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Reply to: “B vitamins for NASH: Use methylcobalamin, not cyanocobalamin”

  • Madhulika Tripathi
    Correspondence
    Corresponding authors. Address: Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, 169857, Singapore. Telephone: (+65) 65166719; Fax (+65) 62212534 (P.M. Yen).
    Affiliations
    Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 169857, Singapore
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  • Brijesh Kumar Singh
    Affiliations
    Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 169857, Singapore
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  • Paul Michael Yen
    Correspondence
    Corresponding authors. Address: Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, 169857, Singapore. Telephone: (+65) 65166719; Fax (+65) 62212534 (P.M. Yen).
    Affiliations
    Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders, Duke-NUS Medical School, 169857, Singapore

    Duke Molecular Physiology Institute, Duke University School of Medicine, 300 N Duke St, Durham, NC 27701, USA

    Endocrinology, Metabolism, and Nutrition, 30 Duke Medicine Circle Clinic 1A, Durham, NC 27710, United States
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Published:October 14, 2022DOI:https://doi.org/10.1016/j.jhep.2022.10.004

      Linked Article

      • B vitamins for NASH: Use methylcobalamin, not cyanocobalamin
        Journal of Hepatology
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          Tripathi et al.1 have elegantly shown how hyperhomocysteinemia aggravates non-alcoholic steatohepatitis (NASH). Their finding that treatment with folate and B12 reduced inflammation and improved hepatic histology suggests that folate and B12 will be important therapies for this condition. However, it is crucial to recognize that the form of B12 used should be methylcobalamin or hydroxycobalamin, not cyanocobalamin, particularly in patients with impaired kidney function, including the elderly.
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      • Vitamin B12 and folate decrease inflammation and fibrosis in NASH by preventing syntaxin 17 homocysteinylation
        Journal of HepatologyVol. 77Issue 5
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          Several recent clinical studies have shown that serum homocysteine (Hcy) levels are positively correlated, while vitamin B12 (B12) and folate levels are negative correlated, with non-alcoholic steatohepatitis (NASH) severity. However, it is not known whether hyperhomocysteinemia (HHcy) plays a pathogenic role in NASH.
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        Open Access
      To the Editor:
      We appreciate the letter by Dr. Spence advocating the use of methylcobalamin or hydroxycobalamin rather than the cyanocobalamin form of vitamin B12 (B12) in future clinical trials investigating the efficacy of B vitamins to prevent or treat NASH.

      Spence JD, B vitamins for NASH: use methylcobalamin, not cyanocobalamin, J Hepatol, https://dx.doi.org/10.1016/j.jhep.2022.08.019

      This is similar to the concern that he raised previously regarding studies that employed B12 for the prevention of stroke.
      • Spence J.D.
      • Hankey G.J.
      Problem in the recent American heart association guideline on secondary stroke prevention: B vitamins to lower homocysteine do prevent stroke.
      ,
      • Saposnik Gustavo
      The role of vitamin B in stroke prevention. A journey from observational studies to clinical trials and critique of the VITAmins to prevent stroke (vitatops).
      Although several large trials previously showed no benefit of folate and/or B vitamins (B6 and B12) in reducing cardiovascular events,
      • Saposnik Gustavo
      The role of vitamin B in stroke prevention. A journey from observational studies to clinical trials and critique of the VITAmins to prevent stroke (vitatops).
      reanalysis of data from one of them (the VISP trial) showed there was a 34% reduction in stroke/myocardial infarction events over 2 years when patients with impaired renal function were excluded.
      • Spence J.D.
      • Bang H.
      • Chambless L.E.
      • Stampfer M.J.
      Vitamin intervention for stroke prevention trial: an efficacy analysis.
      Subsequent studies using folate supplementation of enalapril in the China Stroke Primary Prevention trial and folate, B6, and low dose B12 in the Su.Fol.M3 trial also showed beneficial stroke prevention effects.
      • Xu X.
      • Qin X.
      • Li Y.
      • Sun D.
      • Wang J.
      • Liang M.
      • et al.
      Efficacy of folic acid therapy on the progression of chronic kidney disease: the renal sub study of the China stroke primary prevention trial.
      ,
      • Galan Pilar
      • Kesse-Guyot Emmanuelle
      • Czernichow Sébastien
      • Briancon Serge
      • Blacher Jacques
      • Hercberg Serge
      Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo-controlled trial.
      Almost all clinical studies for stroke prevention by B12 to date were conducted with cyanocobalamin. Dr. Spence has argued that the use of cyanocobalamin in individuals with renal impairment may have obscured the benefit of B vitamins in stroke prevention in earlier studies,
      • Spence J.D.
      • Yi Q.
      • Hankey G.J.
      B vitamins in stroke prevention: time to reconsider.
      ,
      • Spence J.D.
      • Hankey G.J.
      Problem in the recent American heart association guideline on secondary stroke prevention: B vitamins to lower homocysteine do prevent stroke.
      ,
      • Spence J.D.
      • Bang H.
      • Chambless L.E.
      • Stampfer M.J.
      Vitamin intervention for stroke prevention trial: an efficacy analysis.
      since it possible that increased cyanocobalamin leads to harmful accumulation of cyanide and thiocyanate in patients with impaired renal function.
      • Koyama K.
      • Yoshida A.
      • Takeda A.
      • Morozumi K.
      • Fujinami T.
      • Tanaka N.
      Abnormal cyanide metabolism in uraemic patients.
      While Dr. Spence’s recommendation of methylcobalamin or hydroxycobalamin makes sense based upon current available clinical data, it is noteworthy that no clinical studies have directly compared these two compounds vs. cyanocobalamin for stroke prevention in individuals with normal and/or impaired renal function. Moreover, the relative efficacy of these B12 compounds and the generation of toxic metabolites in the context of liver disease has not been examined. Interestingly, Talari et al. recently treated individuals with NASH with 1,000 ug cyanocobalamin for 12 weeks in a randomized control trial and observed statistically significant decreases in serum homocysteine and alanine aminotransferase, and hepatic steatosis after treatment in the treatment group, but found no significant changes when compared to the placebo group.
      • Talari Hamid Reza
      • Molaqanbari Mohamad Reza
      • Mokfi Milad
      • Taghizadeh Mohsen
      • Bahmani Fereshteh
      • Hossein Tabatabaei Seyed Mohammad
      • et al.
      The effects of vitamin B12 supplementation on metabolic profile of patients with non-alcoholic fatty liver disease: a randomized controlled trial.
      Although this study suggested there might be beneficial results with cyanocobalamin, it is not clear whether the findings would have been more robust if patients were treated with either methylcobalamin or hydroxycobalamin. Thus, while it appears that cyanocobalamin may confound the assessment of stroke prevention in patients with renal failure, it is not known whether this is the case for NASH without direct comparisons or further study of the B12 compounds. However, Dr. Spence’s caution on the use of particular B12 compounds in individuals with NASH is reasonable and needs to be considered, particularly if patients have concomitant renal impairment. Thus, in the absence of definitive data in individuals with NASH and renal failure, it still may be prudent to use methylcobalamin or hydroxycobalamin rather than cyanocobalamin for the treatment or prevention of NASH in clinical studies.

      Financial support

      The authors received no financial support to produce this manuscript.

      Conflict of interest

      The authors declare no conflict of interest.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Authors’ contributions

      MT, BKS and PMY finalized the letter.

      Supplementary data

      The following are the supplementary data to this article:

      References

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