Alex Brito

Vitamin B 12 deficiency

Vitamin B12 (B12; also known as cobalamin) is a B vitamin that has an important role in cellular metabolism, especially in DNA synthesis, methylation and mitochondrial metabolism. Clinical B12 deficiency with classic haematological and neurological manifestations is relatively uncommon. However, subclinical deficiency affects between 2.5% and 26% of the general population depending on the definition used, although the clinical relevance is unclear. B12 deficiency can affect individuals at all ages, but most particularly elderly individuals. Infants, children, adolescents and women of reproductive age are also at high risk of deficiency in populations where dietary intake of B12-containing animal-derived foods is restricted. Deficiency is caused by either inadequate intake, inadequate bioavailability or malabsorption. Disruption of B12 transport in the blood, or impaired cellular uptake or metabolism causes an intracellular deficiency. Diagnostic biomarkers for B12 status include decreased levels of circulating total B12 and transcobalamin-bound B12, and abnormally increased levels of homocysteine and methylmalonic acid. However, the exact cut-offs to classify clinical and subclinical deficiency remain debated. Management depends on B12 supplementation, either via high-dose oral routes or via parenteral administration. This Primer describes the current knowledge surrounding B12 deficiency, and highlights improvements in diagnostic methods as well as shifting concepts about the prevalence, causes and manifestations of B12 deficiency.

Combined indicator of vitamin B12 status: modification for missing biomarkers and folate status and recommendations for revised cut-points

Abstract Background: A novel approach to determine vitamin B12 status is to combine four blood markers: total B12 (B12), holotranscobalamin (holoTC), methylmalonic acid (MMA) and total homocysteine (tHcy). This combined indicator of B12 status is expressed as cB12=log10[(holoTC·B12)/(MMA·Hcy)]–(age factor). Here we calculate cB12 in datasets with missing biomarkers, examine the influence of folate status, and revise diagnostic cut-points. Methods: We used a database with all four markers (n=5211) plus folate measurements (n=972). A biomarker Z (assumed missing) was plotted versus X (a combination of other markers) and Y (age). Each chart was approximated by a function Ztheor, which predicted the potentially absent value(s). Statistical distributions of cB12 were aligned with physiological indicators of deficiency and used to determine cut-offs. Results: The predictive functions Ztheor allowed assessment of the “incomplete” indicators, 3cB12 (three markers known) and 2cB12 (two markers known). Predictions contained a systematic deviation associated with dispersion along two axes Z and X (and unaccounted by the least squares fit). Increase in tHcy at low serum folate was corrected (cB12+Δfolate) based on the function of Δfolate=log10(Hcyreal/Hcytheor) versus folate. Statistical distributions of cB12 revealed the boundaries of groups with B12 deficiency, i.e., cB12<–0.5. Conclusions: We provide equations that combine two, three or four biomarkers into one diagnostic indicator, thereby rescaling unmatched data into the same coordinate system. Adjustment of this indicator is required if serum folate is <10 nmol/L and tHcy is measured. Revised cut-points and guidelines for using this approach are provided.

Vitamin B-12 treatment of asymptomatic, deficient, elderly Chileans improves conductivity in myelinated peripheral nerves, but high serum folate impairs vitamin B-12 status response assessed by the combined indicator of vitamin B-12 status

BACKGROUND It is uncertain whether vitamin B-12 supplementation can improve neurophysiologic function in asymptomatic elderly with low vitamin B-12 status or whether folate status affects responses to vitamin B-12 supplementation. OBJECTIVE We assessed the effects of a single intramuscular injection of 10 mg vitamin B-12 (which also contained 100 mg vitamin B-6 and 100 mg vitamin B-1) on vitamin B-12 status and neurophysiologic function in elderly community-dwelling Chileans with low serum vitamin B-12 concentrations who were consuming bread fortified with folic acid. DESIGN A pretreatment and posttreatment study was conducted in 51 participants (median ± SD age: 73 ± 3 y; women: 47%) with serum vitamin B-12 concentrations <120 pmol/L at screening. Vitamin B-12 status was defined by combining vitamin B-12, plasma total homocysteine (tHcy), methylmalonic acid (MMA), and holotranscobalamin into one variable [combined indicator of vitamin B-12 status (cB-12)]. The response to treatment was assessed by measuring cB-12 and neurophysiologic variables at baseline and 4 mo after treatment. RESULTS Treatment increased serum vitamin B-12, holotranscobalamin, and cB-12 (P < 0.001) and reduced plasma tHcy and serum MMA (P < 0.001). Treatment produced consistent improvements in conduction in myelinated peripheral nerves; the sensory latency of both the left and right sural nerves improved on the basis of faster median conduction times of 3.1 and 3.0 ms and 3.3 and 3.4 ms, respectively (P < 0.0001). A total of 10 sensory potentials were newly observed in sural nerves after treatment. Participants with high serum folate at baseline (above the median, ≥33.9 nmol/L) had less improvement in cB-12 (P < 0.001) than did individuals whose serum folate was less than the median concentration (i.e., with a concentration <33.9 nmol/L). CONCLUSION Asymptomatic Chilean elderly with poor vitamin B-12 status displayed improved conductivity in myelinated peripheral nerves after vitamin B-12 treatment and an interaction with folate status, which was detected only with the use of cB-12. This trial was registered at www.controlled-trials.com as ISRCTN02694183.

Less than adequate vitamin D status and intake in Latin America and the Caribbean:a problem of unknown magnitude.

Background The prevalence of vitamin D deficiency in Latin America and the Caribbean is unknown. Objective To examine the prevalence data available on vitamin D deficiency in Latin America and the Caribbean. Methods A systematic review was conducted in 2011. Studies using biochemical biomarkers and dietary intake estimation were included. Studies conducted in apparently healthy individuals, independently of age, latitude, skin pigmentation, and season of the year at the time of blood collection, were included. Results A total of 243 studies were identified. The final number of selected studies was 28, including two National Health Surveys (Mexico and Argentina). There are studies that report the vitamin D status of specific subgroups conducted in Argentina, Brazil, Chile, Colombia, Ecuador, Guatemala, and Mexico. However, the small sample sizes in these studies and thus the low national representativeness of the reported data do not allow for an accurate assessment of vitamin D status at the regional level. In the majority of the countries with available data, we observed that vitamin D insufficiency was classified as a mild, moderate, or severe public health problem. The only country with a nationally representative sample was Mexico, which found 24%, 10%, 8%, and 10% prevalence rates of vitamin D insufficiency (25-hydroxyvitamin D < 50 nmol/L) in preschoolers, schoolchildren, adolescents, and adults, respectively. The prevalence of vitamin D deficiency (25-hydroxyvitamin D < 20 nmol/L) was less than 1% for all groups. Conclusions There is some indication that vitamin D insufficiency may be a public health problem in Latin America and the Caribbean, but the exact magnitude is currently unknown.

Body mass index, iron absorption and iron status in childbearing age women.

BACKGROUND The prevalence of obesity has increased at an alarming rate worldwide. Some studies have observed an association between iron (Fe) deficiency (ID) and obesity, however more research is needed. OBJECTIVE To assess whether body mass index (BMI) is associated with both Fe absorption and Fe status. METHODS A cross sectional sample of 318 Chilean childbearing age women was studied. The women received either a single dose of 0.5mg of Fe (n=137, group 1) or 3mg of Fe plus ascorbic acid (1:2 molar ratio) (n=181, group 2), both as FeSO4 with labeled radioisotopes. Fe absorption was assessed through radio Fe erythrocyte incorporation. Fe status was determined by hemoglobin (Hb), mean corpuscular volume, serum Fe, total iron binding capacity, transferrin saturation, erythrocyte Zn protoporphyrin and serum ferritin (SF). RESULTS 29%, 47% and 24% of the women were classified as normal, overweight or obese, respectively. Fe absorption was significantly lower in obese women (p<0.05). In group 1, the geometric mean and range ±1 SD of the percentage of Fe absorption for normal-weight women was 32.9% vs. 19.7% in obese. For group 2, this percentage was 36% vs. 30%, respectively (2-way ANOVA: BMI classification and Fe dose p<0.05; interaction p=0.34). Although Fe absorption was lower in obese women, they had higher SF (p<0.01) and Hb (p<0.05) concentrations. CONCLUSION Although we did not observe a relationship between BMI and Fe status, obese women displayed lower Fe absorption compared with overweight and normal weight women, possibly due to subclinical inflammation associated with obesity.

Effect of phytic acid, tannic acid and pectin on fasting iron bioavailability both in the presence and absence of calcium.

OBJECTIVE To determine the effect of phytic acid, tannic acid and pectin on fasting non-heme iron bioavailability in both the presence and absence of calcium. RESEARCH METHODS Twenty-eight apparently healthy adult females participated in two iron absorption studies using radioactive iron isotopes ((59)Fe and (55)Fe). One group received 5mg of iron (as FeSO4) alone (control), together with 10mg of phytic acid, 100mg of tannic acid and 250mg of pectin (study A), on different days. The second group received the same iron doses and compounds as the other group, plus 800mg of calcium (CaCl2) (study B). The compounds were administered after an overnight fast, and no food or beverages were consumed for the following 3h. Iron status and circulating radioactivity were measured in venous blood samples. RESULTS The geometric means of iron bioavailability (range±1SD) for iron alone, iron with phytic acid, iron with tannic acid, and iron with citrus pectin were 25.0% (11.9-52.0); 18.9% (9.9-35.8); 16.8% (8.7-32.3); and 21.1% (10.2-43.9), respectively (repeated-measures ANOVA, p<0.02 (Dunnetts post hoc: control vs tannic acid p<0.05). When 800mg of calcium was added (study B), iron bioavailability was 16.7% (10.1-27.5); 13.2% (7.1-24.6); 14.8% (8.8-25.1); and 12.6% (5.5-28.8), respectively (repeated-measures ANOVA, NS). CONCLUSIONS Tannic acid decreases the fasting bioavailability of non-heme iron, however this effect did not exist in the presence of calcium. No effect was observed by phytic acid or citrus pectin on fasting non-heme iron bioavailability in both the presence and absence of calcium.

Prevalence of Anemia in Latin America and the Caribbean

Background: In Latin America and the Caribbean, anemia has been a public health problem that affects mainly women of childbearing age and children under 6 years of age. However, the current prevalence of anemia in this region is unknown. Objective: To examine the latest available prevalence data on anemia in Latin America and the Caribbean. Methods: A systematic review was conducted in 2011 and updated in 2014. Studies determining the prevalence of anemia conducted in apparently healthy populations with national or regional representativeness were included in the review. Results: The lowest prevalence rates of anemia among children under 6 years of age were found in Chile (4.0%), Costa Rica (4.0%), Argentina (7.6%), and Mexico (19.9%). In Nicaragua, Brazil, Ecuador, El Panama, and Honduras, anemia was a moderate public health problem, with prevalence ranging Salvador, Cuba, Colombia, the Dominican Republic, Peru, from 20.1% to 37.3%. Anemia was a severe public health problem in Guatemala, Haiti, and Bolivia. The prevalence of anemia among women of childbearing age was lowest in Chile (5.1%). In Colombia, El Salvador, Costa Rica, Nicaragua, Ecuador, Mexico, Peru, Honduras, and Argentina, anemia was a mild public health problem, with prevalence ranging from 7.6% to 18.7%. In Guatemala, Brazil, the Dominican Republic, and Bolivia, anemia was a moderate public health problem, with prevalence ranging from 21.4% to 38.3%. Panama and Haiti had the highest reported prevalence rates (40.0% and 45.5%, respectively), and anemia was considered a severe public health problem in those countries. Conclusions: Anemia remains a public health problem in children under 6 years of age and women of childbearing age in most Latin America and Caribbean countries for which data are available.

Folate and Vitamin B12 Status in Latin America and the Caribbean: An Update

Background: The current magnitude of folate and vitamin B12 deficiency in Latin America and the Caribbean is uncertain. Objective: To summarize data on plasma or serum vitamin B12 and folate concentrations in Latin America and the Caribbean reported since 1990, a period that covers the era before and after the introduction of folic acid fortification. Methods: A systematic review was conducted in 2012 and updated in 2014. Studies and surveys using biochemical biomarkers and conducted in apparently healthy individuals were identified. Results: Folate deficiency in Latin America and the Caribbean appears not to be a public health problem (prevalence < 5%) after the introduction of folic acid fortification. However, there is some indication that high rates of low or marginal vitamin B12 status remain in most locations and across population groups. Conclusions: Adding vitamin B12 as a fortificant with folic acid may be the best strategy in areas where vitamin B12 deficiency is an established concern.

Iron Status Biomarkers and C-Reactive Protein in Children Aged 19 to 72 Months in Chile

Background The Chilean Ministry of Health has combated iron deficiency through the delivery of fortified milk by the National Complementary Feeding Program (NCFP). Objective To assess iron status and associations between biomarkers of iron status and serum C-reactive protein (CRP) in 218 beneficiaries of the NCFP aged 19 to 72 months in Santiago and Valparaiso, Chile. Methods Blood was collected from a cross-sectional representative sample. Iron status (measured by hemoglobin, zinc protoporphyrin, and serum ferritin levels) and inflammation (according to CRP level) were determined. Results Serum CRP level was positively associated with serum ferritin and zinc protoporphyrin levels (r = 0.16 and r = 0.15; p = .0168 and p = .0290, respectively). Serum ferritin was higher among children with high CRP (> 10 mg/dL) than among those with low CRP (≤ 10 mg/dL) (p = .003). After adjustment for 10, 6, and 5 mg/L CRP, the prevalence of low serum ferritin changed from 56.4% without adjustment to 60.6%, 61.5%, and 42.7%, respectively, and the prevalence of high zinc protoporphyrin changed from 22.9% to 21.6%, 17.4%, and 17.9%, respectively. There were no differences between regions in biomarkers of iron status. There was no association between consumption of fortified milk and the prevalence of abnormal serum ferritin (< 15 μg/L) after adjustment for sex, age, and breastfeeding (OR, 1.00; 95% CI, 0.99 to 1.01; p = .288). After adjustment for 10 mg/L CRP, 5.5% were classified as having iron-deficiency anemia, 42.7% as having iron-deficiency erythropoiesis, 17.9% as having depleted iron stores, and 35.8% as having normal iron status. Conclusions CRP level was positively associated with serum ferritin and zinc protoporphyrin levels. Chilean children aged 19 to 72 months from Santiago and Valparaiso who were beneficiaries of the NCFP had a low prevalence of iron-deficiency anemia, a high prevalence of iron-deficiency erythropoiesis, and a moderate prevalence of depleted iron stores.

Comparison of two modes of vitamin B(12) supplementation on neuroconduction and cognitive function among older people living in Santiago, Chile: a cluster randomized controlled trial. a study protocol ISRCTN 02694183

BackgroundOlder people have a high risk of vitamin B12 deficiency; this can lead to varying degrees of cognitive and neurological impairment. CBL deficiency may present as macrocytic anemia, subacute combined degeneration of the spinal cord, or as neuropathy, but is often asymptomatic in older people. Less is known about subclinical vitamin B12 deficiency and concurrent neuroconduction and cognitive impairment. A Programme of Complementary Feeding for the Older Population (PACAM) in Chile delivers 2 complementary fortified foods that provide approximately 1.4 μg/day of vitamin B12 (2.4 μg/day elderly RDA). The aim of the present study is to assess whether supplementation with vitamin B12 will improve neuroconduction and cognitive function in older people who have biochemical evidence of vitamin B12 insufficiency in the absence of clinical deficiency.MethodsWe designed a cluster double-blind placebo-controlled trial involving community dwelling people aged 70-79 living in Santiago, Chile. We randomized 15 clusters (health centers) involving 300 people (20 per cluster). Each cluster will be randomly assigned to one of three arms: a) a 1 mg vitamin B12 pill taken daily and a routine PACAM food; b) a placebo pill and the milk-PACAM food fortified to provide 1 mg of vitamin B12; c) the routine PACAM food and a placebo pill.The study has been designed as an 18 month follow up period. The primary outcomes assessed at baseline, 4, 9 and 18 months will be: serum levels of vitamin B12, neuroconduction and cognitive function.ConclusionsIn view of the high prevalence of vitamin B12 deficiency in later life, the present study has potential public health interest because since it will measure the impact of the existing program of complementary feeding as compared to two options that provide higher vitamin B12 intakes that might potentially may contribute in preserving neurophysiologic and cognitive function and thus improve quality of life for older people in Chile.Trial registrationISRCTN: ISRCTN02694183