Nutrition Division, Institute of Food Research, Norwich NR4 7UA, UK. birgit.teucher@bbsrc.ac.uk

Ascorbic acid (AA), with its reducing and chelating properties, is the most efficient enhancer of non-heme iron absorption when its stability in the food vehicle is ensured. The number of studies investigating the effect of AA on ferrous sulfate absorption far outweighs that of other iron fortificants. The promotion of iron absorption in the presence of AA is more pronounced in meals containing inhibitors of iron absorption. Meals containing low to medium levels of inhibitors require the addition of AA at a molar ratio of 2:1 (e.g., 20 mg AA: 3 mg iron). To promote absorption in the presence of high levels of inhibitors, AA needs to be added at a molar ratio in excess of 4:1, which may be impractical. The effectiveness of AA in promoting absorption from less soluble compounds, such as ferrous fumarate and elemental iron, requires further investigation. The instability of AA during food processing, storage, and cooking, and the possibility of unwanted sensory changes limits the number of suitable food vehicles for AA, whether used as vitamin fortificant or as an iron enhancer. Suitable vehicles include dry-blended foods, such as complementary, precooked cereal-based infant foods, powdered milk, and other dry beverage products made for reconstitution that are packaged, stored, and prepared in a way that maximizes retention of this vitamin. The consumption of natural sources of Vitamin C (fruits and vegetables) with iron-fortified dry blended foods is also recommended. Encapsulation can mitigate some of the AA losses during processing and storage, but these interventions will also add cost. In addition, the bioavailability of encapsulated iron in the presence/absence of AA will need careful assessment in human clinical trials. The long-term effect of high AA intake on iron status may be less than predicted from single meal studies. The hypothesis that an overall increase of dietary AA intake, or fortification of some foods commonly consumed with the main meal with AA alone, may be as effective as the fortification of the same food vehicle with AA and iron, merits further investigation. This must involve the consideration of practicalities of implementation. To date, programs based on iron and AA fortification of infant formulas and cow's milk provide the strongest evidence for the efficacy of AA fortification. Present results suggest that the effect of organic acids, as measured by in vitro and in vivo methods, is dependent on the source of iron, the type and concentration of organic acid, pH, processing methods, and the food matrix. The iron absorption-enhancing effect of AA is more potent than that of other organic acids due to its ability to reduce ferric to ferrous iron. Based on the limited data available, other organic acids may only be effective at ratios of acid to iron in excess of 100 molar. This would translate into the minimum presence/addition of 1 g citric acid to a meal containing 3 mg iron. Further characterization of the effectiveness of various organic acids in promoting iron absorption is required, in particular with respect to the optimal molar ratio of organic acid to iron, and associated feasibility for food application purposes. The suggested amount of any organic acid required to produce a nutritional benefit will result in unwanted organoleptic changes in most foods, thus limiting its application to a small number of food vehicles (e.g., condiments, beverages). However, fermented foods that already contain high levels of organic acid may be suitable iron fortification vehicles.

Carmel, R., "Subtle and Atypical Cobalamin Deficiency States," Am J Hematol 34.2 (1990) : 108-14.

Ellis, F.R., and Nasser, S., "A Pilot Study of Vitamin B12 in the Treatment of Tiredness," Br J Nutr 30.2 (1973) : 277-83.

Pennypacker, L.C., et al., "High Prevalence of Cobalamin Deficiency in Elderly Outpatients" (see comments), J Am Geriatr Soc 40.12 (1992) : 1197-204.

Markle, H.V., "Cobalamin," Crit Rev Clin Lab Sci 33.4 (1996) : 247-356.

Factors affecting the response to erythropoiesis-stimulating agents

Service de nephrologie et de transplantation renale, hopital Sud, CHU d'Amiens, avenue Rene-Laennec, 80054 Amiens 01, France.

Recombinant human erythropoietin (rHuEPO) has transformed the management chronic renal failure (CKD) and considerably improved the outcome of patients on regular chronic dialysis. However, a significant number of patients fail to respond to high of Erythropoiesis-stimulating agents (ESAs) and several causes of inadequate response to epoetin therapy have been identified. Some factors, such as gender, age, length of time on dialysis, type of dialysis and co-morbidities such as hemoglobinopathy, are not susceptible to clinical intervention. However, many other factors can be adjusted. Iron deficiency, whether functional or absolute, is the most common factor that limits the response to rHuEPO. Monitoring of iron parameters and a large use of iron supplementation result in an efficient epoetin response. Infection and inflammation have been shown to reduce responsiveness to ESAs by disrupting iron metabolism and increasing the release of pro-inflammatory cytokines that inhibit erythropoiesis. Increase dialysis dose is associated with improvements in anemia correction and reduced requirements for ESAs. Severe hyperparathyroidism and aluminum overload lead to a reduced number of responsive erythroid progenitor cells. Finally, a number of nutritional factors, such as deficiencies of carnitine, vitamin B12, folic acid, and vitamin C, are susceptible to alter erythropoiesis. Optimizing patient response to ESAs therefore requires consideration of many of well-established factors and is important for both patient outcomes and cost of treatment. 

Folate and vitamin B-12 status in relation to anemia, macrocytosis, and cognitive impairment in older Americans in the age of folic acid fortifification.

Jean Mayer US Department of Agriculture Human Nutrition Research Center on Aging, Tufts University, Boston, MA 02111, USA.

BACKGROUND: Historic reports on the treatment of pernicious anemia with folic acid suggest that high-level folic acid fortification delays the diagnosis of or exacerbates the effects of vitamin B-12 deficiency, which affects many seniors. This idea is controversial, however, because observational data are few and inconclusive. Furthermore, experimental investigation is unethical. OBJECTIVE: We examined the relations between serum folate and vitamin B-12 status relative to anemia, macrocytosis, and cognitive impairment (ie, Digit Symbol-Coding score < 34) in senior participants in the 1999-2002 US National Health and Nutrition Examination Survey. DESIGN: The subjects had normal serum creatinine concentrations and reported no history of stroke, alcoholism, recent anemia therapy, or diseases of the liver, thyroid, or coronary arteries (n = 1459). We defined low vitamin B-12 status as a serum vitamin B-12 concentration < 148 pmol/L or a serum methylmalonic acid concentration > 210 nmol/L-the maximum of the reference range for serum vitamin B-12-replete participants with normal creatinine. RESULTS: After control for demographic characteristics, cancer, smoking, alcohol intake, serum ferritin, and serum creatinine, low versus normal vitamin B-12 status was associated with anemia [odds ratio (OR): 2.7; 95% CI: 1.7, 4.2], macrocytosis (OR: 1.8; 95% CI: 1.01, 3.3), and cognitive impairment (OR: 2.5; 95% CI: 1.6, 3.8). In the group with a low vitamin B-12 status, serum folate > 59 nmol/L (80th percentile), as opposed to < or = 59 nmol/L, was associated with anemia (OR: 3.1; 95% CI: 1.5, 6.6) and cognitive impairment (OR: 2.6; 95% CI: 1.1, 6.1). In the normal vitamin B-12 group, ORs relating high versus normal serum folate to these outcomes were < 1.0 (P(interaction) < 0.05), but significantly < 1.0 only for cognitive impairment (0.4; 95% CI: 0.2, 0.9). CONCLUSION: In seniors with low vitamin B-12 status, high serum folate was associated with anemia and cognitive impairment. When vitamin B-12 status was normal, however, high serum folate was associated with protection against cognitive impairment

Influence of training volume and acute physical exercise on the homocysteine levels in endurance-trained men: interactions with plasma folate and vitamin B12.

Department of Prevention, Rehabilitation, and Sports Medicine, Center of Internal Medicine, University of Freiburg, Germany.

The interrelation between physical exercise and plasma levels of homocysteine (Hcy), vitamin B(12), and folic acid has not been examined. Therefore, we investigated the influence of extensive endurance training and acute intense exercise on plasma concentrations of total Hcy, vitamin B(12), and folic acid in 42 well-trained male triathletes. Examinations and blood sampling took place before and after a 30-day endurance training period as well as before and 1 and 24 h after a competitive exercise (sprint triathlon). Following the training period, no significant change in Hcy levels could be detected for the whole group. Subgroup analysis in quartiles of training volume revealed that - as compared with the lowest quartile (low-training group: 9.1 h training/week) - athletes in the highest training quartile (high-training group: 14.9 h training/week) exhibited a significant decrease in Hcy levels (from 12.7 +/- 2.3 to 11.7 +/- 2.4 micromol/l as compared with levels of 12.5 +/- 1.5 and 12.86 +/- 1.5 micromol/l in the low-training group; p < 0.05). The plasma folate levels were significantly higher in the high-training group at all points of examination (p < 0.05). 1 h and 24 h after competition, the Hcy concentration increased in all athletes independent of the previous training volume (24 h: 12.3 +/- 1.8 vs. 13.5 +/- 2.6 micromol/l; p < 0.001), although the increase was decisively stronger in the low-training group. 1 h after competition, the plasma folate concentration increased (7.03 +/- 2.1 vs. 8.33 +/- 2.1 ng/ml; p < 0.05) in all athletes. Multivariate analysis showed that the exercise-induced increase in the Hcy levels was dependent on baselines levels of folate and training volume, but not on the vitamin B(12) levels. In conclusion, although intense exercise acutely increased the Hcy levels, chronic endurance exercise was not associated with higher Hcy concentrations. Moreover, athletes with the highest training volume, exhibiting also the highest plasma folate levels, showed a decrease in Hcy levels following the training period as well as a much lower increase of the Hcy concentration after acute intense exercise. The combined effect of training and higher plasma folate levels to reduce Hcy should be investigated in future studies.

The effect of two different doses comprising the simultaneous administration of intravenous B-complex vitamins and oral folic acid on serum homocysteine levels in hemodialysis patients.

Renal Unit, Greece.

Background: Several regimens using different doses of folic acid (FA) alone or supplemented with B-complex vitamins (BCVs) have been tested for their ability to reduce total homocysteine (tHcy) serum levels in hemodialysis (HD) patients. In the present study, we assessed the effect of two different doses comprising the simultaneous administration of intravenous (IV) BCVs and an oral FA supplementation on serum tHCy levels in HD patients. Patients-methods: In a cohort of 49 patients (31 male, 18 female) undergoing chronic HD treatment for a mean of 40.0+/-40.7 months, serum concentrations of tHcy, folate and vitamin-B12 (vB12) were determined at the end of three sequential periods as follows: 20 weeks without any BCV and/or FA supplementation (period A), 20 weeks with a dose comprising the simultaneous administration of IV BCVs and an oral supplementation of 5 mg of FA once a week (period B), and 20 weeks with a dose comprising the simultaneous administration of IV BCVs and an oral supplementation of 5 mg of FA thrice a week (period C). An IV dose of BCVs consisting of a 5 mL solution containing vitamin B(1) (250 mg), vitamin B(6) (250 mg) and vitamin B(12) (1.5 mg) was administered at the end of hemodialysis. Results: Mean serum tHcy levels were significantly higher at the end of period A relative to levels at the end of periods B and C (35.8+/-23 mumol/L vs. 22.0+/-17.6 and 15.0+/-4.5 mumol/L, respectively; p < 0.000001). Mean serum folate levels and mean serum vB12 levels were significantly lower at the end of period A relative to levels at the end of periods B and C (p < 0.000001). Mean serum tHcy levels were lowest at the end of period C (p < 0.000001 in comparison to periods A and B), and 26 of the 49 HD patients (67.3%) possessed tHcy levels below 16 mumol/L. Conclusions: In HD patients, high doses consisting of the simultaneous administration of IV BCVs and an oral FA supplementation resulted in the efficient reduction of serum tHcy levels.

National Center for Environmental Health, Centers for Disease Control and Prevention, Atlanta, GA.

BACKGROUND: Monitoring the folate status of US population groups over time has been a public health priority for the past 2 decades, and the focus has been enhanced since the implementation of a folic acid fortification program in the mid-1990s. OBJECTIVE: We aimed to determine how population concentrations of serum and red blood cell (RBC) folate and serum vitamin B-12 have changed over the past 2 decades. DESIGN: Measurement of blood indicators of folate and vitamin B-12 status was conducted in approximately 23 000 participants in the prefortification third National Health and Nutrition Examination Survey (NHANES III; 1988-1994) and in approximately 8000 participants in 3 postfortification NHANES periods (together covering 1999-2004). RESULTS: Serum and RBC folate concentrations increased substantially (by 119-161% and 44-64%, respectively) in each age group in the first postfortification survey period and then declined slightly (by 5-13% and 6-9%, respectively) in most age groups between the first and third postfortification survey periods. Serum vitamin B-12 concentrations did not change appreciably. Prevalence estimates of low serum and RBC folate concentrations declined in women of childbearing age from before to after fortification (from 21% to <1% and from 38% to 5%, respectively) but remained unchanged thereafter. Prevalence estimates of high serum folate concentrations increased in children and older persons from before to after fortification (from 5% to 42% and from 7% to 38%, respectively) but decreased later after fortification. CONCLUSIONS: The decrease in folate concentrations observed longer after fortification is small compared with the increase soon after the introduction of fortification. The decrease is not at the low end of concentrations and therefore does not raise concerns about inadequate status. 

The hematological effects of oral supplementation of zinc to training athletes are reported in the present study. A total of 30 subjects between 16 and 22 yr of age volunteered to participate in a 4-wk study. They were equally divided into three groups. Group 1 acted as resting controls receiving daily doses of 3 mg Zn/kg body wt. Group 2 was actively engaged in wrestling and exercised for 90-120 min, 5 d a week. Group 3 was also actively engaged in wrestling and exercised for 90-120 min, 5 d a week, but they were supplemented with 3 mg Zn/kg body wt per day. The erythrocyte, leukocyte, and thrombocyte counts and the hemoglobin values of all subjects participating in the study were measured before and after exercise at the beginning and at the end of the 4-wk study period.In all groups, there were no significant differences in the measured parameters before and after exercise. At the end of the supplementation period, the parameters of the subjects in groups 1 and 3 were significantly higher than those of group 2, both before (p<0.005) and after (p<0.05) exercise. These results suggest that zinc supplementation has a positive effect on hematological parameters in athletes.

Effects of zinc supplementation on blood rheology during exercise.

Centre d'Exploration et de Readaptation des Anomalies du Metabolisme et du Muscle (CERAMM), H pital Lapeyronie, Montpellier, France.

We previously reported a higher blood viscosity at corrected hematocrit (45%) (explained by a higher value of erythrocyte rigidity) in football players with low serum zinc (Zn) and thus presumably Zn deficiency; subjects with low serum zinc had also an impairment in performance. This interventional study was undertaken in order to assess the effects of zinc supplementation (compared to placebo) on blood rheology and performance either at rest or during exercise. Ten male healthy volunteers (age: 26+/-1.3 yr; weight 67.9+/-2.24 kg; height 177+/-3 cm) received at random order either zinc (20 mg/day) and placebo, according to a double blind cross-over procedure, during seven days. In each case on the eighth day they performed a 25 min submaximal exercise-test. At rest blood viscosity at corrected hematocrit 45% (gamma = 1000 s(-1)) was lower after Zn (3.56+/-0.14 vs. 4.13+/-0.16 mPa.s, p = 0.009), explained by a lower RBC rigidity index 'k' according to Quemada's equation (1.65+/-0.07 vs. 1.84+/-0.08, p = 0.03). Hematocrit and plasma viscosity were unchanged, but RBC aggregation was decreased (laser retrodiffusion-derived aggregation time 'Ta' 3.52+/-0.51 vs. 2.75+/-0.59, p = 0.02). The increase in blood viscosity during exercise is lower after Zn than placebo. Blood viscosity at corrected hematocrit 45% remains unchanged during exercise after Zn, yet it increases after placebo. RBC rigidity index 'k' remains lower during exercise after Zn. The rating of perceived exertion (Borg's scale) at the 20th minute of exercise is lower after zinc (5.6+/-0.4 vs. 6.6+/-0.4, p = 0.008). This study confirms that Zn improves erythrocyte deformability, decreases the exercise-induced acute increase in blood viscosity, and improves exercise tolerance. Since Zn deficiencies are not unfrequent in sportsmen, these findings may be potentially relevant to sports nutrition.