Accepted Manuscript. Nonalcoholic Fatty Liver Disease and Mortality. Norbert Stefan, MD

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1 Accepted Manuscript Nonalcoholic Fatty Liver Disease and Mortality Norbert Stefan, MD PII: S (18) DOI: /j.cgh Reference: YJCGH To appear in: Clinical Gastroenterology and Hepatology Accepted Date: 8 February 2018 Please cite this article as: Stefan N, Nonalcoholic Fatty Liver Disease and Mortality, Clinical Gastroenterology and Hepatology (2018), doi: /j.cgh This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

2 Editorial * Nonalcoholic Fatty Liver Disease and Mortality * Norbert Stefan, MD 1,2,3 1 Department of Internal Medicine IV, Division of Endocrinology, Diabetology, Vascular Medicine, Nephrology and Clinical Chemistry, University of Tübingen, Tübingen, Germany 2 Institute of Diabetes Research and Metabolic Diseases (IDM) of the Helmholtz Zentrum München at the University of Tübingen, Tübingen, Germany 3 German Center for Diabetes Research (DZD), München-Neuherberg, Germany Address for correspondence Norbert Stefan, MD Department of Internal Medicine Otfried-Müller-Str. 10 D Tübingen, Germany phone: fax: norbert.stefan@med.uni-tuebingen.de * * Word count: 1059 words Conflict of interest: The author has no conflicts of interest with this work 1

3 The prevalence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide and about 25% of the world population are presently affected by this disease (1,2). NAFLD is associated with an increased risk for progression to severe and decompensated liver diseases such as cirrhosis and hepatocellular carcinoma (HCC) and to cardiometabolic diseases such as cardiovascular disease and type 2 diabetes (3-7). Thus, there is a large interest in the scientific field of research and in clinical practice to establish whether and to what extent NAFLD associates with an increased risk of mortality and to determine the major causes of death in NAFLD. In 2009, one of the first long-term outcomes studies of NAFLD found that patients with biopsy-proven nonalcoholic steatohepatitis (NASH) had an increased liver-related mortality and that the major cause of death in NAFLD was coronary artery disease, followed by malignancy (8). Since then much progress has been made in respect to the diagnosis, risk stratification and treatment of NAFLD (9). Still, because of the large variability in the prevalence of NAFLD in different ethnic groups (10,11), and the fact that the prevalence of NASH and fibrosis is similar in obese and non-obese subjects with NAFLD (12,13), there is immense interest in the scientific community to better understand such risk relationships in different populations. In this regards, Hwang et al. (14) investigated whether NAFLD was associated with increased overall and cause-specific mortality in a large population with NAFLD. This is the first study to examine NAFLD and mortality relationship separately in men and women. The authors analyzed data from 318,224 subjects in Korea (165,131 men and 153,093 women) with a mean age of 39.3 years, who participated in the Kangbuk Samsung Health Study cohort. The diagnosis of NAFLD was based on ultrasonography and mortality follow-up between January 1, 2002 and December 31, 2012 was based on nationwide death certificate data from the Korea National Statistical Office. 2

4 The authors found that during a median 5.7-year follow-up period, NAFLD was not associated with increased mortality from any cause in men. Indeed, after adjustment for age, body mass index, smoking status, daily alcohol consumption, and physical activity, men with NAFLD had a lower rate of death from cancer (hazard ratio, 0.79; 95% CI, ; P=.005). In contrast, in women, NAFLD was independently associated with death from all causes (hazard ratio, 1.79; 95% CI, ; P<.0001), death from cancer (hazard ratio, 1.83; 95% CI, ; P<.0001), death from cardiovascular disease (hazard ratio, 1.63; 95% CI, ; P=.0498), and death from liver disease (hazard ratio, 5.58; 95% CI, ; P=.003). So, do the data of this study suggest that NAFLD associates with increased risk of all-cause, cancer-, cardiovascular-, and liver-related death in women, but not in men? It is plausible that the subjects studied by Hwang et al. (14) were relatively healthy and the follow-up period of 5.7 years was too short to draw definite conclusions about the relationship of NAFLD with mortality. This is supported by the relatively low cumulative overall mortality of 0.51% in the study. Furthermore, women were on average 7 years older than men; NAFLD might have been present for a longer period of time in women than in men prior to entering the study. In addition, although women and men with NAFLD had a similar BMI, women with NAFLD had a higher prevalence of diabetes, hypertension, hypercholesterolemia and subclinical inflammation. A metabolically unhealthy condition is a strong predictor of cardiometabolic disease, cancer incidence and mortality in obese as well as non-obese individuals, and is also associated with more advanced stages of liver disease (15,16). Thus, women with NAFLD clearly had a higher cardiometabolic risk profile, which might have increased the power to detect relationships of NAFLD with mortality. Finally, only liver fat content was quantified (14) and no information about NASH or precisely measured fibrosis was available. The latter is important because only fibrosis, but no other histological liver characteristics, has been found to independently predict 3

5 all-cause and disease-specific mortality in patients with NAFLD (18-21). Thus, a valid quantification of fibrosis may be necessary to precisely predict NAFLD-associated mortality. However, in those studies most patients with borderline or definite NASH had stage 1-4 fibrosis (e.g. 84.9% in the study by Angulo et al. (19) and 82.0% in the study by Hagström et al. (21)). Therefore, the group of subjects with NASH stage 0 fibrosis was often too small to draw definite conclusions about the risk of mortality or liver-related endpoints in these subjects. Furthermore, in these studies, ballooning grade, portal inflammation grade and NASH categories also predicted increased mortality and liver-related events in univariate analyses (19), and because it is difficult to state when in the natural history of NASH fibrosis develops, I believe NASH should be considered as a condition that puts subjects at an increased risk. In the absence of histology data, Hwang et al. (14) estimated fibrosis in their subjects using the fibrosis-4 (FIB) score. This score was twice as high in women with NAFLD compared to men with NAFLD. In premenopausal women the prevalence of NAFLD is lower than in men, which is thought to be a result of the protective effect of estrogens regarding hepatic lipid accumulation and hepatic inflammation, which, however, abates after the onset of menopause (22). Furthermore, there are data indicating that the risk of NASH and advanced fibrosis is higher in postmenopausal women than men of a similar age (23-26). While the precise mechanisms explaining this difference are unknown, changes in estrogens and faster loss of subcutaneous adipose tissue in ageing women compared to men may be relevant (15,22,27,28). Of note, both, men and women with NAFLD and evidence of liver fibrosis (per high fibrosis score), had increased overall and cause-specific mortality, compared to subjects with NAFLD and absent fibrosis in the study by Hwang et al. suggesting that differences in fibrosis might explain the observed finding. 4

6 In conclusion, although a better phenotyping of NAFLD is necessary to investigate the relationship of NAFLD with mortality, studies like the one presented by Hwang et al. (14) can help raise awareness about the health consequences of NAFLD. Furthermore, early and noninvasive screening for NAFLD may help to better stratify the risk of overall and cause-specific mortality. Finally, there appears to be sexual dimorphic aspect in the incidence and progression of NAFLD. Postmenopausal women may need close monitor of NAFLD. References 1. Younossi ZM, Koenig AB, Abdelatif D, Fazel Y, Henry L, Wymer M. Global epidemiology of nonalcoholic fatty liver disease-meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 64:73-84, Loomba R, Sanyal AJ. Loomba R, Sanyal AJ. Nat Rev Gastroenterol Hepatol. 10:686-90, Ahmed A, Wong RJ, Harrison SA. Nonalcoholic Fatty Liver Disease Review: Diagnosis, Treatment, and Outcomes. Clin Gastroenterol Hepatol. 13: , Younossi ZM, Otgonsuren M, Henry L, Venkatesan C, Mishra A, Erario M, Hunt S. Association of nonalcoholic fatty liver disease (NAFLD) with hepatocellular carcinoma (HCC) in the United States from 2004 to Hepatology 62: , Pais R, Lebray P, Rousseau G, Charlotte F, Esselma G, Savier E, Thabut D, Rudler M, Eyraud D, Vezinet C, Siksik JM, Vaillant JC, Hannoun L, Poynard T, Ratziu V. Nonalcoholic fatty liver disease increases the risk of hepatocellular carcinoma in patients 5

7 with alcohol-associated cirrhosis awaiting liver transplants. Clin Gastroenterol Hepatol. 13: e2, Adams LA, Anstee QM, Tilg H, Targher G. Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases. Gut 66: , Stefan N, Fritsche A, Schick F, Häring HU. Phenotypes of prediabetes and stratification of cardiometabolic risk. Lancet Diabetes Endocrinol.4: , Rafiq N, Bai C, Fang Y, Srishord M, McCullough A, Gramlich T, Younossi ZM. Longterm follow-up of patients with nonalcoholic fatty liver. Clin Gastroenterol Hepatol. 7:234-8, Younossi ZM. Long-Term Outcomes of Nonalcoholic Fatty Liver Disease: From Nonalcoholic Steatohepatitis to Nonalcoholic Steatofibrosis. Clin Gastroenterol Hepatol. 15: , Saab S, Manne V, Nieto J, Schwimmer JB, Chalasani NP. Nonalcoholic Fatty Liver Disease in Latinos. Clin Gastroenterol Hepatol. 14:5-12, Rich NE, Oji S, Mufti AR, Browning JD, Parikh ND, Odewole M, Mayo H, Singal AG. Racial and Ethnic Disparities in Nonalcoholic Fatty Liver Disease Prevalence, Severity, and Outcomes in the United States: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol Sep 29. pii: S (17) doi: /j.cgh [Epub ahead of print] 12. Younossi ZM, Stepanova M, Negro F, Hallaji S, Younossi Y, Lam B, Srishord M. Nonalcoholic fatty liver disease in lean individuals in the United States. Medicine (Baltimore). 91:319-27,

8 13. Kim D, Kim WR. Nonobese Fatty Liver Disease. Clin Gastroenterol Hepatol. 15: , Hwang YC, Ahn HY, Park SW, Park CY. Non-alcoholic Fatty Liver Disease Associates with Increased Overall Mortality and Death from Cancer, Cardiovascular Disease, and Liver Disease in Women but Not Men. Clin Gastroenterol Hepatol Nov 17. pii: S (17) doi: /j.cgh [Epub ahead of print] 15. Stefan N, Schick F, Häring HU. Causes, Characteristics, and Consequences of Metabolically Unhealthy Normal Weight in Humans. Cell Metab. 26: , Stefan N, Häring HU, Schulze MB. Metabolically healthy obesity: the low-hanging fruit in obesity treatment? Lancet Diabetes Endocrinol Sep 14. pii: S (17) doi: /S (17) [Epub ahead of print] 17. McPherson S, Hardy T, Henderson E, Burt AD, Day CP, Anstee QM. Evidence of NAFLD progression from steatosis to fibrosing-steatohepatitis using paired biopsies: implications for prognosis and clinical management. J Hepatol. 62: , Ekstedt M, Hagström H, Nasr P, Fredrikson M, Stål P, Kechagias S, Hultcrantz R. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology. 61: , Angulo P, Kleiner DE, Dam-Larsen S, Adams LA, Bjornsson ES, Charatcharoenwitthaya P, Mills PR, Keach JC, Lafferty HD, Stahler A, Haflidadottir S, Bendtsen F. Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 149: e10, Dulai PS, Singh S, Patel J, Soni M, Prokop LJ, Younossi Z, Sebastiani G, Ekstedt M, Hagstrom H, Nasr P, Stal P, Wong VW, Kechagias S, Hultcrantz R, Loomba R. Increased 7

9 risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta-analysis. Hepatology 65: , Hagström H, Nasr P, Ekstedt M, Hammar U, Stål P, Hultcrantz R, Kechagias S. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 67: , Ballestri S, Nascimbeni F, Baldelli E, Marrazzo A, Romagnoli D, Lonardo A. NAFLD as a Sexual Dimorphic Disease: Role of Gender and Reproductive Status in the Development and Progression of Nonalcoholic Fatty Liver Disease and Inherent Cardiovascular Risk. Adv Ther Jun;34(6): Yang JD, Abdelmalek MF, Pang H, et al. Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology. 2014;59: Singh DK, Sakhuja P, Malhotra V, Gondal R, Sarin SK. Independent predictors of steatohepatitis and fibrosis in Asian Indian patients with non-alcoholic steatohepatitis. Dig Dis Sci Jul;53(7): Tapper EB, Krajewski K, Lai M, Challies T, Kane R, Afdhal N, Lau D. Simple noninvasive biomarkers of advanced fibrosis in the evaluation of non-alcoholic fatty liver disease. Gastroenterol Rep (Oxf) Nov;2(4): Bambha K, Belt P, Abraham M, et al. Ethnicity and nonalcoholic fatty liver disease. Hepatology. 2012;55: Stefan N, Häring HU, Hu FB, Schulze MB. Divergent associations of height with cardiometabolic disease and cancer: epidemiology, pathophysiology, and global implications. Lancet Diabetes Endocrinol May;4(5):

10 28. Suzuki A, Abdelmalek MF, Unalp-Arida A, Yates K, Sanyal A, Guy C, Diehl AM. Regional anthropometric measures and hepatic fibrosis in patients with nonalcoholic Fatty liver disease. Clin Gastroenterol Hepatol Dec;8(12):