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To the Editor:

We read with interest the article by Ghouri et al.,1 who reviewed data from recent prospective studies evaluating the associations of nonalcoholic fatty liver disease (NAFLD) with incident diabetes and cardiovascular disease (CVD). The authors concluded that there is a large and broadly consistent body of evidence establishing serum liver enzymes as predictors of incident diabetes. In contrast, although strong associations between serum liver enzymes and incident CVD have been described in several prospective studies and some studies have linked imaging-defined and biopsy-confirmed NAFLD with CVD risk, they concluded that the current evidence is inconsistent because of few incident CVD events, insufficient potential confounders, or both.1

We believe that the current evidence for a significant association between NAFLD and diabetes is no stronger than the evidence for the association observed between NAFLD and CVD. The same degrees of uncertainty and the same criticisms raised by the authors (e.g., the heterogeneity of the studies, the paucity of study outcomes, and the varying degrees of baseline adjustments for potential confounders) with respect to interpreting the results of the published studies that link NAFLD and CVD apply to those that link NAFLD and diabetes. Moreover, no studies have used liver biopsy to ascertain NAFLD and its association with diabetes, and only a few retrospective studies (all performed in Asian populations) have assessed ultrasound-diagnosed NAFLD as a determinant of incident diabetes.2-5

With respect to the association between NAFLD and CVD, the authors did not discuss the plentiful data linking NAFLD to an increased prevalence of clinical and subclinical CVD.6, 7 Again, they did not discuss recent data supporting potential pathophysiological and causative mechanisms linking NAFLD and CVD.6

Overall, we believe that the increased CVD morbidity and mortality rates are some of the most important clinical features associated with NAFLD. To date, there is a growing body of evidence suggesting that NAFLD patients carry multiple CVD risk factors; CVD is much more common than liver disease as a cause of death in NAFLD patients, especially in those with more advanced stages of disease; and NAFLD is linked to an increased risk of incident CVD events.6 However, further study is needed to determine whether NAFLD poses an independent risk above and beyond known risk factors. There is a suggestion in that direction, but the studies are too few and are methodologically not rigorous. Additional large-scale studies are also needed to elucidate whether ameliorating NAFLD will ultimately prevent or slow the development and progression of CVD.

In the interim, from the perspective of clinical practice, it is important that specialists and practicing clinicians be aware of the significant association between NAFLD and CVD, especially because of the high and growing prevalence of NAFLD. A multidisciplinary approach to the treatment of NAFLD patients, based on a careful evaluation of related risk factors and monitoring for cardiovascular and liver complications, is warranted. In particular, health care providers who manage patients with NAFLD (especially those with more advanced stages of NAFLD) not only should focus on liver disease but also should recognize the increased CVD risk and undertake early, aggressive risk factor modifications.

References

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  • 1
    Ghouri N, Preiss D, Sattar N. Liver enzymes, nonalcoholic fatty liver disease, and incident cardiovascular disease: a narrative review and clinical perspective of prospective data. HEPATOLOGY 2010; 52: 1156-1161.
  • 2
    Okamoto M, Takeda Y, Yoda Y, Kobayashi K, Fujino MA, Yamagata Z. The association of fatty liver and diabetes risk. J Epidemiol 2003; 13: 15-21.
  • 3
    Shibata M, Kihara Y, Taguchi M, Tashiro M, Otsuki M. Nonalcoholic fatty liver disease is a risk factor for type 2 diabetes in middle-aged Japanese men. Diabetes Care 2007; 30: 2940-2944.
  • 4
    Kim CH, Park JY, Lee KU, Kim JH, Kim HK. Fatty liver is an independent risk factor for the development of type 2 diabetes in Korean adults. Diabet Med 2008; 25: 476-481.
  • 5
    Yamada T, Fukatsu M, Suzuki S, Wada T, Yoshida T, Joh T. Fatty liver predicts impaired fasting glucose and type 2 diabetes mellitus in Japanese undergoing a health check-up. J Gastroenterol Hepatol 2010; 25: 352-356.
  • 6
    Targher G, Marra F, Marchesini G. Increased risk of cardiovascular disease in nonalcoholic fatty liver disease: causal effect or epiphenomenon? Diabetologia 2008; 51: 1947-1953.
  • 7
    Sookoian S, Pirola CJ. Non-alcoholic fatty liver disease is strongly associated with carotid atherosclerosis: a systematic review. J Hepatol 2008; 49: 600-607.

Giovanni Targher M.D.*, Christopher P. Day Ph.D, M.D.†, * Section of Endocrinology, Department of Medicine, University of Verona, Verona, Italy, † Institute of Cellular Medicine, Newcastle University, Newcastle Upon Tyne, United Kingdom.