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Published in: Journal of Gastroenterology 12/2018

01-12-2018 | Original Article—Liver, Pancreas, and Biliary Tract

Evaluation of ballooned hepatocytes as a risk factor for future progression of fibrosis in patients with non-alcoholic fatty liver disease

Authors: Keisuke Kakisaka, Yuji Suzuki, Yudai Fujiwara, Tamami Abe, Miki Yonezawa, Hidekatsu Kuroda, Kazuyuki Ishida, Tamotsu Sugai, Yasuhiro Takikawa

Published in: Journal of Gastroenterology | Issue 12/2018

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Abstract

Background

The prevalence of non-alcoholic fatty liver disease (NAFLD) has increased. Non-alcoholic steatohepatitis (NASH) shows progression of liver fibrosis in NAFLD. It remains unclear which patients with NAFLD will show progression of liver fibrosis. Therefore, we aimed to investigate the risk factor associated with the progression of liver fibrosis among patients with NAFLD.

Methods

This observational study enrolled 157 patients with biopsy-proven NAFLD. Thirty-two patients were excluded because of lack of data. The accuracy of the formulae for estimating liver fibrosis, i.e., the FIB-4 index, APRI, and Forns index, was compared. Using serial changes of the best formula for liver fibrosis, we identified factors associated with the progression of liver fibrosis. Histological liver fibrosis was quantified using the Brunt stage.

Results

Sixty-three patients were diagnosed as having NASH. The FIB-4 index provided the best diagnostic accuracy for liver fibrosis [Brunt stage 0 versus 1–4, areas under the curve (AUC) 0.74; 0–1 versus 2–4, AUC 0.77; 0–2 versus 3–4, AUC 0.78; and 1–3 versus 4, AUC 0.87]. The association between body mass index, sex, observation period, and histological findings (liver fat content, bridging fibrosis, and hepatocyte ballooning) with the change in the FIB-4 index was evaluated among patients with NASH, using multivariate analysis. Among these factors, hepatocyte ballooning was associated with an increase in the FIB-4 index.

Conclusion

The FIB-4 index was the best formula for estimating liver fibrosis in patients with biopsy-proven NAFLD, and the presence of ballooned hepatocytes was a risk factor for the progression of liver fibrosis.
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Literature
1.
go back to reference 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(1):73–84.CrossRef 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(1):73–84.CrossRef
2.
go back to reference Machado MV, Diehl AM. Pathogenesis of nonalcoholic steatohepatitis. Gastroenterology. 2016;150(8):1769–77.CrossRef Machado MV, Diehl AM. Pathogenesis of nonalcoholic steatohepatitis. Gastroenterology. 2016;150(8):1769–77.CrossRef
3.
go back to reference 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(2):389 e10–397 e10.CrossRef 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(2):389 e10–397 e10.CrossRef
4.
go back to reference Caldwell S, Ikura Y, Dias D, et al. Hepatocellular ballooning in NASH. J Hepatol. 2010;53(4):719–23.CrossRef Caldwell S, Ikura Y, Dias D, et al. Hepatocellular ballooning in NASH. J Hepatol. 2010;53(4):719–23.CrossRef
5.
go back to reference Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116(6):1413–9.CrossRef Matteoni CA, Younossi ZM, Gramlich T, et al. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology. 1999;116(6):1413–9.CrossRef
6.
go back to reference Sumida Y, Nakajima A, Itoh Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2014;20(2):475–85.CrossRef Sumida Y, Nakajima A, Itoh Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. World J Gastroenterol. 2014;20(2):475–85.CrossRef
7.
go back to reference Younossi ZM, Gramlich T, Liu YC, et al. Nonalcoholic fatty liver disease: assessment of variability in pathologic interpretations. Mod Pathol. 1998;11(6):560–5.PubMed Younossi ZM, Gramlich T, Liu YC, et al. Nonalcoholic fatty liver disease: assessment of variability in pathologic interpretations. Mod Pathol. 1998;11(6):560–5.PubMed
8.
go back to reference Bota S, Herkner H, Sporea I, et al. Meta-analysis: ARFI elastography versus transient elastography for the evaluation of liver fibrosis. Liver Int. 2013;33(8):1138–47.CrossRef Bota S, Herkner H, Sporea I, et al. Meta-analysis: ARFI elastography versus transient elastography for the evaluation of liver fibrosis. Liver Int. 2013;33(8):1138–47.CrossRef
9.
go back to reference Singh S, Venkatesh SK, Loomba R, et al. Magnetic resonance elastography for staging liver fibrosis in non-alcoholic fatty liver disease: a diagnostic accuracy systematic review and individual participant data pooled analysis. Eur Radiol. 2016;26(5):1431–40.CrossRef Singh S, Venkatesh SK, Loomba R, et al. Magnetic resonance elastography for staging liver fibrosis in non-alcoholic fatty liver disease: a diagnostic accuracy systematic review and individual participant data pooled analysis. Eur Radiol. 2016;26(5):1431–40.CrossRef
10.
go back to reference Forns X, Ampurdanes S, Llovet JM, et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology. 2002;36(4 Pt 1):986–92.CrossRef Forns X, Ampurdanes S, Llovet JM, et al. Identification of chronic hepatitis C patients without hepatic fibrosis by a simple predictive model. Hepatology. 2002;36(4 Pt 1):986–92.CrossRef
11.
go back to reference Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317–25.CrossRef Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict significant fibrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317–25.CrossRef
12.
go back to reference Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38(2):518–26.CrossRef Wai CT, Greenson JK, Fontana RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38(2):518–26.CrossRef
13.
go back to reference Banini BA, Sanyal AJ. Current and future pharmacologic treatment of nonalcoholic steatohepatitis. Curr Opin Gastroenterol. 2017;33(3):134–41.CrossRef Banini BA, Sanyal AJ. Current and future pharmacologic treatment of nonalcoholic steatohepatitis. Curr Opin Gastroenterol. 2017;33(3):134–41.CrossRef
14.
go back to reference Allan GM, Lexchin J, Wiebe N. Physician awareness of drug cost: a systematic review. PLoS Med. 2007;4(9):e283.CrossRef Allan GM, Lexchin J, Wiebe N. Physician awareness of drug cost: a systematic review. PLoS Med. 2007;4(9):e283.CrossRef
15.
go back to reference Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–21.CrossRef Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313–21.CrossRef
16.
go back to reference Shah AG, Lydecker A, Murray K, et al. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7(10):1104–12.CrossRef Shah AG, Lydecker A, Murray K, et al. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 2009;7(10):1104–12.CrossRef
17.
go back to reference Sumida Y, Yoneda M, Hyogo H, et al. Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population. BMC Gastroenterol. 2012;12:2.CrossRef Sumida Y, Yoneda M, Hyogo H, et al. Validation of the FIB4 index in a Japanese nonalcoholic fatty liver disease population. BMC Gastroenterol. 2012;12:2.CrossRef
18.
go back to reference Hirsova P, Gores GJ. Ballooned hepatocytes, undead cells, sonic hedgehog, and vitamin E: therapeutic implications for nonalcoholic steatohepatitis. Hepatology. 2015;61(1):15–7.CrossRef Hirsova P, Gores GJ. Ballooned hepatocytes, undead cells, sonic hedgehog, and vitamin E: therapeutic implications for nonalcoholic steatohepatitis. Hepatology. 2015;61(1):15–7.CrossRef
19.
go back to reference Machado MV, Cortez-Pinto H. Cell death and nonalcoholic steatohepatitis: where is ballooning relevant? Expert Rev Gastroenterol Hepatol. 2011;5(2):213–22.CrossRef Machado MV, Cortez-Pinto H. Cell death and nonalcoholic steatohepatitis: where is ballooning relevant? Expert Rev Gastroenterol Hepatol. 2011;5(2):213–22.CrossRef
20.
go back to reference Kakisaka K, Cazanave SC, Werneburg NW, et al. A hedgehog survival pathway in ‘undead’ lipotoxic hepatocytes. J Hepatol. 2012;57(4):844–51.CrossRef Kakisaka K, Cazanave SC, Werneburg NW, et al. A hedgehog survival pathway in ‘undead’ lipotoxic hepatocytes. J Hepatol. 2012;57(4):844–51.CrossRef
21.
go back to reference Suzuki A, Kakisaka K, Suzuki Y, et al. c-Jun N-terminal kinase-mediated Rubicon expression enhances hepatocyte lipoapoptosis and promotes hepatocyte ballooning. World J Gastroenterol. 2016;22(28):6509–19.CrossRef Suzuki A, Kakisaka K, Suzuki Y, et al. c-Jun N-terminal kinase-mediated Rubicon expression enhances hepatocyte lipoapoptosis and promotes hepatocyte ballooning. World J Gastroenterol. 2016;22(28):6509–19.CrossRef
22.
go back to reference Amir M, Czaja MJ. Autophagy in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol. 2011;5(2):159–66.CrossRef Amir M, Czaja MJ. Autophagy in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol. 2011;5(2):159–66.CrossRef
23.
go back to reference Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128(7):1898–906.CrossRef Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128(7):1898–906.CrossRef
24.
go back to reference Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol. 2008;48(5):835–47.CrossRef Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol. 2008;48(5):835–47.CrossRef
25.
go back to reference Tapper EB, Castera L, Afdhal NH. FibroScan (vibration-controlled transient elastography): where does it stand in the united states practice. Clin Gastroenterol Hepatol. 2015;13(1):27–36.CrossRef Tapper EB, Castera L, Afdhal NH. FibroScan (vibration-controlled transient elastography): where does it stand in the united states practice. Clin Gastroenterol Hepatol. 2015;13(1):27–36.CrossRef
26.
go back to reference Kuno A, Ikehara Y, Tanaka Y, et al. A serum “sweet-doughnut” protein facilitates fibrosis evaluation and therapy assessment in patients with viral hepatitis. Sci Rep. 2013;3:1065.CrossRef Kuno A, Ikehara Y, Tanaka Y, et al. A serum “sweet-doughnut” protein facilitates fibrosis evaluation and therapy assessment in patients with viral hepatitis. Sci Rep. 2013;3:1065.CrossRef
27.
go back to reference Narimatsu H. Development of M2BPGi: a novel fibrosis serum glyco-biomarker for chronic hepatitis/cirrhosis diagnostics. Expert Rev Proteom. 2015;12(6):683–93.CrossRef Narimatsu H. Development of M2BPGi: a novel fibrosis serum glyco-biomarker for chronic hepatitis/cirrhosis diagnostics. Expert Rev Proteom. 2015;12(6):683–93.CrossRef
Metadata
Title
Evaluation of ballooned hepatocytes as a risk factor for future progression of fibrosis in patients with non-alcoholic fatty liver disease
Authors
Keisuke Kakisaka
Yuji Suzuki
Yudai Fujiwara
Tamami Abe
Miki Yonezawa
Hidekatsu Kuroda
Kazuyuki Ishida
Tamotsu Sugai
Yasuhiro Takikawa
Publication date
01-12-2018
Publisher
Springer Japan
Published in
Journal of Gastroenterology / Issue 12/2018
Print ISSN: 0944-1174
Electronic ISSN: 1435-5922
DOI
https://doi.org/10.1007/s00535-018-1468-9

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