To the Editor:
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.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.
[2]
,[3]
In the Vitamin Intervention for Stroke Prevention (VISP) trial, there was no benefit of B vitamins in the entire study population.[4]
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.- 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.
J Am Med Assoc. 2004; 291: 565-575
[5]
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.
[6]
All the events occurred among participants with GFR <50 ml/min/1.72 m2.[7]
In contrast, folic acid improved renal function and reduced a composite outcome including cardiovascular events among participants in the China Stroke Primary Prevention trial.[8]
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).
[9]
These issues were reviewed in 2022.[3]
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:
- Multimedia component 1
References
- Vitamin B12 and folate decrease inflammation and fibrosis in NASH by preventing Syntaxin 17 homocysteinylation.J Hepatol. 2022; 77: 1246-1255
- B vitamins in stroke prevention: time to reconsider.Lancet Neurol. 2017; 16: 750-760
- Problem in the recent American heart association guideline on secondary stroke prevention: B vitamins to lower homocysteine do prevent stroke.Stroke. 2022; 53 (101161STROKEAHA122038640): 2702-2708
- 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.J Am Med Assoc. 2004; 291: 565-575
- Vitamin intervention for stroke prevention trial: an efficacy analysis.Stroke. 2005; 36: 2404-2409
- Effect of B-vitamin therapy on progression of diabetic nephropathy: a randomized controlled trial.JAMA. 2010; 303: 1603-1609
- B-vitamin therapy for diabetic nephropathy: reply.JAMA. 2010; 304: 636-637
- Efficacy of folic acid therapy on the progression of chronic kidney disease: the renal substudy of the China stroke primary prevention trial.JAMA Intern Med. 2016; 176: 1443-1450
- Effects of B vitamins and omega 3 fatty acids on cardiovascular diseases: a randomised placebo controlled trial.BMJ. 2010; 341 (c6273)
Article info
Publication history
Published online: August 28, 2022
Accepted:
August 19,
2022
Received in revised form:
August 18,
2022
Received:
August 13,
2022
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
