Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Sep 13.
doi: 10.1007/s12072-025-10906-3. Online ahead of print.

Paradoxical association between steatotic liver disease and favorable hepatic outcomes in HCV patients with SVRs

Ming-Ling Chang  1   2 , Jur-Shan Cheng  3   4 , Jennifer Tai  3   5 , Wei-Ting Chen  3   5 , Sien-Sing Yang  6 , Cheng-Hsun Chiu  3   7   8 , Rong-Nan Chien  3   5 , Chia-Lin Hsu  9 , Shang-Jung Wu  9 , Cathy Sj Fann  10
Affiliations

Paradoxical association between steatotic liver disease and favorable hepatic outcomes in HCV patients with SVRs

Ming-Ling Chang et al. Hepatol Int. .

Abstract

Background: The effects of genetic predispositions and steatotic liver disease (SLD) on the outcomes of chronic hepatitis C (CHC) patients with sustained virological responses (SVRs) remain unknown.

Methods: A 15-year prospective study of CHC patients with SVRs was conducted.

Results: Among 965 SVR patients, the baseline and 24-week post-HCV therapy SLD rates were 64% and 54%, respectively; the patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M-rs738409 G allele was negatively correlated with the methylenetetrahydrofolate reductase (MTHFR) C677T Ala222Val-rs1801133 T allele (Pearson's correlation: -0.078, p = 0.025). At baseline, body mass index (BMI) (OR: 1.18; 95% CI: 1.12-1.25), cirrhosis (0.34; 0.20-0.56) and the PNPLA3 G allele (1.28; 1.03-1.60) were associated with SLD. At 24 weeks posttherapy, BMI (1.16; 1.09-1.24), the fibrosis-4 index (0.86; 0.75-0.99), cirrhosis (0.23; 0.14-0.40), HOMA-IR (1.16; 1.04-1.30), the ALT level (1.01; 1.00-1.03) and the MTHFR T allele (0.66; 0.48-0.91) were associated with 24-week SLD in SVR patients. Longitudinally, compared with sex- and age-matched patients without 24-week SLD, patients with 24-week SLD had higher BMIs and ALT levels, poorer metabolic profiles, and greater cumulative incidences of cardiovascular events (70.9% vs. 63.7%, p = 0.026) but lower fibrosis-4 indices and cumulative incidences of cirrhosis (12.7% vs. 31.5%, p < 0.001) and HCC (4.6% vs. 12.1%, p < 0.001). A 24-week SLD was negatively associated with the cumulative incidences of cirrhosis (HR: 0.548; 95% CI HR: 0.281 ~ 0.894) and HCC (0.637; 0.32 ~ 0.99).

Conclusions: Poorer metabolic profiles and greater cardiovascular but lower hepatic event cumulative incidences were noted in patients with than in those without 24-week SLD. The paradoxical association between SLD and hepatic events might stem from the negative correlation between the PNPLA3 G allele and the MTHFR T allele, which are HCV-specific SLD factors.

Keywords: HCV; MTHFR; PNPLA3; SLD; SVR.

PubMed Disclaimer

Conflict of interest statement

Declarations. Conflicts of interest: None. Ethical approval: Approval for the research protocol was obtained from the Chang Gung Memorial Hospital institutional review board. Informed Consent: Informed consent was obtained in writing from each patient, and the study protocol conformed to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the Chang Gung Memorial Hospital institutional review board. Registry and the registration: No. of the study/trial: IRB No: 104-7005B. Animal studies: Not Applicable.

References

    1. Martinello M, et al. Hepatitis C. Lancet. 2023;402:1085–1096 - DOI - PubMed
    1. Lonardo A, et al. Hepatitis c and steatosis: a reappraisal. J Viral Hepat. 2006;13:73–80 - DOI - PubMed
    1. Rinella ME, et al. A multi-society Delphi consensus statement on new fatty liver disease nomenclature. J Hepatol. 2023;78:1966–1986 - DOI
    1. European Association for the Study of the Liver (EASL), et al. EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol. 2016;64:1388–402 - DOI
    1. Huang Y, et al. A feed-forward loop amplifies nutritional regulation of PNPLA3. Proc Natl Acad Sci U S A. 2010;107:7892–7897 - DOI - PubMed - PMC

LinkOut - more resources