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Original research
Non-alcoholic fatty liver disease and incident major adverse cardiovascular events: results from a nationwide histology cohort
  1. Tracey G Simon1,2,
  2. Bjorn Roelstraete3,
  3. Hannes Hagström4,5,6,
  4. Johan Sundström7,8,9,
  5. Jonas F Ludvigsson10,11,12,13
  1. 1 Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
  2. 2 Harvard Medical School, Boston, MA, USA
  3. 3 Medical Epidemiology and Biostatistics, Karolinska Institute, Stockhom, Sweden
  4. 4 Center for Digestive Diseases, Division of Hepatology, Karolinska Universitetssjukhuset, Stockholm, Sweden
  5. 5 Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
  6. 6 Department of Medicine, Huddinge, Karolinska Institutet, Stockholm, Sweden
  7. 7 Department of Medical Sciences, Uppsala University, Uppsala, Sweden
  8. 8 The George Institute for Global Health, University of New South Wales, Sydney, New South Wales, Australia
  9. 9 Department of Family Medicine and Community Health, Department of Population Health Science and Policy, Icahn School of Medicine at Mount Sinai, New York, NY, USA
  10. 10 Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden
  11. 11 Department of Pediatrics, Orebro University Hospital, Orebro, Sweden
  12. 12 Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, UK
  13. 13 Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA
  1. Correspondence to Dr Tracey G Simon, Massachusetts General Hospital Department of Medicine, Boston, Massachusetts, USA; tgsimon{at}


Objective Some data suggest a positive association between non-alcoholic fatty liver disease (NAFLD) and incident major adverse cardiovascular events (MACEs). However, data are lacking from large cohorts with liver histology, which remains the gold standard for staging NAFLD severity.

Design This population-based cohort included all Swedish adults with histologically confirmed NAFLD and without cardiovascular disease (CVD) at baseline (1966–2016, n=10 422). NAFLD was defined from prospectively recorded histopathology and categorised as simple steatosis, non-fibrotic steatohepatitis, non-cirrhotic fibrosis and cirrhosis. Patients with NAFLD were matched to ≤5 population controls without NAFLD or CVD, by age, sex, calendar year and county (n=46 517). Using Cox proportional hazards modelling, we calculated multivariable adjusted HRs (aHRs) and 95% CIs for MACE outcomes (ie, ischaemic heart disease (IHD), stroke, congestive heart failure (CHF) or cardiovascular (CV) mortality).

Results Over a median of 13.6 years, incident MACE was confirmed in 2850 patients with NAFLD and 10 648 controls. Patients with NAFLD had higher incidence of MACE than controls (24.3 vs 16.0/1000 person-years (PY); difference=8.3/1000 PY; aHR 1.63, 95% CI 1.56 to 1.70), including higher rates of IHD (difference=4.2/1000 PY; aHR 1.64, 95% CI 1.54 to 1.75), CHF (difference=3.3/1000 PY; aHR 1.75, 95% CI 1.63 to 1.87), stroke (difference=2.4/1000 PY; aHR 1.58, 95% CI 1.46 to 1.71) and CV mortality (difference=1.2/1000 PY; aHR 1.37, 95% CI 1.27 to 1.48). Rates of incident MACE increased progressively with worsening NAFLD severity (ptrend=0.02), with the highest incidence observed with cirrhosis (difference vs controls=27.2/1000 PY; aHR 2.15, 95% CI 1.77 to 2.61).

Conclusion Compared with matched population controls, patients with biopsy-proven NAFLD had significantly higher incidence of MACE, including IHD, stroke, CHF and CV mortality. Excess risk was evident across all stages of NAFLD and increased with worsening disease severity.

  • epidemiology
  • fibrosis
  • cardiovascular disease

Data availability statement

No data are available. No additional data are available due to Swedish regulations.

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Data availability statement

No data are available. No additional data are available due to Swedish regulations.

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  • Contributors Guarantor: the corresponding author (TGS) had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Acquisition of data: JFL. Analysis: BR. Writing the first draft of the manuscript: TGS and JFL.

    Study concept and design, interpretation of data, critical revision of the manuscript for important intellectual content and approval of final version: all coauthors.

  • Funding TGS was supported by NIH K23 DK122104, the Harvard University Center for AIDS Research and the Dana Farber/Harvard Cancer Center GI SPORE. HH was supported by grants from Region Stockholm (postdoctoral appointment). JFL was supported by the Karolinska Institutet.

  • Competing interests JFL coordinates an unrelated study on behalf of the Swedish IBD Quality Register that has received funding from Janssen Corporation. TGS has received research funding from Amgen and has received consulting fees from Aetion for work unrelated to this manuscript. HH reports research grants to his institution from AstraZeneca, Pfizer, Merck, EchoSens, Intercept and Gilead, and board advisory for Bristol-Myers Squibb and Gilead. JS reports ownership in companies providing services to Itrim, Amgen, Janssen, Novo Nordisk, Eli Lilly, Boehringer, Bayer, Pfizer and AstraZeneca, outside the submitted work. The remaining authors have no disclosures and no conflicts of interest to disclose.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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