1.67 ± 0.39. More importantly, both HbSS and HbSC subjects demonstrated an improvement in mean change in endothelial function with increasing doses of 6R-BH4 with corresponding % mean changes from baseline being 48.8% and 15.5% respectively following 16 weeks of treatment. The majority of subjects in the study (17/27; 63%) were prescribed folic acid supplement by their physicians at baseline and throughout the study. Post hoc analysis demonstrated no difference in baseline PAT scores between subjects on folic acid supplementation and those not on it (1.60 ± 0.47 vs 1.55 ± 0.37). However, patients on folic acid demonstrated a better dose response to treatment with 6R-BH4 compared to patients not receiving folic acid (2.5 mg/kg: 1.72 ± 0.38 vs 1.69 ± 0.41; 5mg/kg: 1.93 ± 0.74 vs 1.56 ± 0.38; 10mg/kg: 1.89 ± 0.51 vs 2.06 ± 0.34; 20 mg/kg: 2.09 ± 0.73 vs 1.62 ± 0.34) In summary, 6R-BH4 is safe, well-tolerated and demonstrates a dose-dependent improvement in endothelial function in subjects with SCD. Best results were achieved in those with baseline endothelial dysfunction. Improvement in ED occurs regardless of genotype. Finally, patients receiving folic acid showed a better response to 6R-BH4 than those not receiving this supplement. These data provide further support for the development of 6R-BH4 as a treatment for sickle cell disease. 6R-BH4 is a potentially new effective modulator of NO for SCD patients who have ED.

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