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   Table of Contents      
ORIGINAL ARTICLE
Year : 2021  |  Volume : 7  |  Issue : 1  |  Page : 72-76

Is There A Need to Supplement Transfusion-Dependent Thalassemics with Vitamin B12?


1 Department of Pediatrics, Atal Bihari Vajpayee Institute of Medical Sciences and Dr Ram Manohar Lohia Hospital, Baba Kharag Singh Marg, New Delhi, India
2 Department of Pathology, Atal Bihari Vajpayee Institute of Medical Sciences and Dr Ram Manohar Lohia Hospital, Baba Kharag Singh Marg, New Delhi, India

Date of Submission28-Jan-2021
Date of Decision28-Feb-2021
Date of Acceptance05-Mar-2021
Date of Web Publication28-Apr-2021

Correspondence Address:
Shilpa K. Arora
Associate Professor, Department of Pediatrics, Atal Bihari Vajpayee Institute of Medical Sciences and Dr Ram Manohar Lohia Hospital, Baba Kharag Singh Marg, New Delhi - 110001
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mamcjms.mamcjms_6_21

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  Abstract 


Purpose: The aim of this study was to compare the levels of serum vitamin B12 of transfusion-dependent thalassemic (TDT) children with that of healthy controls. The other objectives were to compare the occurrence of vitamin B12 deficiency in cases and controls and to find out any correlation between serum vitamin B12 of cases with their clinical, hematological, and laboratory parameters. This study was proposed as routine supplementation with folic acid is advised in TDT, but there are no guidelines for screening and supplementation of vitamin B12 for these patients. Methods: Thirty TDT children under 18 years and an equal number of age- and sex-matched controls were evaluated. Results: The mean levels of vitamin B12 in TDT group (260.17 ± 86.26 pg/mL) were lower than that of controls (337 ± 213 pg/mL) (P = 0.57). Correlation analysis of serum vitamin B12 levels with several parameters did not reveal any significant result. Conclusions: Similar large-scale multicentric studies are warranted before formulating guidelines for vitamin B12 screening and supplementation in thalassemics. Till then it may be prudent that TDT must be regularly screened for deficiency if the resources permit or else they must be routinely supplemented.

Keywords: Folic acid, thalassemia, transfusion, vitamin B12


How to cite this article:
Sharma A, Arora SK, Hemal A, Kumar V. Is There A Need to Supplement Transfusion-Dependent Thalassemics with Vitamin B12?. MAMC J Med Sci 2021;7:72-6

How to cite this URL:
Sharma A, Arora SK, Hemal A, Kumar V. Is There A Need to Supplement Transfusion-Dependent Thalassemics with Vitamin B12?. MAMC J Med Sci [serial online] 2021 [cited 2021 Jun 13];7:72-6. Available from: https://www.mamcjms.in/text.asp?2021/7/1/72/314886




  Introduction Top


Thalassemia is a genetic disorder of globin chain production that results in either partial or complete reduction in production of globin chain in hemoglobin molecule. This leads to anemia of variable severity that may or may not be transfusion dependent, depending on the degree of genetic defect. In thalassemic patients, there is accelerated red cell turnover resulting in increased demand of nutrients required for red cell production. Iron, folic acid, and vitamin B12 are important micronutrients required for red cell production. Nutritional deficiencies are common in developing countries like India and patients with chronic illnesses like β-thalassemia major are expected to be suffering from it due to poor nutrition and increased red cell turnover. Iron overload is a known complication in thalassemics. Folate deficiency is known to occur in these children, and hence supplementation with folic acid is advised in transfusion-dependent thalassemics (TDTs).[1] However, the status of vitamin B12 deficiency as well as its supplementation in TDT is not well defined.

The prevalence of vitamin B12 deficiency in Indian children is high ranging from 7% to as high as 68%.[2],[3],[4],[5] These children are also likely to be deficient, more so due to a high red blood cells (RBC) turnover. The true macrocytic picture of megaloblastic anemia as seen in vitamin B12 deficiency is likely to be masked in thalassemia patients due to presence of microcytosis and hypochromia. Though the transfused blood is likely to contribute vitamin B12 to recipients, a few past studies indicate that packed red cell transfusion does not result in a significant change in the serum levels of vitamin B12.[6],[7] There have been reports of missing cobalamin deficiency in these children in absence of overt neurological signs.[8],[9],[10],[11] There is no established guideline to screen these children for cobalamin or vitamin B12 deficiency as a routine in thalassemics. Hence, this study was carried out with the objective to compare the levels of serum vitamin B12 of TDT children up to 18 years with age and sex matched healthy controls. The secondary objectives were to compare the occurrence of vitamin B12 deficiency in cases and controls and to find out any correlation between serum vitamin B12 of cases with their clinical, hematological, and laboratory parameters.


  Methods Top


This cross-sectional case control study was carried out from January to June 2018 in a tertiary care teaching hospital of Northern India after obtaining clearance from the institutional ethics committee. TDTs are defined as thalassemia patients who require regular blood transfusion for survival, that is, β-thalassemia major, severe Hemoglobin E (HbE)/β-thalassemia, transfusion-dependent Hemoglobin H (HbH) disease or HbH hydrops, and surviving Hb Bart’s hydrops (all diagnosed by hemoglobin electrophoresis).

The sample size was calculated considering the power of the study to be 90%, with a two-sided α error of 5% and confidence level 95% to compare the means of serum vitamin B12 levels of TDTs with that of age and sex matched controls. Assuming mean serum vitamin B12 levels to be 245 ± 57.7 pg/mL in cases and 409 ± 112 pg/mL in age and sex matched controls, the minimum sample size was calculated to be seven in each group.[12]

Thirty TDT children under 18 years registered in pediatric hematology out-patients department (OPD) were enrolled consecutively when they came for their routine blood transfusion. Thirty age and sex matched controls were enrolled from general pediatric OPD cases who came with minor ailments such as nonspecific abdominal pain, upper respiratory tract infection, and acute gastroenteritis (lasting ≤14 days). Subjects (both cases and controls) who had received vitamin B12 therapy or prolonged antibiotics (≥14 days) in past 3 months, undergone gastrointestinal surgery in past, were on anticonvulsants or anticancer drugs, suffering from malabsorption syndrome, or with acute onset illness (as ferritin is an acute phase reactant) were excluded from the study. Written informed consent was taken from the parents/guardians of all the subjects before recruitment.

A complete medical history was taken and study proforma was filled for each subject. Clinical details of TDT such as age at diagnosis, age at initiation of transfusions, frequency of transfusion, the total number of transfusions received in the last 1 year, annual blood requirement, and duration since last transfusion were recorded. Other relevant history such as dietary habits and details of folic acid supplementation including dose, duration, and whether taking regularly or irregularly (<3 times/week) was noted. Chelation details such as drug, dose (in milligram per kilogram body weight), and duration (in months and years) was also recorded. History of any paresthesias, tingling, or numbness suggestive of symptoms of vitamin B12 deficiency was also recorded.

Blood samples were drawn for investigations. Estimation of hemoglobin (Hb); total leucocyte count; platelet count; and RBC indices such as packed cell volume (PCV), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), RBC count, and red cell distribution width was done in automated analyzer. Serum vitamin B12 and folic acid levels were estimated by chemiluminescence assays. The normal reference range of vitamin B12 and folic acid was taken from 239 to 931 pg/mL and 2.78 to 20 ng/mL, respectively. Serum was also analyzed for ferritin and lactate dehydrogenase (LDH) levels.

During statistical analysis, data was expressed as median and standard deviation if it followed normal distribution and as median and interquartile range if it followed nonnormal distribution. Independent t test (Mann–Whitney for nonnormal distribution) was used to compare parameters between cases and controls. Chi-square test was also used where appropriate. Spearman correlation was used to study the relation between vitamin B12 levels and MCV of RBCs, serum LDH, and ferritin levels in thalassemic subjects. P < 0.05 was taken as significant. Data was analyzed using SPSS software ver 21.


  Results Top


This study evaluated 30 TDT cases under 18 years of age and an equal number of age and sex matched controls. The baseline characteristics of the two groups are given in [Table 1]. The TDT group (21/30, 70%) had a significantly higher proportion of nonvegetarians in comparison to control group (9/30, 30%) (P = 0.002). In comparison to control group, TDT group also had significantly lower mean hemoglobin (9.58 ± 7.33 g/dL vs 7.15 ± 1.56 g/dL) (P < 0.001) and mean hematocrit (PCV) levels (29.3 ± 7.33% vs 21.74 ± 45%) (P < 0.001). The two groups were comparable in terms of body mass index (BMI) and other hematological indices such as MCV, MCH, MCHC, and RBC counts.
Table 1 Basic profile of the subjects in two groups

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Comparison of the serum vitamin B12 levels of the two groups revealed that although the mean levels of the TDT group (260.17 ± 86.26 pg/mL) were lower than that of controls (337 ± 213 pg/mL), the difference was not statistically significant (P = 0.57) [Table 1]. The proportion of vitamin B12 deficient subjects was similar in both the groups (TDT 56.67%, controls 53.33%). Likewise, there was no significant difference in the mean serum folic acid levels between the two groups (TDT = 8.99 ± 6.11 ng/mL, control = 7.94 ± 4.82 ng/mL, P = 0.848). Only one subject among the control group was found to be deficient in serum folic acid levels and none was deficient among the TDT group. The mean serum ferritin (2426.9 ± 1915 ng/mL vs 65.78 ± 57.13 ng/mL) and mean serum LDH (571.73 ± 241.43 U/L vs 318.27 ± 195.57 U/L) levels of the TDT group were also significantly higher than those of the control group (P < 0.001 for both).

Subgroup analysis was done in the TDT group to assess the factors associated with vitamin B12 deficiency. Comparison of deficient TDT cases (17/30) with that of nondeficient TDT cases (13/30) was done [Table 2] in terms of age, BMI, diet, age at initiation of transfusion, annual blood requirement rate (ABRR) and monthly transfusion frequency, Hb, MCH, MCHC, MCV, serum ferritin, and serum LDH. The mean monthly transfusion frequency was significantly lower among vitamin B12 deficient TDT cases (1.09 ± 0.48/month) in comparison to nondeficient ones (1.62 ± 0.51/month) (P < 0.01). Correspondingly the ABRR of the vitamin B12 deficient TDT cases was lower (133 ± 67.15 mL/kg/year) in comparison to the nondeficient ones (165 ± 53.13 mL/kg/year), but the difference was not statistically significant (P = 0.17). There was no significant difference between the two subgroups in terms of the rest of the parameters analyzed.
Table 2 Comparison of mean levels of various parameters of vitamin B12 deficient TDT cases with those of nondeficient TDT cases

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Correlation analysis of serum vitamin B12 levels was carried out with age, BMI, age at initiation of transfusion, ABRR, Hb, MCH, MCHC, MCV, PCV, RBC count, serum ferritin, and serum LDH [Table 3], but none of them was statistically significant.
Table 3 Correlation of various parameters with vitamin B12 levels of TDT subjects

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  Discussion Top


The present study compared the serum vitamin B12 and folic acid levels of 30 TDT subjects aged under 18 years with an equal number of age and sex matched controls. The TDT group had a lower mean vitamin B12 level (260.17 ± 86.26 pg/mL) than that of the control group (337 ± 213 pg/mL), but the difference was not statistically significant. Also, the proportion of vitamin B12 deficient subjects in the two groups was comparable. Some previous studies have assessed vitamin B12 levels in thalassemia patients that showed variable results. Claster et al.[13] evaluated the occurrence of nutritional deficiencies in iron overloaded patients with hemoglobinopathies. They did not observe any deficiency of vitamin B12 in iron overloaded thalassemia patients and the mean serum levels of the vitamin in these patients was 528 ± 152 pg/mL. This study did not involve any control subjects. The literature search revealed some case control studies that observed significantly lower vitamin B12 levels in thalassemia cases in comparison to controls. Sherief et al.[14] observed that mean vitamin B12 levels were 33.3 ± 40.7 pg/mL in cases and 332.7 ± 136.4 pg/mL in controls (P < 0.001). A study carried out in Maharashtra, India also observed significantly lower levels of serum vitamin B12 in cases (245 ± 57.7 pg/mL) in comparison to controls (409 ± 112 pg/mL) (P < 0.001).[12] The present study failed to demonstrate a significant difference between cases and controls probably because of a small sample size.

The present study did not observe a significant difference in the mean serum folic acid levels between case and control groups. In fact, one of the control subjects was found to be deficient but none of the TDT subjects as all of them were on daily folic acid supplementation.

Within the TDT group, comparison of vitamin B12 deficient and nondeficient cases revealed that the deficient ones had a lower mean monthly transfusion frequency (P < 0.01) as well as lower ABRR (P = 0.17). The likely reason was that these subjects were probably undertransfused and hence having higher RBC turnover that resulted in lower B12 levels. It is also likely that the TDTs with higher blood requirement were protected from deficiency probably due to vitamin B12 being provided by blood transfusion. Thus, the cases with lower blood requirement are more likely to be deficient and must be screened more proactively. Also, the transfusion requirement of TDT subjects with documented vitamin B12 deficiency must be reviewed and revised keeping in mind other parameters such as pretransfusion hemoglobin and intercurrent illness.Majority of the guidelines for management of TDT recommend routine supplementation of folic acid. Karimi et al.[15] suggested that it might potentially mask the manifestations of vitamin B12 deficiency that is often associated with neuropsychiatric symptoms, more so in the subjects with lower serum vitamin B12 levels. Thus they recommend that annual evaluation of vitamin B12 must be carried out in TDT. Observing the lower mean serum levels of vitamin B12 in the present study, it is suggested that screening for its deficiency must be carried out on regular (annual) basis. As the TDTs with lower transfusion requirement are more likely to be deficient, they must be screened on more frequent basis, may be biannually.


  Conclusion Top


It may be prudent to screen TDT for vitamin B12 deficiency on regular basis. It is all the more important in populations where the deficiency is already prevalent in general population and routine supplementation/fortification with vitamin B12 is not carried out as in India. Keeping in mind the high cost of vitamin B12 assessment and the resource constraints of developing nations, it may be imperative to supplement TDT children with vitamin B12 on routine basis. Considering the low sample size of the present study, further studies with a larger sample size are warranted to formulate guidelines regarding routine supplementation of thalassemics.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Cappellini MD, Cohen A, Porter J, Taher A, Viprakasit V. Guidelines for the Management of Transfusion Dependent Thalassemia. 3rd ed. Nicosia, Cyprus: Thalassemia International Federation.  Back to cited text no. 1
    
2.
Chandra J. Megaloblastic anemia: back in focus. Indian J Pediatr 2010;77:795-9.  Back to cited text no. 2
    
3.
Gupta A, Kapil U, Ramakrishnan L, Pandey RM, Yadav CP. Prevalence of vitamin B12 and folate deficiency in school children residing at high altitude regions in India. Indian J Pediatr 2017;84:289-93.  Back to cited text no. 3
    
4.
Kapil U, Toteja GS, Bhadoria AS. Cobalamin and folate deficiencies among children in the age group of 12-59 months in India. Biomed J 2015;38:162-6.  Back to cited text no. 4
[PUBMED]  [Full text]  
5.
Kapil U, Sareen N. Prevalence of ferritin, folate and vitamin B12 deficiencies amongst children in 5-18 years of age in Delhi. Indian J Pediatr 2014;81:312.  Back to cited text no. 5
    
6.
Berz D, Singh H, McCormack E, Mazur E. Modification of anemia parameters after blood transfusion. Blood 2006;108:966.  Back to cited text no. 6
    
7.
Ho CH. The effects of blood transfusion on serum ferritin, folic acid, and cobalamin levels. Transfusion 1992;32:764-5.  Back to cited text no. 7
    
8.
Tavil B, Sipahi T. Masked deficit of vitamin B12 in a Turkish girl with thalassemia. Pediatr Hematol Oncol 2004;21:363-5.  Back to cited text no. 8
    
9.
Mazzone A, Vezzoli M, Ottini E. Masked deficit of B(12) and folic acid in thalassemia. Am J Hematol 2001;67:274.  Back to cited text no. 9
    
10.
Bilic E, Bilic E, Zagar M, Juric S. Masked deficit of vitamin B12 in the patient with heterozygous beta-thalassemia and spastic paraparesis. Acta Neurol Belg 2004;104:173-5.  Back to cited text no. 10
    
11.
Reibke R, Hausmann A, Cnossen J, Hiddemann W, Spiekermann K, Braess J. [Severe microcytic anemia with megaloblastic changes in the bone marrow. A hematological paradoxon?]. Internist (Berl) 2009;50:881-6.  Back to cited text no. 11
    
12.
Patil VW, Mujawar SA. Deficiency of folic acid, vitamins B12, and their correlation with ferritin in childhood β thalassemia major. Curr Pediatr Res 2010;14:111-4.  Back to cited text no. 12
    
13.
Claster S, Wood JC, Noetzli L, Carson SM, Hofstra TC, Khanna R, Coates TD. Nutritional deficiencies in iron overloaded patients with hemoglobinopathies. Am J Hematol 2009;84:344-8.  Back to cited text no. 13
    
14.
Sherief LM, Abd El-Salam SM, Kamal NM, El Safy O, Almalky MAA, Azab SF et al. Nutritional biomarkers in children and adolescents with beta thalassemia major: an Egyptian centre experience. Biomed Res Int 2014:261761. doi:10.1155/2014/261761  Back to cited text no. 14
    
15.
Karimi MD, Cohan N, De Sanctis V. Thalassemia intermedia; folic acid and vitamin B12 supplementation. What we know and what is needed? Iran J Ped Hematol Oncol 2016;7:57-62.  Back to cited text no. 15
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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