What will happen in patients with advanced nonalcoholic fatty liver disease?

What will happen in patients with advanced nonalcoholic fatty liver disease?

Takefumi Kimura1,2, Naoki Tanaka3,4, Eiji Tanaka2

1Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA; 2Department of Internal Medicine, Division of Gastroenterology, 3Department of Metabolic Regulation, Shinshu University School of Medicine, Matsumoto, Japan; 4International Research Center for Agricultural Food Industry, Shinshu University, Matsumoto, Japan

Correspondence to: Takefumi Kimura, MD, PhD. Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bldg 8, B1A07, Bethesda, MD 20892, USA. Email: kimuratakefumii@yahoo.co.jp; takefumi.kimura@nih.gov.

Comment on: Vilar-Gomez E, Calzadilla-Bertot L, Wai-Sun Wong V, et al. Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study. Gastroenterology 2018;155:443-457.e17.

Submitted Dec 20, 2018. Accepted for publication Jan 11, 2019.

doi: 10.21037/hbsn.2019.01.04

Non-alcoholic fatty liver disease (NAFLD) and advanced form non-alcoholic steatohepatitis (NASH) have been become globally major chronic liver diseases (1,2). NAFLD is one of the leading causes of liver cirrhosis, hepatic failure, and hepatocellular carcinoma (HCC) (3). A large number of retrospective studies reported the importance of hepatic fibrosis with NAFLD patients as the strongest factor of liver-related mortality (4,5). On the other hand, NAFLD patients with advanced hepatic fibrosis are thought to have higer risk of developing vascular events and extrahepatic cancers because of the high prevalence of coexisting cardiometabolic risk factors, such as hypertension, diabetes mellitus, dyslipidemia, and obesity (6). However, since former literatures included only few NAFLD patients with advanced hepatic fibrosis, it is hard to estimate the accurate risk on the whole spectrum of these complications.

Vilar-Gomez et al. reported a multinational prospective study to clarify predictive factors for outcomes in large numbers of biopsy-confirmed NAFLD patients with advanced fibrosis, which investigated the long period overall liver transplantation free survival and cumulative incidences of major clinical events such as hepatic failure, HCC, vascular event (ischemic heart disease or stroke), and extrahepatic cancer (7,8). In the mean follow-up time of 5.5 years (range, 2.7–8.2 years), 37 NAFLD patients passed away, 37 underwent liver transplantation, 88 developed first hepatic failure events, 41 developed HCC, 14 occurred vascular events, and 30 had extrahepatic cancers. The authors reported that death/transplantation, hepatic failure, and HCC were significantly related with baseline cirrhosis and mild steatosis (<33%). Less hepatic fat was thought to be associated with ‘burned-out NASH’ status in NAFLD patients with cirrhosis (9), and these results were quite consistent with previous reports.

What impressed us in this manuscript was mainly following three points. Firstly, the cumulative incidence rate of vascular events was higher in NAFLD patients with F3 grade fibrosis (7%; 95% CI: 3–18%) than NAFLD patients with cirrhosis (2%; 95% CI: 0–6%). It was generally well known that there are many vascular events in patients with liver cirrhosis (10). According to author’s results, it turned out that NAFLD patients with F3 grade fibrosis should be paid more attention to the occurrence of vascular events compared to NAFLD patients with cirrhosis. As shown in Table 1, blood pressure, cholesterol values, and body mass index in NAFLD patients with cirrhosis were lower than those of patients with F3 grade fibrosis, which may at least partially describe the lower rates of vascular events in NAFLD patients with cirrhosis.

Secondly, the cumulative incidence of extrahepatic cancers was higher in patients with F3 fibrosis (14%; 95% CI: 7–23%) than patients with cirrhosis (6%; 95% CI: 2–15%). The most frequent cancer was colorectal cancer (n=15, 50%), followed by skin cancer (n=6, 20%), breast cancer (n=3, 10%), and uterine cancer (n=2, 7%). Many literatures reported a higher prevalence of colorectal cancer in NAFLD cohort compared to healthy control, while the relation of NAFLD with other extrahepatic cancers was not fully proven (6). Although higher liver-related mortality in NAFLD cirrhotic patients may have possibility to preclude the development of extrahepatic cancers, they could not accurately describe the mechanism at this moment.

Thirdly, which we felt most impressive, the authors reported that mild alcohol consumption was associated with higher risk of death/transplantation (HR, 2.3; 95% CI: 1.32–4.02), liver failure (HR, 1.65; 95% CI: 1.01–2.61) and HCC (HR, 3.22; 95% CI: 1.64–6.32) among NAFLD cirrhotic. Although heavy alcohol consumption is clearly damaging with the liver, mild drinking habit reported improved insulin sensitivity and lowered cardiovascular mortality in the general population (11). Whether mild alcohol consumption is equally valuable for NAFLD patients or not has been controversial. Ascha et al. showed that mild drinking habit was related with higher risk of HCC in NASH cirrhotic patients cohort (12). Recently, our multivariate survival analysis in NAFLD patients with advanced fibrosis (F3 and cirrhosis) showed mild drinking habit was one of the factors significantly associated with HCC (13). We need to discuss and investigate more the impact of mild drinking habit on HCC development in NAFLD patients with F3 (or lower) grade fibrosis. Even in study of Vilar-Gomez et al., HCC development rate in mild drinking-NAFLD patients with F3 grade fibrosis was not significantly different, but close to significantly higher than in patients without drinking [P=0.15, 1 case (7%) and 1 case (1%) without drinking, respectively] (shown in Supplementary Table 8 in their article). Additionally, we should take into consideration about sampling error by liver biopsy on decision of fibrosis grade. Data of Vilar-Gomez et al. actually showed 7 patients (4%) with F3 fibrosis had gastroesophageal varices, suggesting there could be some lower misclassification cases by liver biopsy in this study. A bigger cohort and longer observation period are needed to precisely evaluate the risk of mild drinking in patients with F3 grade, since the frequency of HCC development from patients with F3 grade is relatively low. Collectively, we propose the abstinence of ethanol in cirrhotic NAFLD patients.


We thank Jonathan Pham for his English assistance.


Conflicts of Interest: The authors have no conflicts of interest to declare.


  1. Younossi ZM, Koenig AB, Abdelatif D, et al. Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes. Hepatology 2016;64:73-84. [Crossref] [PubMed]
  2. Kim D, Li AA, Gadiparthi C, et al. Changing Trends in Etiology-Based Annual Mortality From Chronic Liver Disease, From 2007 Through 2016. Gastroenterology 2018;155:1154-63.e3. [Crossref] [PubMed]
  3. Kimura T, Kobayashi A, Tanaka N, et al. Clinicopathological characteristics of non-B non-C hepatocellular carcinoma without past hepatitis B virus infection. Hepatol Res 2017;47:405-18. [Crossref] [PubMed]
  4. Angulo P, Kleiner DE, Dam-Larsen S, et al. Liver Fibrosis, but No Other Histologic Features, Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease. Gastroenterology 2015;149:389-97.e10. [Crossref] [PubMed]
  5. Fujimori N, Umemura T, Kimura T, et al. Serum autotaxin levels are correlated with hepatic fibrosis and ballooning in patients with non-alcoholic fatty liver disease. World J Gastroenterol 2018;24:1239-49. [Crossref] [PubMed]
  6. Sanna C, Rosso C, Marietti M, et al. Non-Alcoholic Fatty Liver Disease and Extra-Hepatic Cancers. Int J Mol Sci 2016. [Crossref] [PubMed]
  7. Chang Y, Ryu S, Sung KC, et al. Alcoholic and non-alcoholic fatty liver disease and associations with coronary artery calcification: evidence from the Kangbuk Samsung Health Study. Gut 2018. [Epub ahead of print]. [Crossref] [PubMed]
  8. Vilar-Gomez E, Calzadilla-Bertot L, Wong VWS, et al. Fibrosis Severity as a Determinant of Cause-Specific Mortality in Patients With Advanced Nonalcoholic Fatty Liver Disease: A Multi-National Cohort Study. Gastroenterology 2018;155:443-57.e17. [Crossref] [PubMed]
  9. Nagaya T, Tanaka N, Suzuki T, et al. Down-regulation of SREBP-1c is associated with the development of burned-out NASH. J Hepatol 2010;53:724-31. [Crossref] [PubMed]
  10. Fede G, Privitera G, Tomaselli T, et al. Cardiovascular dysfunction in patients with liver cirrhosis. Ann Gastroenterol 2015;28:31-40. [PubMed]
  11. Thun MJ, Peto R, Lopez AD, et al. Alcohol consumption and mortality among middle-aged and elderly US adults. N Engl J Med 1997;337:1705-14. [Crossref] [PubMed]
  12. Ascha MS, Hanouneh IA, Lopez R, et al. The Incidence and Risk Factors of Hepatocellular Carcinoma in Patients with Nonalcoholic Steatohepatitis. Hepatology 2010;51:1972-8. [Crossref] [PubMed]
  13. Kimura T, Tanaka N, Fujimori N, et al. Mild drinking habit is a risk factor for hepatocarcinogenesis in non-alcoholic fatty liver disease with advanced fibrosis. World J Gastroenterol 2018;24:1440-50. [Crossref] [PubMed]
Cite this article as: Kimura T, Tanaka N, Tanaka E. What will happen in patients with advanced nonalcoholic fatty liver disease? Hepatobiliary Surg Nutr 2019;8(3):283-285. doi: 10.21037/hbsn.2019.01.04