ARTICLE Obese Children and Adolescents

A Risk Group for Low B12 Concentration

Orit Pinhas-Hamiel, MD; Noa Doron-Panush, RD; Brian Reichman, MD; Dorit Nitzan-Kaluski, MD, MPH, RD; Shlomit Shalitin, MD; Liat Geva-Lerner, MD

Objective: To assess whether overweight children and Results: Median concentration of serum B12 in normal- adolescents are at an increased risk for . weight children was 530 pg/mL and in obese children, Ͻ 400 pg/mL (P .001). Low B12 concentrations were noted Design: Prospective descriptive study. in 10.4% of the obese children compared with only 2.2% Ͻ of the normal weight group (P .001). Vitamin B12 defi- Setting: Two pediatric endocrine centers in Israel. ciency was noted in 12 children, 8 (4.9%) of the obese subjects and 4 (1.8%) of the normal weight group (P=.08). Participants: Three hundred ninety-two children and After we adjusted for age and sex, obesity was associ- adolescents were divided into 2 groups as follows: the ated with a 4.3-fold risk for low serum B12, and each unit normal-weight group had body mass indexes, calcu- increase in standard deviation score re- lated as weight in kilograms divided by height in meters sulted in an increased risk of 1.24 (95% confidence in- squared, under the 95th percentile (Ͻ1.645 standard de- terval, 0.99-1.56). viation scores; n=228); the obese group had body mass indexes equal to or above the 95th percentile (Ն1.645 standard deviation scores; n=164). Conclusions: Obesity in children and adolescents was associated with an increased risk of low vitamin B12 con- Intervention: We measured vitamin B12 concentra- centration. We recommend that dietary assessment of tions. Low serum B12 was defined as a B12 concentration obese children should include an estimation of vitamin less than 246 pg/mL, and vitamin B12 deficiency was de- B12 intake. The possibility of vitamin B12 deficiency in ad- fined as a concentration below 211 pg/mL. dition to other micronutrient deficiencies should be con- sidered in obese children. Main Outcome Measure: Vitamin B12 concentra- tions corrected for body mass index standard deviation scores, age, and sex. Arch Pediatr Adolesc Med. 2006;160:933-936

N GENERAL, FOOD HABITS OF ADO- sociated with poor dietary calcium intake lescents are characterized by an ir- both in adults and in children.4 We have re- regular meal pattern with skipped ported that 38.8% of obese children had low meals.1 In a national survey among iron levels compared with only 4.4% of nor- youth in the United States, the per- mal-weight children.5 Iron levels showed a Icentage of youth meeting national dietary significant negative correlation with greater recommendations was approximately 30% standard deviation scores (SDSs) of body for the fruit, grain, meat, and dairy pyra- mass index (BMI), calculated as weight in mid groups. Sixteen percent of youth did kilograms divided by height in meters not meet any recommendations, and only squared. Similarly, the National Health and 1% met all dietary recommendations.2 Di- Nutrition Examination Survey III (1988 etary intakes of several micronutrients were through 1994), providing cross-sectional found to be inadequate among adolescents data on among children aged in several studies.2,3 2 to 16 years, showed that the prevalence Although it is hard to conceive of a nu- of iron deficiency increased with increas- tritional deficiency occurring in subjects ing BMI and iron deficiency was particu- with excessive dietary and caloric intake, larly common among obese adolescents obese children tend to consume foods rich (9.1% compared with 3.5% in nonobese in carbohydrates and fat and thus may be adolescents).6 Author Affiliations are listed at at increased risk of micronutrient defi- Vitamin B12, also known as cobala- the end of this article. ciency. For example, obesity has been as- min, is a required nutrient; its main source

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Table 1. Age, Sex, and Vitamin B12 Levels According Table 2. Multivariate Analysis for Low Serum to Weight Status Vitamin B12 Levels*

Normal Weight Obese P Low B12, Adjusted OR P Characteristic (n = 228) (n = 164) Value Characteristic No. No. (%) (95% CI) Value Age, mean ± SD, y 11.4 ± 2.7 12.4 ± 3.3 .002 BMI SDSs Age, No. (%) Normal 228 5 (2.9) 1 Ͻ12 y 137 (60.1) 69 (42.1) Ͻ.001 Obese 164 17 (10.4) 4.33 (1.54-12.2) Ͻ.01 Ն12 y 91 (39.9) 95 (57.9) Ͻ.001 Age Body mass index, median 16.8 (15.2-18.7) 31.5 (27.0-36.3) Ͻ.001 Ͻ12 y 206 4 (1.9) 1 (interquartile range)* Ն12 y 186 18 (9.7) 4.46 (1.46-13.6) Ͻ.01 Sex, No. (%) Sex Male 86 (37.7) 70 (42.7) Male 156 7 (4.5) 1 Female 142 (62.3) 94 (57.3) .32 Female 236 15 (6.4) 1.67 (0.45-4.31) .29

Vitamin B12 concentration, median, pg/mL Abbreviations: BMI, body mass index (calculated as weight in kilograms (interquartile range) divided by height in meters squared); CI, confidence interval; OR, odds ratio; All 530 (410-663) 400 (304-518) Ͻ.001 SDSs, standard deviation scores.

Boys 526 (384-695) 410 (304-520) Ͻ.001 *Serum B12 concentration was less than 246 pg/mL. Girls 530 (420-635) 396 (304-504) Ͻ.001 Age Ͻ12 y 541 (425-709) 490 (401-598) .02 Ն Ͻ Age 12 y 504 (385-614) 337 (279-439) .001 pg/mL borderline were considered low, and concentrations less than 211 pg/mL indicated a B12 deficiency as recommended by *Body mass index is calculated as weight in kilograms divided by height the manufacturer. in meters squared. Data were analyzed with SAS software version 8.0 (SAS In- stitute, Cary, NC). Variables were compared using a ␹2 test for discrete variables and t test or Wilcoxon rank sum test for con- is from foods of animal origin. Vitamin B12 deficiency is tinuous variables. All tests were 2-tailed and P values below .05 associated with hematologic, neurologic, and psychiat- were considered statistically significant. Adjusted odds ratios ric manifestations.7 Furthermore, vitamin B deficiency and 95% confidence intervals were obtained from logistic re- 12 Ͻ results in hyperhomocystinemia, which is an indepen- gression models with low serum B12 concentration ( 246 dent risk factor for atherosclerotic .8 This study pg/mL) as a dependent variable and age, sex, and obesity as pre- dictors. Goodness-of-fit of the models was estimated by a aimed to assess whether obese children are at increased Hosmer-Lemeshow test and c statistics. risk for vitamin B12 deficiency. RESULTS METHODS Of 392 study participants, 228 were of normal weight, The study population comprised 392 children and adoles- and 164 were obese. Age and sex distribution, BMI, and cents aged 6 to 19 years of Sephardic and Ashkenazi Jewish ori- gin. One hundred sixty-four were obese subjects referred to the vitamin B12 concentrations of each group are shown in obesity clinics of 2 endocrine centers in Israel. Two hundred Table 1. The median serum B12 concentration of obese twenty-eight were normal weight children referred to the en- children was significantly lower than that of normal weight docrine clinics because of familial short stature, precocious or children; 400 vs 530 pg/mL, respectively (PϽ.001). This delayed puberty, or hirsutism and in whom no endocrine dis- difference was especially marked in children aged 12 years order was subsequently detected. Celiac disease was excluded and older. Ͻ in 103 of 128 children with short stature. We excluded chil- Low vitamin B12 concentrations ( 246 pg/mL) were dren who had chronic , those using vitamin supple- present in 22 subjects (5.6%), 17 (10.4%) of whom were ments, those who were declared vegetarians, and those treated obese and 5 (2.2%) of whom were normal-weight chil- with metformin. dren (PϽ.001). Vitamin B concentrations below 246 Subjects were divided into 2 groups on the basis of BMI for 12 age and sex according to the National Institutes of Health data9 pg/mL were noted in 18 (9.7%) of 186 children older than as follows: the normal weight group had BMIs under the 95th 12 years of age compared with 4 (1.9%) of 206 children percentile (Ͻ1.645 SDSs) for age and sex, and the obese group aged 6 to 11 years (P=.001). The percentages of boys had BMIs at or above the 95th percentile (Ն1.645 SDSs) for (4.5%) and girls (6.4%) with B12 concentrations below age and sex. 246 pg/mL were not statistically different. Ͻ The study protocol was approved by the human experimen- Vitamin B12 deficiency ( 211 pg/mL) occurred in 12 tation committees of Sheba and Schneider medical centers (Tel children, 8 of whom were aged 12 to 19 years. Vitamin Hashomer and Petah Tikva, Israel, respectively). Written pa- B12 deficiency was present in 8 (4.9%) of the obese sub- rental informed consent and child assent were obtained from jects and in 4 (1.8%) of the normal weight group (P=.08). obese participants. Serum B concentrations were routinely 12 On multivariant analysis (Table 2), obesity was as- taken from patients as part of initial blood test screening fol- sociated with an excess risk for low vitamin B12 levels (odds lowing an overnight fast. Serum B12 concentration was mea- sured using the ADVIA Centaur System, a competitive immu- ratio, 4.33) after adjustment for age and sex. The Hosmer- noassay using direct chemiluminescent technology (Bayer Lemeshow goodness-of-fit test and c statistics showed that Diagnostics, Tarrytown, NY). Serum B12 concentrations above the model fitted well (P=.90, c=0.77). A similar model 246 pg/mL were deemed normal, results between 211 and 246 was conducted with BMI SDSs and age as continuous vari-

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 ables. An increase of 1 BMI SDS resulted in increased risk B12 leads to hyperhomocystinemia. Longitudinal cohort for low B12 levels of 1.24 (95% confidence interval, 0.99- studies have established that even mild hyperhomocys- 1.56), and an increase in 1 year of age resulted in in- tinemia both predicts and precedes the development of car- creased risk of 1.35 (95% confidence interval, 1.13- diovascular morbidity and mortality.19,20 Hyperhomocys- 1.61). Linear regression that included BMI SDSs, age, and tinemia correlated with insulin resistance in obese sex (r=−0.42) revealed that an increase of each unit of prepubertal children.21 Among adults with the metabolic BMI SDSs decreased vitamin B12 concentration by 28 syndrome, levels of homocysteine were significantly higher Ͻ pg/mL (P .001). Each increase in 1 year of age de- and levels of vitamin B12 were significantly lower com- Ͻ 12 creased vitamin B12 concentration by 22 pg/mL (P .001). pared with those of healthy subjects. Homocysteine- There was no sex effect on vitamin B12 level (P=.33). lowering treatments have resulted in improvement of car- diovascular reactivity and coagulation factors.22 It is thus COMMENT possible that vitamin B12 deficiency may further contrib- ute to the high risk of developing cardiovascular disease among obese children. Folate and vitamin B12 treatment Our results show that obese children and adolescents had improved insulin resistance and endothelial dysfunction, significantly lower B12 concentrations than normal-weight along with decreasing homocysteine levels, in patients with children and that 10% of obese children had low serum B12 metabolic syndrome.23 concentrations. Obesity was associated with a greater than In assessing the results of this study, a number of limi- 4-fold risk for low vitamin B12 concentrations, and for each tations should be considered. First, although measure- unit increase in BMI SDS, there was a 24% increase risk of ment of serum vitamin B12 concentration has been widely low serum B12 concentrations. To the best of our knowledge, used as the standard screening test for deficiency, the test this is the first report of low B12 concentrations in obese chil- has poor positive and negative predictive values.24 A “nor- dren. Lower serum B12 concentrations were detected in over- mal” concentration does not reliably exclude deficiency weightBrazilianadolescentscomparedwiththoseofnormal- and low serum of vitamin B12 concentration does not nec- weight adolescents; however, this difference did not reach essarily indicate deficiency. Other assays are expensive, statistical significance.10 Among Thai adults, no statistically such as those for methylmalonic acid and homocyste- significantdifferenceinvitaminB concentrationswasfound 12 ine, which seem to provide greater sensitivity and speci- in overweight and obese subjects compared with normal ficity, and concerns about the use of these assays and the control subjects.11 Among adult Turkish patients with meta- interpretation of their results are emerging.25 Second, in bolic syndrome, serum B concentrations were significantly 12 the absence of an Israeli population-based reference, we lower than those of healthy subjects.12 used the manufacturer reference for definitions of low Vitamin B12 deficiency results from decreased intake, abnormal nutrient absorption, and rare inborn errors of and deficient. Vitamin B12 concentrations in serum vary 13-15 with the analytical method used and the laboratory con- vitamin B12 metabolism. Abnormal absorption may be due to medications that decrease gastric acid secre- ducting the analysis. Data from the National Health Ex- tion, pernicious anemia, infection with giardia lamblia, amination Survey in the United States (1988-1994) de- and any disruption of the ileal mucosa such as Crohn and fined B12 deficiency as levels lower than the fifth percentile for age, which in the US population aged 4 years and older celiac disease. Because obese children gain weight eas- 18 ily, there is no reason to suspect they have a problem with corresponded to 233 pg/mL. The fifth percentile for chil- absorption. Although declared vegetarians were ex- dren aged 6 to 11 years was 380 pg/mL and for those aged cluded from our study, dietary habits of obese children 12 to 19 years was 289 pg/mL. These values are higher may be high in carbohydrate and fat and low in proteins than our cutoff levels. A detailed dietary questionnaire was not obtained from the children, so we could not cor- from animal sources that contain vitamin B12. Indeed in a recent study, low-nutrient-density foods contributed relate B12 levels with intake. more than 30% of daily energy intake,16 and intake of mi- Third, vitamin B12 levels reflect results in Israeli chil- cronutrients related inversely to intake of low-nutrient- dren and may not be comparable with data from other coun- density foods. In the present study, although obese chil- tries. Lower B12 levels have been reported in a population dren were new to our clinic and had not yet been started of young adult men in Israel compared with those of the 26 on a weight-loss diet, it is possible that some of them had United States. Unfortunately, B12 levels of healthy chil- tried unbalanced diets prior to their referral to the clinic. dren in Israel have not been reported. Finally, although low Furthermore, it is possible that obese children have in- vitamin B12 levels were significantly more prevalent among creased vitamin B12 needs compared with nonobese chil- obese children, B12 deficiency was more prevalent only with dren because of their increased growth and body sur- borderline significance, maybe because of the relatively small 17 face area. Finally, B12 concentrations noted reflect the sample size. These results are therefore preliminary obser- status in Israeli children and may not be comparable with vations and need further investigation. data from other countries. For example, in our cohort, In summary, our findings show that obese children the mean B12 concentration of normal-weight children are at high risk for low serum vitamin B12 levels. We specu- aged 6 to 11 years was 541 pg/mL and in the 12- to 18- late that causes may include poor dietary content, re- year-old group, 504 pg/mL, compared with 708 and 528 peated short-term restrictive diets, and increased require- pg/mL in same age groups in the United States.18 ments. We recommend that dietary assessment of obese Vitamin B12 is a cofactor in the synthesis of methio- children should include an estimation of vitamin B12 and nine from homocysteine; therefore, deficiency in vitamin other micronutrient intakes.

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©2006 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Accepted for Publication: March 24, 2006. 6. Nead KG, Halterman JS, Kaczorowski JM, Auinger P, Weitzman M. Overweight Author Affiliations: Pediatric and Dia- children and adolescents: a risk group for iron deficiency. Pediatrics. 2004; 114:104-108. betes Unit, Edmond and Lily Safra Children’s Hospital, 7. Oh R, Brown DL. Vitamin B12 deficiency. Am Fam Physician. 2003;67:979-986. Sheba Medical Center, Tel Hashomer, Israel (Dr Pinhas- 8. Strain JJ, Dowey L, Ward M, Pentieva K, McNulty H. B-, homocysteine Hamiel, Ms Doron-Panush, and Dr Reichman); Pediat- metabolism and CVD. Proc Nutr Soc. 2004;63:597-603. ric Endocrinology and Metabolism Unit, Schneider 9. CDC growth charts. US National Center for Health Statistics. http://www.cdc.gov Children’s Medical Center, Petah Tikva, Israel (Ms Doron- /nchs/about/major/nhanes/growthcharts/charts.htm. Accessed January 9, 2006. 10. Brasileiro RS, Escrivao MA, Taddei JA, D’Almeida V, Ancona-Lopez F, Carval- Panush and Dr Shatilin); Women and Children’s Health haes JT. Plasma total homocysteine in Brazilian overweight and non-overweight Research Unit, Gertner Institute, Tel Hashomer adolescents: a case-control study. Nutr Hosp. 2005;20:313-319. (Drs Reichman and Geva-Lerner); Food and Nutrition 11. Tungtrongchitr R, Pongpaew P, Tongboonchoo C, et al. Serum homocysteine, Administration and Department of Epidemiology and Pre- B12 and folic acid concentration in Thai overweight and obese subjects. Int J Vitam Nutr Res. 2003;73:8-14. ventive Medicine, Ministry of Health, Jerusalem, Israel 12. Guven A, Inanc F, Kilinc M, Ekerbicer H. Plasma homocysteine and lipoprotein (Dr Nitzan-Kaluski); and Sackler School of Medicine, Tel- (a) levels in Turkish patients with metabolic syndrome. Heart Vessels. 2005; Aviv University, Tel-Aviv, Israel (Dr Pinhas-Hamiel, 20:290-295. Ms Doron-Panush, and Drs Reichman, Nitzan-Kaluski, 13. Allen LH. Folate and vitamin B12 status in the Americas. Nutr Rev. 2004;62:S29-S33. Shalitin, and Geva-Lerner). 14. Rasmussen SA, Fernhoff PM, Scanlon KS. Vitamin B12 deficiency in children and adolescents. J Pediatr. 2001;138:10-17. Correspondence: Orit Pinhas-Hamiel, MD, Pediatric En- 15. Goraya JS. Vitamin B12 deficiency in childhood and adolescence. J Pediatr. 2002; docrine and Diabetes Unit, Sheba Medical Center, Ramat- 140:636. Gan, 52621, Israel ([email protected]). 16. Kant AK. Reported consumption of low-nutrient-density foods by American chil- Author Contributions: Study concept and design: Pinhas- dren and adolescents: nutritional and health correlates, NHANES III, 1988 to 1994. Hamiel, Doron-Panush, and Nitzan-Kaluski. Acquisi- Arch Pediatr Adolesc Med. 2003;157:789-796. 17. Food and nutrition guidelines for healthy adolescents. New Zealand Ministry of tion of data: Pinhas-Hamiel, Doron-Panush, and Shalitin. Health. http://www.moh.govt.nz. Accessed on July 7, 2006. Analysis and interpretation of data: Pinhas-Hamiel, 18. Wright JD, Bialostosky K, Gunter EW, et al. Blood folate and vitamin B12: United Reichman, and Geva-Lerner. Drafting of the manuscript: States, 1988-94. Vital Health Stat 11. 1998;243:1-78. Pinhas-Hamiel, Reichman, and Geva-Lerner. Critical re- 19. Herrmann W. The importance of hyperhomocysteinemia as a risk factor for dis- vision of the manuscript for important intellectual content: eases: an overview. Clin Chem Lab Med. 2001;39:666-674. 20. Homocysteine Studies Collaboration. Homocysteine and risk of ischemic heart Pinhas-Hamiel, Reichman, Nitzan-Kaluski, and Geva- disease and stroke: a meta-analysis. JAMA. 2002;288:2015-2022. Lerner. Statistical analysis: Geva-Lerner. Study supervi- 21. Martos R, Valle M, Morales R, Canete R, Gavilan MI, Sanchez-Margalet V. Hy- sion: Pinhas-Hamiel. perhomocysteinemia correlates with insulin resistance and low-grade systemic inflammation in obese prepubertal children. 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