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Hyperhomocysteinemia predicts liver-related clinical outcomes in the general population

Published:November 29, 2022DOI:https://doi.org/10.1016/j.jhep.2022.11.021

      Keywords

      Abbreviations:

      NASH (non-alcoholic steatohepatitis), ELF (Enhanced Liver Fibrosis), sHR (subdistribution hazards ratio)

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      Conflicts of interest

      The authors declare that they have no conflict of interest regarding the content of this manuscript.

      Financial support

      Dr. Åberg was supported by Finska Läkaresällskapet, Academy of Finland (#338544), and Sigrid Jusélius Foundation. Dr. Männistö was supported by the Finnish Medical Foundation and State Research Funding (VTR). The researchers are all independent of the funders. The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

      Data availability statement

      Health 2000 data are available from the THL Biobank based on a research application, as explained on the website of the THL Biobank (https://thl.fi/en/web/thl-biobank/for-researchers).
      Tripathi and colleagues elegantly provided insight into the mechanisms by which hyperhomocysteinemia is involved in the progression of non-alcoholic steatohepatitis (NASH).
      • 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.
      The authors further found that vitamin B12 and folate supplementation alleviated steatohepatitis in this setting. The relevance of these findings for progression of chronic liver disease on the population level could, however, not be established in their experimental setting.
      We here further validate and elaborate on the association between blood homocysteine and liver disease in a large population-based cohort linked with electronic healthcare registers for liver-related clinical outcomes.
      From the Health 2000 study, a Finnish population-based health examination survey conducted in 2000–2001, we included 6024 adult participants with plasma homocysteine measured and without baseline liver disease.

      Aromaa A, Koskinen S. Health and functional capacity in Finland: baseline results of the Health 2000 health examination survey. Publications of National Public Health Institute, Series B 12/2004 Helsinki, Finland 2004

      Mean age was 53 years, 46% were men, mean body mass index 27 kg/m2, and 34% had a fatty liver index >60. Mean fasting plasma homocysteine levels at baseline was 12.0 μmol/L (median 11.0, IQR 9.2-13.5, range 3.7-111.3). Plasma homocysteine level was above the upper reference limit (15 μmol/L) in 977 (16%) individuals. At baseline, homocysteine levels correlated with the fatty liver index (r=0.18, P<0.001) and the Enhanced Liver Fibrosis (ELF) test score (r=0.38, P<0.001). Homocysteine levels remained significantly and positively associated with the ELF value (P<0.001) in linear regression analysis adjusted for age, sex, weekly alcohol intake, binge drinking frequency, smoking (current, never, previous), prevalent cardiovascular disease, diabetes, metabolic syndrome, body mass index, exercise habits, dietary energy intake and daily fat, protein and sugar intake.
      The cohort was linked with electronic healthcare registries for hospitalizations, cancers, and deaths regarding liver-related outcomes, incident cardiovascular disease, or incident cancer as previously described.
      • Åberg F.
      • Luukkonen P.K.
      • But A.
      • Salomaa V.
      • Britton A.
      • Petersen K.M.
      • et al.
      Development and validation of a model to predict incident chronic liver disease in the general population: the CLivD score.
      ,
      • Åberg F.
      • Puukka P.
      • Salomaa V.
      • Männistö S.
      • Lundqvist A.
      • Valsta L.
      • et al.
      Risks of light and moderate alcohol use in fatty liver disease: follow-up of population cohorts.
      During a median 13.1-year follow-up, there were 67 liver-related outcomes and 1018 deaths without liver disease, as well as 706 incident cardiovascular events and 605 incident cancers.
      We found a linear association between plasma homocysteine and incident liver-related outcomes (Figure 1). By age- and sex-adjusted Fine-Gray competing risk regression analysis, the subdistribution hazards ratio (sHR) of baseline plasma homocysteine level for liver-related outcomes was 1.05 (95% CI 1.03-1.07) and for the competing risk of death without liver disease, 1.03 (95% CI 1.02-1.04) (Figure 1). The association with liver-related outcomes remained robust and significant in multivariable propensity-score adjusted analysis, and in the subgroup of individuals with either non-alcoholic fatty liver disease (n=1964) or alcohol risk use (n=705) at baseline (Figure 1). These findings provide strong support for hyperhomocysteinemia as an important population-level risk factor for severe liver disease.
      Figure thumbnail gr1
      Figure 1The association between baseline plasma homocysteine level and incident liver-related liver outcomes (A) using restricted cubic splines and (B) by propensity-score adjusted Fine-Gray competing risk regression analysis. Associations with incident cardiovascular disease (CVD) and incident cancers are also shown.
      Furthermore, homocysteine also predicted liver-related outcomes independent of both the propensity score and baseline ELF score (sHR 1.04, 95% CI 1.02-1.06, P<0.001), which suggests that the association between hyperhomocysteinemia and liver outcomes is independent of baseline liver fibrosis stage. This finding, in turn, seems to support the observation by Tripathi and colleagues that hyperhomocysteinemia might reflect liver disease activity and risk for disease progression.
      • 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.
      Evidence exists to conclude that hyperhomocysteinemia (a) is relatively common in the population, (b) is pathophysiologically linked with NASH severity,
      • 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.
      (c) might be independently associated with liver-related outcomes, and (d) meta-analysis has shown that oral vitamin B/folate supplementation is able to reduce blood homocysteine levels.
      Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials
      Homocysteine lowering trialists’ collaboration.
      Such vitamin supplementation might even ameliorate NASH activity as indicated by Tripathi and colleagues.
      • 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.
      This combined evidence urgently calls for trials to investigate the effect of vitamin supplementation in persons with hyperhomocysteinemia for prevention and treatment of chronic liver disease.

      Acknowledgments

      The samples/data used for the research were obtained from THL Biobank (study numbers: BB2016_98, BB2017_101 and BB2019_31). We thank all study participants for their generous participation at THL Biobank and the Health 2000 Survey. We thank Siemens Healthineers for supplying reagents and consumables needed to conduct ELF testing.

      References

        • 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.
        J Hepatol. 2022; 77: 1246-1255https://doi.org/10.1016/j.jhep.2022.06.033
      1. Aromaa A, Koskinen S. Health and functional capacity in Finland: baseline results of the Health 2000 health examination survey. Publications of National Public Health Institute, Series B 12/2004 Helsinki, Finland 2004

        • Åberg F.
        • Luukkonen P.K.
        • But A.
        • Salomaa V.
        • Britton A.
        • Petersen K.M.
        • et al.
        Development and validation of a model to predict incident chronic liver disease in the general population: the CLivD score.
        J Hepatol. 2022; (S0168-82783): 128https://doi.org/10.1016/j.jhep.2022.02.021
        • Åberg F.
        • Puukka P.
        • Salomaa V.
        • Männistö S.
        • Lundqvist A.
        • Valsta L.
        • et al.
        Risks of light and moderate alcohol use in fatty liver disease: follow-up of population cohorts.
        Hepatology. 2020; 71: 835-848https://doi.org/10.1002/hep.30864
        • Lowering blood homocysteine with folic acid based supplements: meta-analysis of randomised trials
        Homocysteine lowering trialists’ collaboration.
        BMJ. 1998; 316: 894-898