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B vitamins for NASH: Use methylcobalamin, not cyanocobalamin

  • J. David Spence
    Correspondence
    Corresponding author. Address: Professor Emeritus of Neurology & Clinical Pharmacology, Western University, and Director, Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute, 1400 Western Road, London N6G 2V4, ON, Canada. Tel.: +1-519-931-5731, fax: +1-519-931-5737.
    Affiliations
    Stroke Prevention & Atherosclerosis Research Centre, Robarts Research Institute, Western University, London, ON, Canada
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Published:August 28, 2022DOI:https://doi.org/10.1016/j.jhep.2022.08.019

      Linked Article

      • 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
      • Reply to: “B vitamins for NASH: Use methylcobalamin, not cyanocobalamin”
        Journal of HepatologyVol. 78Issue 1
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          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.1 This is similar to the concern that he raised previously regarding studies that employed B12 for the prevention of stroke.3,4 Although several large trials previously showed no benefit of folate and/or B vitamins (B6 and B12) in reducing cardiovascular events,4 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.
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      To the Editor:
      Tripathi et al.
      • Tripathi M.
      • Singh B.K.
      • Zhou J.
      • Tikno K.
      • Widjaja A.
      • Sandireddy R.
      • et al.
      Vitamin B12 and folate decrease inflammation and fibrosis in NASH by preventing Syntaxin 17 homocysteinylation.
      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.
      It is now clear that folic acid and B12 reduce the risk of stroke; however, the benefit of B vitamins was obscured in the early trials by harm from cyanocobalamin among participants with renal failure.
      • 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.
      In the Vitamin Intervention for Stroke Prevention (VISP) trial, there was no benefit of B vitamins in the entire study population.
      • Toole J.F.
      • Malinow M.R.
      • Chambless L.E.
      • Spence J.D.
      • Pettigrew L.C.
      • Howard V.J.
      • et al.
      Lowering plasma total homocysteine to prevent recurrent stroke, myocardial infarction, and death in ischemic stroke patients: results of the vitamin intervention for stroke prevention (VISP) randomized trial.
      However, in a subgroup from which patients with impaired kidney function (an estimated glomerular filtration rate [eGFR] <46 ml/min/1.72 m2 – the 10th percentile of eGFR in the study population), there was a 34% reduction of stroke/myocardial infarction over 2 years.
      • Spence J.D.
      • Bang H.
      • Chambless L.E.
      • Stampfer M.J.
      Vitamin intervention for stroke prevention trial: an efficacy analysis.
      A trial in patients with diabetic nephropathy randomized to placebo vs. folate 2.5 mg, B6 25 mg and cyanocobalamin 1,000 μg daily showed faster decline of renal function, and a doubling of cardiovascular events, with B vitamins.
      • House A.A.
      • Eliasziw M.
      • Cattran D.C.
      • Churchill D.N.
      • Oliver M.J.
      • Fine A.
      • et al.
      Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial.
      All the events occurred among participants with GFR <50 ml/min/1.72 m2.
      • Spence J.D.
      • Eliasziw M.
      • House A.A.
      B-vitamin therapy for diabetic nephropathy: reply.
      In contrast, folic acid improved renal function and reduced a composite outcome including cardiovascular events among participants in the China Stroke Primary Prevention trial.
      • 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 substudy of the China stroke primary prevention trial.
      The greatest reduction of stroke with folate/B6/B12 was in the French Su.Fol.M3 trial, in which the renal function was much better than in the early trials, and the dose of cyanocobalamin was much lower: the mean serum creatinine was 78, vs. 99 in VISP, and the daily dose of cyanocobalamin was only 20 μg, vs. 400 μg in VISP. There was a 43% reduction of stroke in Su.Fol.OM3 over a median of 4.7 years (hazard ratio 0.57; 95% CI 0.33 to 0.97; p = 0.04).
      • Galan P.
      • Kesse-Guyot E.
      • Czernichow S.
      • Briancon S.
      • Blacher J.
      • Hercberg S.
      Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial.
      These issues were reviewed in 2022.
      • 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.
      B vitamins to lower homocysteine do reduce stroke, and seem to be beneficial in NASH, but methylcobalamin or hydroxycobalamin should be used instead of cyanocobalamin. Methylcobalamin is readily available, and not significantly more costly than cyanocobalamin. The dose of methylcobalamin would be equivalent to the dose of cyanocobalamin. A randomized controlled trial of B vitamins for NASH is needed.

      Financial support

      The authors received no financial support to produce this manuscript.

      Conflict of interest

      I have no financial conflict of interest related to this topic. I was the PI of the DIVINe trial, and a member of the Executive Committee of the VISP trial.
      Please refer to the accompanying ICMJE disclosure form for further details.

      Supplementary data

      The following are the supplementary data to this article:

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        Vitamin B12 and folate decrease inflammation and fibrosis in NASH by preventing Syntaxin 17 homocysteinylation.
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        B vitamins in stroke prevention: time to reconsider.
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        Problem in the recent American heart association guideline on secondary stroke prevention: B vitamins to lower homocysteine do prevent stroke.
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