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      Elevated Plasma Vitamin B 12 in Patients with Hepatic Glycogen Storage Diseases

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          Abstract

          Background: Hepatic glycogen storage diseases (GSDs) are inborn errors of metabolism affecting the synthesis or breakdown of glycogen in the liver. This study, for the first time, systematically assessed vitamin B 12 status in a large cohort of hepatic GSD patients. Methods: Plasma vitamin B 12, total plasma homocysteine (tHcy) and methylmalonic acid concentrations were measured in 44 patients with hepatic GSDs and compared to 42 healthy age- and gender-matched controls. Correlations of vitamin B 12 status with different disease markers of GSDs (including liver transaminase activities and triglycerides) as well as the vitamin B 12 intake were studied. Results: GSD patients had significantly higher plasma vitamin B 12 concentrations than healthy controls ( p = 0.0002). Plasma vitamin B 12 concentration remained elevated in GSD patients irrespective of vitamin B 12 intake. Plasma vitamin B 12 concentrations correlated negatively with triglyceride levels, whereas no correlations were detected with liver transaminase activities (GOT and GPT) in GSD patients. Merging biomarker data of healthy controls and GSD patients showed a positive correlation between vitamin B 12 status and liver function, which suggests complex biomarker associations. A combined analysis of biomarkers permitted a reliable clustering of healthy controls versus GSD patients. Conclusions: Elevated plasma concentration of vitamin B 12 (irrespective of B 12 intake) is a common finding in patients with hepatic GSD. The negative correlation of plasma vitamin B 12 with triglyceride levels suggests an influence of metabolic control on the vitamin B 12 status of GSD patients. Elevated vitamin B 12 was not correlated with GOT and GPT in our cohort of GSD patients. Merging of data from healthy controls and GSD patients yielded positive correlations between these biomarkers. This apparent dichotomy highlights the intrinsic complexity of biomarker associations and argues against generalizations of liver disease and elevated vitamin B 12 in blood. Further studies are needed to determine whether the identified associations are causal or coincidental, and the possible impact of chronically elevated vitamin B 12 on GSD.

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          Most cited references49

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          Microbial production of vitamin B12.

          One of the most alluring and fascinating molecules in the world of science and medicine is vitamin B12 (cobalamin), which was originally discovered as the anti pernicious anemia factor and whose enigmatic complex structure is matched only by the beguiling chemistry that it mediates. The biosynthesis of this essential nutrient is intricate, involved and, remarkably, confined to certain members of the prokaryotic world, seemingly never have to have made the eukaryotic transition. In humans, the vitamin is required in trace amounts (approximately 1 microg/day) to assist the actions of only two enzymes, methionine synthase and (R)-methylmalonyl-CoA mutase; yet commercially more than 10 t of B12 are produced each year from a number of bacterial species. The rich scientific history of vitamin B12 research, its biological functions and the pathways employed by bacteria for its de novo synthesis are described. Current strategies for the improvement of vitamin B12 production using modern biotechnological techniques are outlined.
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            Guidelines for the diagnosis and treatment of cobalamin and folate disorders.

            The clinical picture is the most important factor in assessing the significance of test results assessing cobalamin status because there is no 'gold standard' test to define deficiency. Serum cobalamin currently remains the first-line test, with additional second-line plasma methylmalonic acid to help clarify uncertainties of underlying biochemical/functional deficiencies. Serum holotranscobalamin has the potential as a first-line test, but an indeterminate 'grey area' may still exist. Plasma homocysteine may be helpful as a second-line test, but is less specific than methylmalonic acid. The availability of these second-line tests is currently limited. Definitive cut-off points to define clinical and subclinical deficiency states are not possible, given the variety of methodologies used and technical issues, and local reference ranges should be established. In the presence of discordance between the test result and strong clinical features of deficiency, treatment should not be delayed to avoid neurological impairment. Treatment of cobalamin deficiency is recommended in line with the British National Formulary. Oral therapy may be suitable and acceptable provided appropriate doses are taken and compliance is not an issue. Serum folate offers equivalent diagnostic capability to red cell folate and is the first-line test of choice to assess folate status.
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              Combined indicator of vitamin B12 status: modification for missing biomarkers and folate status and recommendations for revised cut-points.

              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.
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                Author and article information

                Journal
                J Clin Med
                J Clin Med
                jcm
                Journal of Clinical Medicine
                MDPI
                2077-0383
                22 July 2020
                August 2020
                : 9
                : 8
                : 2326
                Affiliations
                [1 ]Department of General Pediatrics, Adolescent Medicine and Neonatology, Faculty of Medicine, Medical Center—University of Freiburg, 79106 Freiburg, Germany; julia.hinkel@ 123456uniklinik-freiburg.de (J.H.); johannes.schmitt@ 123456uniklinik-freiburg.de (J.S.); stefanie.rosenbaum-fabian@ 123456uniklinik-freiburg.de (S.R.-F.); karl.otfried.schwab@ 123456uniklinik-freiburg.de (K.O.S.); ute.spiekerkoetter@ 123456uniklinik-freiburg.de (U.S.)
                [2 ]Department of Pediatrics, St. Hedwigs Campus, University Children’s Hospital Regensburg, 93049 Regensburg, Germany; Michael.Wurm@ 123456barmherzige-regensburg.de
                [3 ]Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA; jacobsd@ 123456ccf.org
                [4 ]Department of Molecular Biology and Genetics, Aarhus University, DK-8000 Aarhus C, Denmark; snf@ 123456mbg.au.dk
                [5 ]Laboratory of Clinical Biochemistry and Metabolism, Department of General Pediatrics, Adolescent Medicine and Neonatology, Medical Center - University of Freiburg, Faculty of Medicine, 79106 Freiburg, Germany
                Author notes
                [†]

                Equal senior contribution.

                Author information
                https://orcid.org/0000-0002-0911-5758
                https://orcid.org/0000-0001-5986-0468
                Article
                jcm-09-02326
                10.3390/jcm9082326
                7463656
                32707782
                18f5a23e-eee4-4c53-b534-a4f85b060a6c
                © 2020 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 19 June 2020
                : 17 July 2020
                Categories
                Article

                glycogen storage disease,glycogen,vitamin b12,cobalamin,liver transaminases,vitamin b12 intake

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