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Caucasian lean subjects with non-alcoholic fatty liver disease share long-term prognosis of non-lean: time for reappraisal of BMI-driven approach?
  1. Ramy Younes1,2,3,
  2. Olivier Govaere1,
  3. Salvatore Petta4,
  4. Luca Miele5,6,
  5. Dina Tiniakos1,7,
  6. Alastair Burt1,
  7. Ezio David3,
  8. Fabio Maria Vecchio5,8,
  9. Marco Maggioni9,
  10. Daniela Cabibi10,
  11. Duncan McLeod11,
  12. Maria Jesus Pareja12,
  13. Anna Ludovica Fracanzani13,
  14. Rocio Aller14,
  15. Chiara Rosso3,
  16. Javier Ampuero15,
  17. Rocío Gallego-Durán15,
  18. Angelo Armandi3,
  19. Gian Paolo Caviglia3,
  20. Marco Y W Zaki1,16,
  21. Antonio Liguori5,
  22. Paolo Francione13,
  23. Grazia Pennisi4,
  24. Antonio Grieco5,6,
  25. Giovanni Birolo3,
  26. Piero Fariselli3,
  27. Mohammed Eslam17,
  28. Luca Valenti18,
  29. Jacob George17,
  30. Manuel Romero-Gómez15,
  31. Quentin Mark Anstee1,19,
  32. Elisabetta Bugianesi3
  1. 1 The Newcastle Liver Research Group, Translational & Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
  2. 2 Boehringer Ingelheim International GmbH, Ingelheim, Germany
  3. 3 Department of Medical Sciences, Division of Gastroenterology and Hepatology, A.O. Città della Salute e della Scienza di Torino, Università degli Studi di Torino, Torino, Italy
  4. 4 Sezione di Gastroenterologia, PROMISE, Università di Palermo, Palermo, Italy
  5. 5 Dipartimento Universitario Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Rome, Italy
  6. 6 Area Medicina Interna, Gastroenterologia e Oncologia Medica, Fondazione Policlinico A. Gemelli IRCCS, Rome, Italy
  7. 7 Dept of Pathology, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
  8. 8 Area Anatomia Patologica, Fondazione Policlinico Gemelli IRCCS, Rome, Italy
  9. 9 Department of Pathology, Ca’ Granda IRCCS Foundation, Milan, Italy
  10. 10 Pathology Institute, PROMISE, University of Palermo, Palermo, Italy
  11. 11 Department of Anatomical Pathology, Institute of Clinical Pathology and Medical Research (ICPMR), Westmead Hospital, Sydney, New South Wales, Australia
  12. 12 Pathology Unit, Hospital Universitario de Valme, Sevilla, Spain
  13. 13 Unit of Medicine and Metabolic Disease Ca' Granda IRCCS Foundation, Policlinico Hospital, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
  14. 14 Gastroenterology, Hospital Clínico Universitario de Valladolid, Centro de Investigación de Endocrinología y Nutrición, Universidad de Valladolid, Valladolid, Spain
  15. 15 UCM Digestive Diseases and SeLiver Group, Virgen del Rocio University Hospital, Institute of Biomedicine of Seville, University of Seville, Seville, Spain
  16. 16 Biochemistry Department, Faculty of Pharmacy, Minia University, El Minia, Egypt
  17. 17 Storr Liver Centre, Westmead Institute for Medical Research, Westmead Hospital and University of Sydney, Westmead, New South Wales, Australia
  18. 18 Translational Medicine, Department of Transfusion Medicine and Hematology, Fondazione IRCCS C'a Granda Ospedale Maggiore Policlinico, Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy
  19. 19 Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
  1. Correspondence to Dr Elisabetta Bugianesi, Department of Medical Sciences, University of Turin, Corso Dogliotti 14, Torino 10126, Italy; elisabetta.bugianesi{at}; Dr Quentin Mark Anstee, Translational & Clinical Research Institute, Newcastle University, Newcastle upon Tyne, UK; quentin.anstee{at}


Objective The full phenotypic expression of non-alcoholic fatty liver disease (NAFLD) in lean subjects is incompletely characterised. We aimed to investigate prevalence, characteristics and long-term prognosis of Caucasian lean subjects with NAFLD.

Design The study cohort comprises 1339 biopsy-proven NAFLD subjects from four countries (Italy, UK, Spain and Australia), stratified into lean and non-lean (body mass index (BMI) </≥25 kg/m2). Liver/non-liver-related events and survival free of transplantation were recorded during the follow-up, compared by log-rank testing and reported by adjusted HR.

Results Lean patients represented 14.4% of the cohort and were predominantly of Italian origin (89%). They had less severe histological disease (lean vs non-lean: non-alcoholic steatohepatitis 54.1% vs 71.2% p<0.001; advanced fibrosis 10.1% vs 25.2% p<0.001), lower prevalence of diabetes (9.2% vs 31.4%, p<0.001), but no significant differences in the prevalence of the PNPLA3 I148M variant (p=0.57). During a median follow-up of 94 months (>10 483 person-years), 4.7% of lean vs 7.7% of non-lean patients reported liver-related events (p=0.37). No difference in survival was observed compared with non-lean NAFLD (p=0.069).

Conclusions Caucasian lean subjects with NAFLD may progress to advanced liver disease, develop metabolic comorbidities and experience cardiovascular disease (CVD) as well as liver-related mortality, independent of longitudinal progression to obesity and PNPLA3 genotype. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD where the disease manifests at lower overall BMI thresholds.

Lay summary NAFLD may affect and progress in both obese and lean individuals. Lean subjects are predominantly males, have a younger age at diagnosis and are more prevalent in some geographic areas. During the follow-up, lean subjects can develop hepatic and extrahepatic disease, including metabolic comorbidities, in the absence of weight gain. These patients represent one end of a wide spectrum of phenotypic expression of NAFLD.

  • nonalcoholic steatohepatitis
  • fatty liver

Data availability statement

Data are available on reasonable request. N/A—No clinical trials.

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Data availability statement

Data are available on reasonable request. N/A—No clinical trials.

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  • QMA and EB are joint senior authors.

  • Twitter @RamyYounes9, @Dina Tiniakos, @lucavalenti75, @mromerogomez, @qanstee

  • Contributors Manuscript concept and design: RY, EB and QMA, writing: RY, data collection: RY, OG, SP, LM, DT, AB, ED, FMV, MM, DC, DM, MJP, ALF, RA, CR, JA, RG-D, AA, GPC, MYWZ, AL, PF, GP, AG, ME, LV, JG, MR-G, QMA and EB, statistical analyses: RY, EB, PF and QMA, revision and editing: EB, QMA, LV, JG and MR-G, acceptance of the final version: all authors.

  • Funding This study has been supported by the EPoS (Elucidating Pathways of Steatohepatitis) consortium funded by the Horizon 2020 Framework Program of the European Union under Grant Agreement 634413 and the Newcastle NIHR Biomedical Research Centre. The authors are contributing members of The European NAFLD Registry. The study was also supported by the Italian Ministry of Health, grant RF-2016-02364358 (Ricerca Finalizzata, Ministero della Salute). ME and JG are supported by the Robert W. Storr Bequest to the Sydney Medical Foundation, University of Sydney; a National Health and Medical Research Council of Australia (NHMRC) Program Grant (APP1053206, APP1149976) and Project grants (APP1107178 and APP1108422).

  • Competing interests None declared.

  • 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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