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TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus by interferon-free therapy

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
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Abstract

Background

The aim of this study is to ascertain whether the TLL1 variant at rs17047200 is associated with the development of HCC after achieving sustained virological response (SVR) by interferon (IFN)-free therapy for chronic hepatitis C (CHC).

Methods

A total of 1029 Japanese CHC patients with the following inclusion criteria were enrolled: (i) achieved SVR by IFN-free therapy, (ii) followed up at least 1 year from the end of treatment (EOT) (median 104 weeks), (iii) no history of hepatocellular carcinoma (HCC) by 1 year from the EOT.

Results

Nineteen patients developed HCC (HCC group) and 1010 did not (non-HCC group). The proportion of rs17047200 AT/TT was significantly higher in the HCC group than the non-HCC group (47.4% vs. 20.1%, P = 0.008). Multivariate analysis showed that higher levels of α-fetoprotein, FIB-4 and rs17047200 AT/TT were independent risk factors for developing HCC (HR = 3.22, P = 0.021 for α-fetoprotein > 4.6 ng/ml; HR = 3.89, P = 0.036 for FIB-4 > 2.67; HR = 2.80, P = 0.026 for rs17047200 AT/TT). Cumulative incidence of HCC was significantly higher in patients with rs17047200 AT/TT than in those with AA (P = 0.006). Comparing clinical characteristics according to the TLL1 genotypes, patients with rs17047200 AT/TT had significantly lower platelet counts and higher levels of FIB-4 than those with AA (P = 0.011 and 0.032, respectively).

Conclusions

The TLL1 variant was independently associated with HCC development after HCV eradication by IFN-free regimen. It might be involved in hepatic fibrogenesis and thereby carcinogenesis.

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Abbreviations

AFP:

α-Fetoprotein

ALT:

Alanine aminotransaminase

AST:

Aspartate aminotransferase

CHC:

Chronic hepatitis C

DAA:

Direct-acting antiviral agent

EOT:

End of treatment

HCC:

Hepatocellular carcinoma

HCV:

Hepatitis C virus

IFN:

Interferon

LC:

Liver cirrhosis

SNP:

Single nucleotide polymorphism

SVR:

Sustained virological responses

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Acknowledgements

The authors would like to thank Shintaro Ogawa and Kyoko Ito of Nagoya City University Graduate School of Medical Sciences.

Funding

This research was supported by the Research Program on Hepatitis from the Japan Agency for Medical Research and Development (AMED) to Yasuhito Tanka, project code: JP18fk0210001h0003 and the JSPS KAKENHI Grant-in-Aid for Young Scientists (A) to Etsuko Iio, Grant Number: 17K15960

Author information

Author notes

  1. Etsuko Iio, Kentaro Matsuura authors were equally contributed to this work (shared first authorship).

Authors and Affiliations

  1. Nagoya City University, Graduate School of Medical Sciences, Nagoya, Japan

    Etsuko Iio, Kentaro Matsuura, Kei Fujiwara, Kayoko Matsunami, Susumu Tsutsumi & Yasuhito Tanaka

  2. Ootakanomori Hospital, Kashiwa, Japan

    Noritomo Shimada

  3. Nippon Medical School Hospital, Tokyo, Japan

    Masanori Atsukawa & Katsuhiko Iwakiri

  4. Nippon Medical School Chiba Hokusoh Hospital, Chiba, Japan

    Norio Itokawa

  5. Shinmatsudo Central General Hospital, Chiba, Japan

    Hiroshi Abe & Keizo Kato

  6. Kagawa Prefectural Central Hospital, Takamatsu, Japan

    Koichi Takaguchi & Tomonori Senoh

  7. Saga University Hospital, Saga, Japan

    Yuichiro Eguchi

  8. Shin-Kokura Hospital, Kitakyushu, Japan

    Hideyuki Nomura

  9. Machida Municipal Hospital, Tokyo, Japan

    Kai Yoshizawa

  10. Teine Keijinkai Hospital, Sapporo, Japan

    Jong-Hon Kang & Takeshi Matsui

  11. National Hospital Organization Nagoya Medical Center, Nagoya, Japan

    Noboru Hirashima

  12. Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan

    Atsunori Kusakabe

  13. Toyokawa City Hospital, Toyokawa, Japan

    Tomokatsu Miyaki

Authors
  1. Etsuko Iio
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Corresponding author

Correspondence to Yasuhito Tanaka.

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Conflict of interest

Yasuhito Tanaka is currently conducting research sponsored by Chugai Pharmaceutical Co., Ltd and has received honoraria from Janssen Pharmaceutical K.K, and Gilead Sciences. Masanori Atsukawa is currently conducting research sponsored by MSD K.K., and AbbVie Inc., and has received honoraria from MSD K.K. and Gilead Sciences. Koichi Takaguchi has received honoraria from Gilead Sciences, MSD K.K., AbbVie Inc., Bristol-Myers Squibb, and Astrazeneka KK. Hideyuki Nomura has received honoraria from Gilead Sciences. The other authors declare no conflicts of interest.

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Iio, E., Matsuura, K., Shimada, N. et al. TLL1 variant associated with development of hepatocellular carcinoma after eradication of hepatitis C virus by interferon-free therapy. J Gastroenterol 54, 339–346 (2019). https://doi.org/10.1007/s00535-018-1526-3

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  • DOI: https://doi.org/10.1007/s00535-018-1526-3

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