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Non-alcoholic fatty liver disease in children and young adults is associated with increased long-term mortality

  • Tracey G. Simon
    Correspondence
    Corresponding author. Address: Massachusetts General Hospital, 55 Fruit Street, Wang 5, Gastroenterology Division, Boston, MA, USA; Tel.: +1-617-724-2401, fax: +1-617-724-5997.
    Affiliations
    Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA

    Harvard Medical School, Boston, MA, USA

    Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital, Boston, MA, USA
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  • Bjorn Roelstraete
    Affiliations
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
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  • Kayla Hartjes
    Affiliations
    Harvard Medical School, Boston, MA, USA

    Division of Pediatric Gastroenterology, Hepatology and Nutrition, Massachusetts General Hospital for Children, Boston, MA, USA
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  • Uzma Shah
    Affiliations
    Harvard Medical School, Boston, MA, USA

    Division of Pediatric Gastroenterology, Hepatology and Nutrition, Massachusetts General Hospital for Children, Boston, MA, USA
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  • Hamed Khalili
    Affiliations
    Division of Gastroenterology, Massachusetts General Hospital, Boston, MA, USA

    Harvard Medical School, Boston, MA, USA

    Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital, Boston, MA, USA
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  • Henrik Arnell
    Affiliations
    Department of Pediatric Gastroenterology, Hepatology and Nutrition, Astrid Lindgren Children’s Hospital, Karolinska University Hospital, Stockholm, Sweden

    Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
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  • Jonas F. Ludvigsson
    Affiliations
    Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden

    Department of Pediatrics, Orebro University Hospital, Orebro, Sweden

    Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, UK

    Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
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      Highlights

      • Biopsy-proven pediatric and young-adult NAFLD contributes to substantial excess mortality.
      • Mortality is increased with simple steatosis, and further amplified with steatohepatitis.
      • This excess mortality was primarily from cancer, cardiometabolic disease and liver disease.

      Background & Aims

      Longitudinal data are scarce regarding the natural history and long-term risk of mortality in children and young adults with biopsy-confirmed non-alcoholic fatty liver disease (NAFLD).

      Methods

      This nationwide, matched cohort study included all Swedish children and young adults (≤25 years) with biopsy-confirmed NAFLD (1966–2017; n = 718). NAFLD was confirmed histologically from all liver biopsies submitted to Sweden’s 28 pathology departments, and further categorized as simple steatosis or steatohepatitis (NASH). Patients with NAFLD were matched to ≤5 general population controls by age, sex, calendar year and county (n = 3,457). To account for shared genetic and early-life factors, we also matched patients with NAFLD to full-sibling comparators. Using Cox regression, we estimated multivariable-adjusted hazard ratios (aHRs) and 95% CIs.

      Results

      Over a median of 15.8 years, 59 patients with NAFLD died (5.5/1,000 person-years [PY]) compared to 36 population controls (0.7/1,000 PY; difference = 4.8/1,000 PY; multivariable aHR 5.88; 95% CI 3.77–9.17), corresponding to 1 additional death per 15 patients with NAFLD, followed for 20 years. The 20-year absolute risk of overall mortality was 7.7% among patients with NAFLD, and 1.1% among controls (difference = 6.6%; 95% CI 4.0–9.2). Findings persisted after excluding those who died within the first 6 months (aHR 4.65; 95% CI 2.92–7.42), and after using full-sibling comparators (aHR 11.72; 95% CI 3.18–43.23). Simple steatosis was associated with a 5.26-fold higher adjusted rate of mortality compared to controls (95% CI 3.05–9.07), and this was amplified with NASH (aHR 11.51, 95% CI 4.77–27.79). Most of the excess mortality was from cancer (1.67 vs. 0.07/1,000PY; aHR 15.60; 95% CI 4.97–48.93), liver disease (0.93 vs. 0.04/1,000PY; aHR 16.46; 95% CI 2.75–98.43) and cardiometabolic disease (1.12 vs. 0.14/1,000PY; aHR 4.32, 95% CI 1.73–10.79).

      Conclusions

      Swedish children and young adults with biopsy-confirmed NAFLD have significantly higher rates of overall, cancer-, liver- and cardiometabolic-specific mortality compared to matched general population controls.

      Lay summary

      Currently, the natural history and long-term risk of mortality in children and young adults with biopsy-confirmed non-alcoholic fatty liver disease (NAFLD) is unknown. This nationwide cohort study compared the risk of all-cause and cause-specific mortality in pediatric and young adult patients in Sweden with biopsy-confirmed NAFLD to matched general population controls. We found that compared to controls, children and young adults with biopsy-confirmed NAFLD and NASH have significantly higher rates of overall, cancer-, liver- and cardiometabolic-specific mortality.

      Graphical abstract

      Keywords

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