Dataset Information

Experimental folate deficiency in human subjects: what is the influence of vitamin C status on time taken to develop megaloblastic anaemia?

ABSTRACT:

Background

In 1962 Victor Herbert developed megaloblastic anaemia four months after commencing a severely folate-deficient diet whereas, in his self-experiment 50 years later, this author took 19 months to fully deplete his liver folate store. This author proposed that his own larger initial liver folate store, due to his vegetarian diet and consumption of fortified foods, was the cause of the time difference.

Main text

This author now proposes that Herbert was also likely to have been deficient in vitamin C, thus shortening the time taken to develop folate deficiency. Several human experiments have confirmed the role of vitamin C in protecting reduced forms of folate from oxidation. Although there has historically been no consensus on the required intake of vitamin C, and official recommendations set a level below that required to ensure plasma saturation, recent research supports an intake that would ensure saturation. There have been no longitudinal experiments on human subjects since the introduction of voluntary or mandatory folic acid fortification of food, and the few published models differ significantly in their estimates of human liver folate storage capacity.

Conclusion

Because of the importance of folate in one-carbon metabolism, the potential influence of vitamin C intake on the time taken to deplete the liver folate store should be experimentally investigated.

SUBMITTER: Golding PH

PROVIDER: S-EPMC6007024 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Publications

Experimental folate deficiency in human subjects: what is the influence of vitamin C status on time taken to develop megaloblastic anaemia?

Golding Paul Henry PH

BMC hematology 20180619

<h4>Background</h4>In 1962 Victor Herbert developed megaloblastic anaemia four months after commencing a severely folate-deficient diet whereas, in his self-experiment 50 years later, this author took 19 months to fully deplete his liver folate store. This author proposed that his own larger initial liver folate store, due to his vegetarian diet and consumption of fortified foods, was the cause of the time difference.<h4>Main text</h4>This author now proposes that Herbert was also likely to have ...[more]

PMID: 29946471

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Project description:BackgroundThe few published studies comparing results between commercial red-cell folate immunoassays have found significant differences. None have provided longitudinal data during the development of megaloblastic anaemia from severe folate deficiency. The objective was to produce longitudinal data, comparing results between three commercial immunoassays for red-cell folate, generated by means of severe experimental folate deficiency.MethodsThis 58 year old male, initially replete in folate, used a folate-deficient diet to severely deplete himself of folate until overt megaloblastic anaemia developed. The Siemens Advia Centaur, Roche Elecsys 2010 and Beckman UniCel DxI 800 Access immunoassay systems were used, by different clinical pathology laboratories, to perform weekly assays for red-cell folate throughout the depletion stage. The results were analysed graphically four ways: comparison with lines of equality; number of standard deviations difference against the means; number of standard deviations difference over time; variation over time.ResultsThere were very significant differences, varying with time and folate concentration, between the results reported by the three laboratories. The differences were greatest, up to 17 standard deviations, between the Siemens Advia Centaur and each of the other two systems. Of the 85 results comparing the Siemens Advia Centaur and the Roche Elecsys 2010, two were within the 99.9% confidence interval. Of the 91 results comparing the Siemens Advia Centaur and the Beckman UniCel DxI 800 Access, 22 were within the 99.9% confidence interval. Of the 83 results comparing the Beckman UniCel DxI 800 Access and the Roche Elecsys 2010, 37 were within the 99.9% confidence interval.ConclusionsComparative longitudinal data from clinical pathology laboratories, produced during experimental folate deficiency, have exposed very significant differences in results between commercial red-cell folate immunoassays. One immunoassay, the Roche Elecsys 2010, failed to detect overt megaloblastic anaemia of severe folate deficiency.

Project description:BackgroundThe currently accepted theory, that the human liver store of folate is limited to about four months, is based on the findings of Victor Herbert and others of the era before folate fortification of food. A recent model, developed by Lin et al., predicts far greater liver folate storage capacity than reported by Herbert. The conflict between Herbert's and Lin's models needs to be resolved experimentally, however current research is restricted because ethical considerations prevent such risky experimentation on patients or healthy human volunteers. The objective was to provide a detailed record of the biochemical and haematological responses to the development of severe experimental folate deficiency in an initially replete human subject.MethodsThis 58 year old male severely depleted himself of folate, using a folate-deficient diet, until overt megaloblastic anaemia developed. The biochemical and haematological responses were monitored by routine blood tests. Daily intake of dietary supplements prevented deficiencies of other relevant nutrients.ResultsThe rate of change of all analytes was significantly slower, and the delay before any change for several analytes was significantly longer, than reported for previous experiments. The time before reporting of abnormal biochemical and haematological results was therefore very significantly longer than reported by Herbert, but was consistent with the recent model of Lin et al. Serum folate and red-cell folate became abnormally low after 219 and 413 days respectively. Macrocytic anaemia was produced after 469 days, and megaloblastic anaemia was confirmed by bone marrow biopsy on day 575. Folate starvation ceased on day 586, and recovery was complete on day 772.ConclusionsThe currently accepted four month time scale for development of megaloblastic anaemia from folate deficiency, based on the early work of Herbert and others, is not consistent with the results from this study. The > 300 day liver folate storage time, predicted by the model of Lin et al., is supported by this experiment. Self-experimentation has produced a detailed record of the biochemical and haematological responses to severe experimental folate deficiency, whereas using patients or healthy volunteers as subjects would be unethical.

Project description:BackgroundAgeing is characterised by physiological changes that can affect the nutrient availability and requirements. In particular, the status of vitamin D, cobalamin and folate has often been found to be critical in older people living in residential care. However, there is a lack of studies investigating the status of these nutrients in healthy and active home-dwelling elderly people.MethodsThe aim of this cross-sectional study was to assess the status of vitamin D based on serum concentrations of 25-hydroxycholecalciferol [25-(OH)D], cobalamin based on serum concentrations of holotranscobalamin (holoTC) and folate based on red blood cell (RBC) folate in unsupplemented, healthy and active German home-dwelling subjects ≥ 70 years of age (n = 134, mean ± SD: 75.8 ± 4.5 years). Dietary intake was assessed by 3-day food recalls. The study was conducted between March and November of 2021 (during the COVID-19 pandemic).ResultsThe mean 25-(OH)D concentration was high at 85.1 ± 26.0 nmol/L, while the majority of women (92%) and men (94%) had 25-(OH)D concentrations ≥ 50 nmol/L. Less than 10% of men and women had 25-(OH)D concentrations < 50 nmol/L. The mean holoTC concentration was 88.9 ± 33.7 pmol/L (94.8 ± 34.6 pmol/L in women and 73.6 ± 25.6 in men). Only 8% of the women were cobalamin deficient (< 50 pmol/L holoTC) compared to 22% of the men. The mean RBC folate concentration was 831 ± 244 nmol/L, while the prevalence of folate deficiency was 10%. Linear regression analysis showed that only folate equivalent intake was associated with the relevant nutrient status marker.ConclusionOur findings suggest that healthy, independently living older people with high levels of education, physical activity, and health awareness are not necessarily at higher risk of vitamin D, folate and cobalamin deficiency. Further studies are needed to verify these findings and to identify lifestyle and dietary patterns that can predict adequate nutrient status for healthy ageing.Trial registrationThis study is officially recorded in the German Clinical Trials Register (DRKS00021302).

Dataset Information

Experimental folate deficiency in human subjects: what is the influence of vitamin C status on time taken to develop megaloblastic anaemia?

Background

Main text

Conclusion

Publications

Experimental folate deficiency in human subjects: what is the influence of vitamin C status on time taken to develop megaloblastic anaemia?

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