Download PDF
Thromb Haemost 2023; 123(03): 270-282
DOI: 10.1055/a-1952-1946
Review Article

Hyperhomocysteinemia in Cardiovascular Diseases: Revisiting Observational Studies and Clinical Trials

Jean-Louis Guéant‡   *
1   Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, Departments of Hepato-Gastroenterology and Molecular Medicine, University Hospital of Nancy, F-54000 Nancy, France
2   Reference Centre for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, F-54000 Nancy, France
3   INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, F-54000 Nancy, France
,
Rosa-Maria Guéant-Rodriguez‡   *
1   Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, Departments of Hepato-Gastroenterology and Molecular Medicine, University Hospital of Nancy, F-54000 Nancy, France
2   Reference Centre for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, F-54000 Nancy, France
3   INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, F-54000 Nancy, France
,
Abderrahim Oussalah
1   Division of Biochemistry, Molecular Biology, Nutrition, and Metabolism, Departments of Hepato-Gastroenterology and Molecular Medicine, University Hospital of Nancy, F-54000 Nancy, France
2   Reference Centre for Inborn Errors of Metabolism (ORPHA67872), University Hospital of Nancy, F-54000 Nancy, France
3   INSERM UMR_S 1256, Nutrition, Genetics, and Environmental Risk Exposure (NGERE), Faculty of Medicine of Nancy, F-54000 Nancy, France
,
Stéphane Zuily
4   Vascular Medicine Division and Regional Competence Center for Rare Auto-Immune Diseases, INSERM UMR_S 1116 DCAC and CHRU-Nancy, Université de Lorraine, F-54000 Nancy, France
,
Irwin Rosenberg
5   Friedman School of Nutrition Science and Policy, Tufts University, Boston, Massachusetts, United States
› Author Affiliations Funding This work was financed by FHU ARRIMAGE, CHRU of Nancy and University of Lorraine, the AGIR grant of Université de Lorraine and CHRU of Nancy, and the French PIA project “Lorraine Université d'Excellence,” reference ANR-15-IDEX-04-LUE.
› Further Information
   Buy Article Permissions and Reprints


Abstract

Thromboembolic manifestations are relatively frequent in patients with intermediate/severe hyperhomocysteinemia (>30 µmol/L) related to inherited disorders and deficiencies in vitamin B12 and folate. In contrast, moderate hyperhomocysteinemia (15–30 µmol/L) is a modest predictor of cardiovascular risk. The recognition of homocysteine as a cardiovascular risk factor has been challenged by some but not all randomized clinical trials. We reviewed the main data of this controversy and formulated conclusions to be translated in clinical practice.

Homocysteine-lowering trials have been performed in cardiovascular subjects with moderate but not intermediate/severe hyperhomocysteinemia despite the dose–effect risk association. The first meta-analyses found no benefit and led cardiology societies not recommending homocysteine in the assessment of cardiovascular risk. This guideline challenged the need to diagnose and treat the nutritional and genetic causes of intermediate/major hyperhomocysteinemia and was not revised when larger meta-analyses concluded to a reduced risk of stroke. In a recent observational study, 84% of consecutive cardiovascular patients assessed for homocysteine had intermediate or major hyperhomocysteinemia, which was properly assessed in only half of the cases and related to B12 and/or folate deficiency and Addison/Biermer disease in 55% of these cases.

In conclusion, revisiting observational studies and clinical trials suggests that cardiovascular patients should be screened for hyperhomocysteinemia, when no other risk factor is found. Patients with intermediate/major hyperhomocysteinemia should be properly assessed and treated for B vitamin deficiencies and inherited disorders according to current guidelines. Further trials are needed to assess the effect of lowering homocysteine according to hyperhomocysteinemia categories at baseline.

Keywords

homocysteine - vascular risk - cardiovascular disease - vitamin B12 deficiency - folate deficiency - one-carbon metabolism

Author Contributions

J.-L.G. and R.-M.G.-R. conducted research, analyzed data, performed statistical analysis, wrote the manuscript, and had primary responsibility for the final content. A.O. conducted research, performed analyses, analyzed data, and revised the manuscript. S.Z. and I.R. conducted research, analyzed data, and revised the manuscript.


* These authors contributed equally to this work.


Supplementary Material



Publication History

Received: 27 June 2022

Accepted: 28 September 2022

Accepted Manuscript online:
28 September 2022

Article published online:
31 December 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany