Tracey G Simon1,2,3, Bjorn Roelstraete4, Rajani Sharma5,6, Hamed Khalili1,2,3, Hannes Hagström7,8, Jonas F Ludvigsson4,9,10,11. 1. Division of Gastroenterology and Hepatology, Massachusetts General Hospital, Boston, MA. 2. Harvard Medical School, Boston, MA. 3. Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital, Boston, MA. 4. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden. 5. Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY. 6. Center for Liver Disease and Transplantation, Division of Digestive and Liver Diseases, Columbia University Irving Medical Center, New York, NY. 7. Division of Hepatology, Department of Upper Gastrointestinal Diseases, Karolinska University Hospital, Stockholm, Sweden. 8. Clinical Epidemiology Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden. 9. Department of Pediatrics, Orebro University Hospital, Orebro, Sweden. 10. Division of Epidemiology and Public Health, School of Medicine, University of Nottingham, Nottingham, United Kingdom. 11. Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY.
Abstract
BACKGROUND AND AIMS: Recent studies link NAFLD to an increased incidence of HCC and extrahepatic cancers. However, earlier studies were small or lacked liver histology, which remains the gold standard for staging NAFLD severity. APPROACH AND RESULTS: We conducted a population-based cohort study of all adults with histologically defined NAFLD in Sweden from 1966 to 2016 (N = 8,892). NAFLD was defined from prospectively recorded liver histopathology submitted to all 28 Swedish pathology departments and categorized as simple steatosis, nonfibrotic NASH, noncirrhotic fibrosis, and cirrhosis. NAFLD patients were individually matched to ≤5 general population controls without NAFLD by age, sex, calendar year, and county (N = 39,907). Using Cox proportional hazards modeling, we calculated multivariable adjusted HRs (aHRs) and 95% CIs. Over a median of 13.8 years, we documented 1,691 incident cancers among NAFLD patients and 6,733 among controls. Compared with controls, NAFLD patients had significantly increased overall cancer incidence (10.9 vs. 13.8 per 1,000 person-years [PYs]; difference = 2.9 per 1,000 PYs; aHR, 1.27 [95% CI, 1.18-1.36]), driven primarily by HCC (difference = 1.1 per 1,000 PYs; aHR, 17.08 [95% CI, 11.56-25.25]). HCC incidence rates increased monotonically across categories of simple steatosis, nonfibrotic NASH, noncirrhotic fibrosis, and cirrhosis (0.8 per 1,000 PYs, 1.2 per 1,000 PYs, 2.3 per 1,000 PYs, and 6.2 per 1,000 PYs, respectively; Ptrend < 0.01) and were further amplified by diabetes (1.2 per 1,000 PYs, 2.9 per 1,000 PYs, 7.2 per 1,000 PYs, and 15.7 per 1,000 PYs, respectively). In contrast, NAFLD was associated with modestly increased rates of pancreatic cancer, kidney/bladder cancer, and melanoma (differences = 0.2 per 1,000 PYs, 0.1 per 1,000 PYs, and 0.2 per 1,000 PYs, respectively), but no other cancers. CONCLUSIONS: Compared with controls, patients with biopsy-proven NAFLD had significantly increased cancer incidence, attributable primarily to HCC, whereas the contribution of extrahepatic cancers was modest. Although HCC risk was highest with cirrhosis, substantial excess risk was also found with noncirrhotic fibrosis and comorbid diabetes.
BACKGROUND AND AIMS: Recent studies link NAFLD to an increased incidence of HCC and extrahepatic cancers. However, earlier studies were small or lacked liver histology, which remains the gold standard for staging NAFLD severity. APPROACH AND RESULTS: We conducted a population-based cohort study of all adults with histologically defined NAFLD in Sweden from 1966 to 2016 (N = 8,892). NAFLD was defined from prospectively recorded liver histopathology submitted to all 28 Swedish pathology departments and categorized as simple steatosis, nonfibrotic NASH, noncirrhotic fibrosis, and cirrhosis. NAFLD patients were individually matched to ≤5 general population controls without NAFLD by age, sex, calendar year, and county (N = 39,907). Using Cox proportional hazards modeling, we calculated multivariable adjusted HRs (aHRs) and 95% CIs. Over a median of 13.8 years, we documented 1,691 incident cancers among NAFLD patients and 6,733 among controls. Compared with controls, NAFLD patients had significantly increased overall cancer incidence (10.9 vs. 13.8 per 1,000 person-years [PYs]; difference = 2.9 per 1,000 PYs; aHR, 1.27 [95% CI, 1.18-1.36]), driven primarily by HCC (difference = 1.1 per 1,000 PYs; aHR, 17.08 [95% CI, 11.56-25.25]). HCC incidence rates increased monotonically across categories of simple steatosis, nonfibrotic NASH, noncirrhotic fibrosis, and cirrhosis (0.8 per 1,000 PYs, 1.2 per 1,000 PYs, 2.3 per 1,000 PYs, and 6.2 per 1,000 PYs, respectively; Ptrend < 0.01) and were further amplified by diabetes (1.2 per 1,000 PYs, 2.9 per 1,000 PYs, 7.2 per 1,000 PYs, and 15.7 per 1,000 PYs, respectively). In contrast, NAFLD was associated with modestly increased rates of pancreatic cancer, kidney/bladder cancer, and melanoma (differences = 0.2 per 1,000 PYs, 0.1 per 1,000 PYs, and 0.2 per 1,000 PYs, respectively), but no other cancers. CONCLUSIONS: Compared with controls, patients with biopsy-proven NAFLD had significantly increased cancer incidence, attributable primarily to HCC, whereas the contribution of extrahepatic cancers was modest. Although HCC risk was highest with cirrhosis, substantial excess risk was also found with noncirrhotic fibrosis and comorbid diabetes.
Authors: Jeffrey V Lazarus; Henry E Mark; Quentin M Anstee; Juan Pablo Arab; Rachel L Batterham; Laurent Castera; Helena Cortez-Pinto; Javier Crespo; Kenneth Cusi; M Ashworth Dirac; Sven Francque; Jacob George; Hannes Hagström; Terry T-K Huang; Mona H Ismail; Achim Kautz; Shiv Kumar Sarin; Rohit Loomba; Veronica Miller; Philip N Newsome; Michael Ninburg; Ponsiano Ocama; Vlad Ratziu; Mary Rinella; Diana Romero; Manuel Romero-Gómez; Jörn M Schattenberg; Emmanuel A Tsochatzis; Luca Valenti; Vincent Wai-Sun Wong; Yusuf Yilmaz; Zobair M Younossi; Shira Zelber-Sagi Journal: Nat Rev Gastroenterol Hepatol Date: 2021-10-27 Impact factor: 46.802
Authors: Hannes Hagström; Maja Thiele; Tracey G Simon; Rajani Sharma; Anna Röckert Tjernberg; Bjorn Roelstraete; Jonas Söderling; Jonas F Ludvigsson Journal: United European Gastroenterol J Date: 2022-01-28 Impact factor: 4.623