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Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops.

ABSTRACT: BACKGROUND:The 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. METHODS:This 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. RESULTS:The 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. CONCLUSIONS:The 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.

SUBMITTER: Golding PH

PROVIDER: S-EPMC4190280 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops.

Golding Paul Henry PH

SpringerPlus 20140923

<h4>Background</h4>The 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 preve ...[more]

PMID: 25332850

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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:BackgroundCancer patients are at increased risk of death from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Cancer and its treatment affect many haematological and biochemical parameters, therefore we analysed these prior to and during coronavirus disease 2019 (COVID-19) and correlated them with outcome.Patients and methodsConsecutive patients with cancer testing positive for SARS-CoV-2 in centres throughout the United Kingdom were identified and entered into a database following local governance approval. Clinical and longitudinal laboratory data were extracted from patient records. Data were analysed using Mann-Whitney U test, Fisher's exact test, Wilcoxon signed rank test, logistic regression, or linear regression for outcomes. Hierarchical clustering of heatmaps was performed using Ward's method.ResultsIn total, 302 patients were included in three cohorts: Manchester (n = 67), Liverpool (n = 62), and UK (n = 173). In the entire cohort (N = 302), median age was 69 (range 19-93 years), including 163 males and 139 females; of these, 216 were diagnosed with a solid tumour and 86 with a haematological cancer. Preinfection lymphopaenia, neutropaenia and lactate dehydrogenase (LDH) were not associated with oxygen requirement (O2) or death. Lymphocyte count (P < 0.001), platelet count (P = 0.03), LDH (P < 0.0001) and albumin (P < 0.0001) significantly changed from preinfection to during infection. High rather than low neutrophils at day 0 (P = 0.007), higher maximal neutrophils during COVID-19 (P = 0.026) and higher neutrophil-to-lymphocyte ratio (NLR; P = 0.01) were associated with death. In multivariable analysis, age (P = 0.002), haematological cancer (P = 0.034), C-reactive protein (P = 0.004), NLR (P = 0.036) and albumin (P = 0.02) at day 0 were significant predictors of death. In the Manchester/Liverpool cohort 30 patients have restarted therapy following COVID-19, with no additional complications requiring readmission.ConclusionPreinfection biochemical/haematological parameters were not associated with worse outcome in cancer patients. Restarting treatment following COVID-19 was not associated with additional complications. Neutropaenia due to cancer/treatment is not associated with COVID-19 mortality. Cancer therapy, particularly in patients with solid tumours, need not be delayed or omitted due to concerns that treatment itself increases COVID-19 severity.

Dataset Information

Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops.

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Severe experimental folate deficiency in a human subject - a longitudinal study of biochemical and haematological responses as megaloblastic anaemia develops.

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