Laurent Lam1, Hélène Fontaine2, Marc Bourliere3, Clovis Lusivika-Nzinga4, Céline Dorival4, Dominique Thabut5, Fabien Zoulim6, François Habersetzer7, Tarik Asselah8, Jean-Charles Duclos-Vallee9, Jean-Pierre Bronowicki10, Philippe Mathurin11, Thomas Decaens12, Nathalie Ganne13, Dominique Guyader14, Vincent Leroy15, Isabelle Rosa16, Victor De Ledinghen17, Paul Cales18, Xavier Causse19, Dominique Larrey20, Olivier Chazouilleres21, Moana Gelu-Simeon22, Véronique Loustaud-Ratti23, Sophie Metivier24, Laurent Alric25, Ghassan Riachi26, Jérôme Gournay27, Anne Minello28, Albert Tran29, Claire Geist30, Armand Abergel31, François Raffi32, Louis D'Alteroche33, Isabelle Portal34, Nathanaël Lapidus1, Stanislas Pol35, Fabrice Carrat36. 1. Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Department of Public Health, Hôpital Saint-Antoine, Paris, France; Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, Paris, France. 2. Department of Hepatology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France. 3. Department of Hepatology and Gastroenterology, Hôpital Saint-Joseph, Marseille, France. 4. Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, Paris, France. 5. Sorbonne Université, Department of Hepatology and Gastroenterology, Groupe Hospitalier Pitié-Salpétrière, AP-HP, INSERM UMR-S938, Paris, France. 6. Department of Hepatology, Hospices Civils de Lyon, INSERM U1052, Université de Lyon, Lyon, France. 7. CIC, Inserm 1110 et Pôle Hépato-digestif des Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, Strasbourg, France. 8. INSERM UMR 1149, Hepatology, Hospital Beaujon, Centre de Recherche sur l'Inflammation, (CRI), University Paris Diderot, Clichy, France. 9. AP-HP Hôpital Paul-Brousse, Centre Hépato-Biliaire, Villejuif, UMR-S 1193, Université Paris-Saclay, DHU HEPATINOV, Villejuif, France. 10. Inserm U1254 and Department of Hepato-Gastroenterology, University Hospital of Nancy Brabois, Université de Lorraine, Vandoeuvre-les-Nancy, France. 11. Service des Maladies de l'Appareil Digestif, Université Lille 2 and Inserm U795, France. 12. Department of Hepatology and Gastroenterology, Centre Hospitalo-Universitaire, INSERM U1209, Université Grenoble Alpes, Grenoble, France. 13. Department of Hepatology, Hôpitaux Universitaires Paris Seine-Saint-Denis, Site Jean Verdier, AP-HP, Bondy, France; Université Paris 13, Sorbonne Paris Cité et INSERM UMR 1162, Paris, France. 14. CHU de Rennes, Service d'Hépatologie, Univ Rennes 1, Inra, Inserm, Institut NUMECAN (Nutrition, Métabolismes et Cancer), UMR A 1341, UMR S 1241, F-35033 Rennes, France. 15. Department of Hepatology and Gastroenterology, Hôpital Henri Mondor, AP-HP, Université Paris-Est, INSERM U955, Créteil, France. 16. Department of Hepatology and Gastroenterology, Centre Hospitalier Intercommunal, Créteil, France. 17. Hepatology Unit, University Hospital Bordeaux and INSERM U1053, Bordeaux University, Pessac, France. 18. Hepatology Department, University Hospital, Angers, France; HIFIH Laboratory, Angers University, Angers, France. 19. Department of Hepatology and Gastroenterology, CHR Orléans, France. 20. Liver Unit-IRB-INSERM 1183, Hôpital Saint Eloi, Montpellier, France. 21. Department of Hepatology, Hôpital Saint-Antoine, AP-HP, Sorbonne Université, Paris, France. 22. Service d'Hépato-Gastroentérologie, CHU de la Guadeloupe - Faculté de Médecine, Université des Antilles, Pointe-à-Pitre Cedex, F-97110, France - INSERM, UMR-S1085/IRSET, F-35043 Rennes, France. 23. Department of Hepatology and Gastroenterology, CHU Limoges, U1248 INSERM, Univ. Limoges, F-87000 Limoges, France. 24. Hepatology Unit, CHU Rangueil, 31059 Toulouse, France. 25. Department of Internal Medicine and Digestive Diseases, CHU Purpan, UMR 152 Pharma Dev, IRD Toulouse 3 University, France. 26. Department of Hepatology and Gastroenterology, CHU Charles Nicolle, Rouen, France. 27. Gastroenterology and Hepatology Department, Institut des Maladies de l'Appareil Digestif, University Hospital of Nantes, Nantes, France. 28. Department of Hepatology and Gastroenterology, University Hospital Dijon, INSERM UMR 1231, France. 29. Digestive Center, Centre Hospitalier Universitaire de Nice, INSERM U1065-8, Nice, France. 30. Department of Hepatology and Gastroenterology, Centre Hospitalier Régional, Metz, France. 31. Department of Digestive and Hepatobiliary Diseases, Estaing University Hospital, Clermont-Ferrand, France; UMR 6602 CNRS-Sigma-Université Clermont Auvergne, Clermont-Ferrand, France. 32. Department of Infectious Diseases, Hotel-Dieu Hospital - INSERM CIC 1413, Nantes University Hospital, Nantes, France. 33. Unit of Hepatology, Hépatogastroentérologie, CHU Trousseau, 37044 Tours, France. 34. Service d'Hépato-Gastroentérologie, Hôpital de la Timone, Aix-Marseille Université, AP-HM, Marseille, France. 35. Department of Hepatology, Assistance Publique-Hôpitaux de Paris, Hôpital Cochin, Paris, France; Université de Paris; Inserm U-1223 and ICD, Institut Pasteur, Paris, France. 36. Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Department of Public Health, Hôpital Saint-Antoine, Paris, France; Sorbonne Université, INSERM, Institut Pierre Louis d'Épidémiologie et de Santé Publique, Paris, France. Electronic address: fabrice.carrat@iplesp.upmc.fr.
Abstract
BACKGROUND & AIMS: The factors predicting hepatocellular carcinoma (HCC) occurrence in chronic hepatitis B need to be precisely known to improve its detection. We identified pathways and individual predictive factors associated with HCC in the ANRS CO22 HEPATHER cohort. METHODS: The study analyzed HBV-infected patients recruited at 32 French expert hepatology centers from August 6, 2012, to December 31, 2015. We excluded patients with chronic HCV, HDV and a history of HCC, decompensated cirrhosis or liver transplantation. Structural equation models were developed to characterize the causal pathways leading to HCC occurrence. The association between clinical characteristics (age, gender, body-mass index, liver fibrosis, alcohol consumption, smoking status, diabetes, hypertension, dyslipidemia, alpha-fetoprotein, HBV DNA levels, antiviral therapy) and incident HCC was quantified. RESULTS: Among the 4489 patients included, 33 patients reported incident HCC. The median follow-up was 45.5 months. Age (β = 0.18 by decade, 95% CI 0.14-0.23), male gender (β = 0.23, 95% CI 0.18-0.29), metabolic syndrome (β = 0.28, 95% CI 0.22-0.33), alcohol consumption (β = 0.09, 95% CI 0.05-0.14) and HBV DNA (β = 0.25, 95% CI 0.170.34) had a significant and direct effect on the occurrence of advanced liver fibrosis. Liver fibrosis (β = 0.71, 95% CI 0.55-0.87) predicted, in turn, the occurrence of HCC. CONCLUSIONS: Liver fibrosis mediates the effects of age, gender, alcohol, metabolic syndrome and HBV DNA on the occurrence of HCC. Elderly men with chronic hepatitis B, risky alcohol use, advanced liver fibrosis, metabolic syndrome and high HBV DNA levels should be monitored closely to detect the development of HCC.
BACKGROUND & AIMS: The factors predicting hepatocellular carcinoma (HCC) occurrence in chronic hepatitis B need to be precisely known to improve its detection. We identified pathways and individual predictive factors associated with HCC in the ANRS CO22 HEPATHER cohort. METHODS: The study analyzed HBV-infected patients recruited at 32 French expert hepatology centers from August 6, 2012, to December 31, 2015. We excluded patients with chronic HCV, HDV and a history of HCC, decompensated cirrhosis or liver transplantation. Structural equation models were developed to characterize the causal pathways leading to HCC occurrence. The association between clinical characteristics (age, gender, body-mass index, liver fibrosis, alcohol consumption, smoking status, diabetes, hypertension, dyslipidemia, alpha-fetoprotein, HBV DNA levels, antiviral therapy) and incident HCC was quantified. RESULTS: Among the 4489 patients included, 33 patients reported incident HCC. The median follow-up was 45.5 months. Age (β = 0.18 by decade, 95% CI 0.14-0.23), male gender (β = 0.23, 95% CI 0.18-0.29), metabolic syndrome (β = 0.28, 95% CI 0.22-0.33), alcohol consumption (β = 0.09, 95% CI 0.05-0.14) and HBV DNA (β = 0.25, 95% CI 0.170.34) had a significant and direct effect on the occurrence of advanced liver fibrosis. Liver fibrosis (β = 0.71, 95% CI 0.55-0.87) predicted, in turn, the occurrence of HCC. CONCLUSIONS: Liver fibrosis mediates the effects of age, gender, alcohol, metabolic syndrome and HBV DNA on the occurrence of HCC. Elderly men with chronic hepatitis B, risky alcohol use, advanced liver fibrosis, metabolic syndrome and high HBV DNA levels should be monitored closely to detect the development of HCC.