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

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

A Letter to the Editor to this article was published on 26 March 2019

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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Abbreviations

ALT:

Alanine transaminase

APRI:

Aspartate transaminase to platelet ratio index

AST:

Aspartate transaminase

AUROC:

Area under the receiver operating characteristic

BF:

Bridging fibrosis

BH:

Ballooned hepatocyte

BMI:

Body mass index

FIB-4:

Fibrosis 4

γGT:

Gamma-glutamyl transferase

HOMA-R:

Homeostatic model assessment for insulin resistance

M2BPGi:

Mac-2 binding protein glycan isomer

MR:

Magnetic resonance

NAFL:

Non-alcoholic fatty liver

NAFLD:

Non-alcoholic fatty liver disease

NASH:

Non-alcoholic steatohepatitis

ROC:

Receiver operating characteristic

SHH:

Sonic hedgehog

T4C7s:

Type 4 collagen 7s

TC:

Total cholesterol

References

  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(1):73–84.

    Article  Google Scholar 

  2. Machado MV, Diehl AM. Pathogenesis of nonalcoholic steatohepatitis. Gastroenterology. 2016;150(8):1769–77.

    Article  CAS  Google Scholar 

  3. 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.

    Article  Google Scholar 

  4. Caldwell S, Ikura Y, Dias D, et al. Hepatocellular ballooning in NASH. J Hepatol. 2010;53(4):719–23.

    Article  Google Scholar 

  5. 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.

    Article  CAS  Google Scholar 

  6. 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.

    Article  Google Scholar 

  7. 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  CAS  Google Scholar 

  8. 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.

    Article  Google Scholar 

  9. 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.

    Article  Google Scholar 

  10. 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.

    Article  Google Scholar 

  11. 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.

    Article  CAS  Google Scholar 

  12. 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.

    Article  Google Scholar 

  13. Banini BA, Sanyal AJ. Current and future pharmacologic treatment of nonalcoholic steatohepatitis. Curr Opin Gastroenterol. 2017;33(3):134–41.

    Article  CAS  Google Scholar 

  14. Allan GM, Lexchin J, Wiebe N. Physician awareness of drug cost: a systematic review. PLoS Med. 2007;4(9):e283.

    Article  Google Scholar 

  15. 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.

    Article  Google Scholar 

  16. 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.

    Article  CAS  Google Scholar 

  17. 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.

    Article  CAS  Google Scholar 

  18. Hirsova P, Gores GJ. Ballooned hepatocytes, undead cells, sonic hedgehog, and vitamin E: therapeutic implications for nonalcoholic steatohepatitis. Hepatology. 2015;61(1):15–7.

    Article  Google Scholar 

  19. Machado MV, Cortez-Pinto H. Cell death and nonalcoholic steatohepatitis: where is ballooning relevant? Expert Rev Gastroenterol Hepatol. 2011;5(2):213–22.

    Article  Google Scholar 

  20. Kakisaka K, Cazanave SC, Werneburg NW, et al. A hedgehog survival pathway in ‘undead’ lipotoxic hepatocytes. J Hepatol. 2012;57(4):844–51.

    Article  CAS  Google Scholar 

  21. 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.

    Article  CAS  Google Scholar 

  22. Amir M, Czaja MJ. Autophagy in nonalcoholic steatohepatitis. Expert Rev Gastroenterol Hepatol. 2011;5(2):159–66.

    Article  Google Scholar 

  23. Ratziu V, Charlotte F, Heurtier A, et al. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology. 2005;128(7):1898–906.

    Article  Google Scholar 

  24. Castera L, Forns X, Alberti A. Non-invasive evaluation of liver fibrosis using transient elastography. J Hepatol. 2008;48(5):835–47.

    Article  Google Scholar 

  25. 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.

    Article  Google Scholar 

  26. 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.

    Article  CAS  Google Scholar 

  27. Narimatsu H. Development of M2BPGi: a novel fibrosis serum glyco-biomarker for chronic hepatitis/cirrhosis diagnostics. Expert Rev Proteom. 2015;12(6):683–93.

    Article  CAS  Google Scholar 

  28. Shirabe K, Bekki Y, Gantumur D, et al. Mac-2 binding protein glycan isomer (M2BPGi) is a new serum biomarker for assessing liver fibrosis: more than a biomarker of liver fibrosis. J Gastroenterol. 2018. https://doi.org/10.1007/s00535-017-1425-z

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by KAKENHI Grant no. JP16K21307 and the Keiryokai Research Foundation Grant no. Y117.

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Authors and Affiliations

  1. Division of Hepatology, Department of Internal Medicine, School of Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka, Iwate, 0208505, Japan

    Keisuke Kakisaka, Yuji Suzuki, Yudai Fujiwara, Tamami Abe, Miki Yonezawa, Hidekatsu Kuroda & Yasuhiro Takikawa

  2. Department of Molecular Diagnostic Pathology, Iwate Medical University, Morioka, Japan

    Kazuyuki Ishida & Tamotsu Sugai

Authors
  1. Keisuke Kakisaka
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  2. Yuji Suzuki
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  4. Tamami Abe
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  9. Yasuhiro Takikawa
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Correspondence to Keisuke Kakisaka.

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Electronic supplementary material

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535_2018_1468_MOESM1_ESM.pptx

Supplemental Fig. 1. Difference of liver fat volume according to ballooned hepatocytes. A and B: Distribution of the liver fat volume among subjects divided by the presence or absence of ballooned hepatocytes (A) or the grading of ballooned hepatocytes (B). (PPTX 73 kb)

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Kakisaka, K., Suzuki, Y., Fujiwara, Y. et al. Evaluation of ballooned hepatocytes as a risk factor for future progression of fibrosis in patients with non-alcoholic fatty liver disease. J Gastroenterol 53, 1285–1291 (2018). https://doi.org/10.1007/s00535-018-1468-9

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  • DOI: https://doi.org/10.1007/s00535-018-1468-9

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