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Estimation of serum folate and vitamin b12 levels in children with hematologic malignancies.

Byline: Sneha Tandon Kalpana Singh Anand Ruban Bhawna Singh Abbas Ali Mahdi and Archana Kumar

Abstract

Background: Patients of hematological malignancies are reported to be deficient in folate and vitamin B12. The aim of this study was to estimate serum folate and vitamin B12 levels in children with hematological malignancies to find out the frequency of deficiencies in different type of hematological malignancies.

Material and Methods: In this case control study 102 children (24 females and 78 males aged 1.5-16 years) presenting with different hematological malignancies were enrolled. Serum folate and vitamin B12 levels were estimated and matched with controls (30) children with non-hematological malignancies. Folic acid and vitamin B12 levels were estimated by electrochemiluminescence technique.

Result: Children with hematological malignancies were categorized into acute lymphoblastic leukemia (ALL 61) acute myeloid leukemia (AML 18) Hodgkin's disease (HD 12) and non-Hodgkin lymphoma (NHL 11). The vitamin B12 levels in these cases and controls were 482.06480.29 pg/mL 582.33500.43 pg/mL 438.2355.09 pg/mL 324.91198.14 pg/mL and 864.54733.49 pg/mL respectively. The serum folate was 9.238.53 ng/mL 6.323.85 ng/mL 9.6610.16 ng/mL 10.5610.30 ng/mL and 12.7315.96 ng/mL respectively. Serum vitamin B12 levels varied differently among different hematological malignancies it was significantly lower in ALL (p=0.003) followed by NHL (p=0.02). Serum folate was lowest in AML as compared to controls but not statistically significant.

Conclusion: The frequency of vitamin B12 deficiency was higher in children with HD while folate deficiency in AML. Serum vitamin B12 levels varied differently among different hematological malignancies it was significantly lower in ALL followed by NHL. While folate levels were lowest in AML as compared to controls but not statistically significant.

KEY WORDS: Hematologic malignancy; Anemia; Vitamin B12; Folic acid; Cobalamin.

Introduction

The folate and vitamin B12 (cobalamin) are two vital micronutrients that play diverse roles in body metabolism. Folate mediated one-carbon metabolic pathway is central to DNA metabolism including its synthesis repair and methylation.1 This strategy is utilized therapeutically for hematological and trophoblastic malignancies.23 The one carbon metabolism also involves regulation of epigenetic mechanisms including CpG island and histone methylation and DNA uracil incorporation hence not surprisingly a number of studies have shown aberrant folate and vitamin B12 metabolism to be associated with cardiovascular risk4 neurodegeneration5 and malignancies of various tissues.6-10 There are only some studies that explore the status of folate and vitamin B12 in acute lymphoid leukemias (ALL).

It is seen that maternal folate supplementation is associated with a decreased risk of childhood acute leukemia11 suggesting low levels of these nutrients may indeed be a contributing factor for the tumor initiation promotion as well as progression. There are a few reports of a lack of association between methylenetetrahydrofolate reductase (MTHFR) C677T polymorphisms and ALL12 but a recent meta analysis has concluded that the C677T polymorphism not A1298C in MTHFR gene is associated with a decreased risk of ALL particularly among children and Caucasians subjects.13 There are only a few reports that have assessed the circulating levels of folate and vitamin B12 in hematological malignancies in particular in pediatric group hence this study was planned with the objective of estimating the circulating levels of vitamin B12 and folate in childhood hematologic malignancies.14

Since the levels are also sensitive to the chemotherapy offered and vitamins supplementation the study was planned to assess the levels at the time of diagnosis prior to chemotherapy.

The aim of our study was to estimate serum folate and vitamin B12 levels in children with hematological malignancies at the time of admission in a tertiary care hospital and to find out the frequency of deficiencies in different type of hematological malignancies.

MATERIAL AND METHODS

Study was conducted in Pediatric Hemato-Oncology Clinic Department of Pediatric King George's Medical University U.P Lucknow (India). Study was approved by Institutional Ethical committee and informed consent was taken from the parents. All cases of hematological malignancies between 1.516 years of age both sexes who were registered during a period of one year in the clinic were enrolled in the study. In the control group (30) age and sex matched children with non hematological malignant children were selected based on history and general physical examination. Cases of childhood hematological malignancies were selected either on the basis of hematological or bone marrow or histological findings. Under aseptic conditions 2ml peripheral venous blood sample was obtained in plain vial and the serum was used for further analysis. Samples were obtained from the cases at the time of diagnosis.

Both vitamin B12 and folate levels were estimated by electrochemiluminescence on Roche cobas e411 analyzer using commercial kits (Roche diagnostics KK Tokyo Japan). The statistical analysis was done by using SPSS version 15.0. Chi-square test was used to find out the association of type of malignancy and vitamin B12 and folate deficiency and also to compare the deficiency between cases and controls. The values were expressed as mean standard deviation. Unpaired student t test was used to compare mean folate and vitamin B12 levels in different hematological malignancies.

RESULTS

Thirty age and sex matched children with non hematological malignancy constituted the control group (group 1). The demographics of group 1 are as follows: N=30 mean age 7.8 3.96 years (range 1.2-16.1 years). Cases enrolled in the study comprised of total 102 children (group 2) with mean age being 7.163.62 years (24 females and 78 males) presenting with different hematological malignancies were enrolled in the study. Mean folate levels were 8.918.31 ng/mL in group 2 as compared to controls 12.73 15.96 ng/mL while mean vitamin B12 were 479.74 450.23 pg/mL in group 2 as compared controls 864.54 733.49 ng/ml. Percentage of vitamin B12 and folate deficiencies in cases were 36.3% and 62.7% respectively as shown in table 1. Cases (group 2) were sub-categorized in acute lymphoblastic leukemia (61) acute myeloid leukemia (18) Hodgkin Disease (12) and Non-Hodgkin lymphoma (11).

The vitamin B12 and folate levels in 4 sub-groups are shown in table 2 and values are expressed as mean standard deviation and unpaired student t test was used to compare different groups with controls. Mean

Table 1: Comparison of vitamin B12 deficiency between cases and controls.

###Patients with vitamin B12 deficiency###Patients with folate deficiency

###Number###Percentage###Number###Percentage

Controls (n=30)###3###10###19###63.3

Cases (n=102)###37###36.3###64###62.7

Significance###p = 0.006###p = 0.953

Table 2: Comparison of mean serum vitamin B12 and serum folate levels in different hematological malignancies as compared to controls.

Study group (n)###Serum Vitamin B12###Significance###Serum Folate###Significance

###MeanSD (pg/mL)###MeanSD (ng/mL)

Controls (30)###864.54 733.49###12.7315.96

ALL (61)###482.06 480.29###t=2.98; p=0.003###9.238.53###t=1.36; p=0.17

AML (18)###582.33 500.43###t=1.66; p=0.10###6.323.85###t=1.43; p=0.15

HD (12)###438.2 355.09###t=1.91; p=0.06###9.6610.16###t=0.61; p=0.54

NHL (11)###334.91 198.14###t=2.34; p=0.02###10.5610.30###t=0.41; p=0.67

Table 3: Association between type of malignancy and vitamin B12 and folate deficiency.

Type of malignancy Number of patients###Patients with vitamin B12###Patients with folate

###(n=102)###deficiency###deficiency

###Number###Percentage###Number###Percentage

ALL###61###23###37.7###39###63.9

AML###18###5###27.8###12###66.7

HD###12###6###50###7###58.3

NHL###11###3###27.3###6###54.5

Chi-square test###2###1.98###0.57

###p###0.57###0.93

vitamin B12 levels were lowest in children with ALL (482.06 480.29 pg/ml) and NHL (334.91 198.14 pg/ml) as compared to controls (864.54 733.49 pg/mL) which was statistically significant. Mean folate levels were lowest in AML children (6.32 3.85 ng/ml) as compared to controls (12.73 15.96 ng/ml) but it was not statistically significant. Vitamin B12 deficiency varied differently among different hematological malignancies as shown in table 3. Fifty percent of the children diagnosed as HD were vitamin B12 deficient but it was not statistically significant (p=0.57). Similarly the folate deficiency was 66.7% in AML but it was not significant statistically (p=0.93) as shown in Table 3.

DISCUSSION

Several molecular mechanisms that underpin genomic integrity and function are sensitive to vitamin B12 status and in particular are responsive to the interaction between folate nutrition and folate dependent enzyme polymorphisms. Folate a key component in one carbon metabolism is crucial in purine and pyrimidine synthesis and provides methyl group for DNA and RNA methylation. Vitamin B12 and folate deficiency results in impairment of DNA synthesis which promotes carcinogenesis.1516 Hanumante et al17 in their assessment of vitamin B12 and folic acid levels among asymptomatic Indian toddlers reported a mean level of 282.3 140.4 pmol/L for vitamin B12 and 18.3 7.5 nmol/L for folate levels whereas in our study mean vitamin B12 and folic acid levels in hematological malignant children were 479.74 400.23 pg/mL and 8.91 8.31 ng/mL. In our study mean vitamin B12 and folate levels in children with hematological malignancies were lower as compared to controls.

In the present study mean folate levels were lower though not statistically significant in majority of children (62.7%) with hematological disease in contrast to vitamin B12 (36.3%) which was statistically significant (p value 0.006) when compared to controls as shown in table 1. In 1998 it has been reported by Nath et al approximately 33% of Indian population suffers from folate deficiency.18 A recent report shows vitamin B12 and folate deficiency in 26% and 6% in toddlers.17 However in the present study B12 and folate deficiency was observed to be 36.3% and 62.7% in hematological malignant children.

Comparison of vitamin B12 and folate levels in different sub categories of group 2 revealed statistically significant difference among groups for mean vitamin B12 levels however the difference was not significant for folate levels. Comparison of mean vitamin B12 levels from control group was significantly lower in ALL patients (p value 0.003) followed by NHL (p=0.02) which was also statistically significant as shown in table 2. Mean vitamin B12 levels were also low in children with HD though it was not statistically significant. Mean folate levels in our study were lower in cases as compared to controls however levels in NHL were higher than other hematological malignancies. Lowest folate levels were observed in AML which was closely followed by ALL however no significant statistical association was seen (p=0.35).

These findings are contrary to Adiga et al14 who reported a significant difference between healthy controls and ALL for mean folate levels however they had not observed the difference between two groups for vitamin B12 levels.

The incidence of vitamin B12 deficiency in present study varied differently among different hematological malignancies. It was maximum among children's with HD (50%) and minimum in NHL (27.3%) however the difference among the hematological malignancies were not statistically significant (p=0.57). The incidence of folate deficiency was maximum in AML (66.7%) and minimum in NHL (54.5%) but no significant difference was observed among different type of malignancies (p=0.93).

Our study shows that the incidence of vitamin B12 deficiency was maximum in HD though it was not significant statistically which could be due to small sample size. Studies are available according to which vitamin B12 deficiency was found in ALL children at the time of diagnosis. But no study is available in which vitamin B12 and folate status have been evaluated in different type of childhood hematological malignancies.

CONCLUSION

In our study we found that vitamin B12 deficiency is more common in hematological diseases when compared to non-hematological diseases. The incidence of vitamin B12 deficiency was highest in children with Hodgkin's disease while the incidence of folate deficiency was highest in AML as compared to other hematological malignancies though not statistically significant. Mean vitamin B12 levels were significantly lower in ALL and NHL while folate levels were lowest in AML which was not statistically significant. From current study we can conclude that vitamin B12 deficiency is more commonly associated with ALL and NHL type of hematological malignancies. More studies on large sample size are required to dive into the depths of vitamin B12 and folate status in different type of hematological malignancies in children.

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Article Details
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Author:Tandon, Sneha; Singh, Kalpana; Ruban, Anand; Singh, Bhawna; Ali Mahdi, Abbas; Kumar, Archana
Publication:Gomal Journal of Medical Sciences
Article Type:Report
Geographic Code:9INDI
Date:Jun 30, 2014
Words:2666
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