While the global prevalence of hepatitis C virus (HCV) infection decreased to approximately 0.6% in 2024 following the introduction of direct-acting antivirals (DAAs) in late 2013, it remains a leading cause of cirrhosis, hepatic decompensation, hepatocellular carcinoma, and death [
1]. Individuals infected with HCV are at risk of hepatic and extrahepatic morbidity and mortality if left untreated [
2,
3]. Conversely, prognosis significantly improves with effective antiviral treatment. Today, more than 95% of patients with HCV infection can achieve viral eradication using a short course of potent and safe DAAs, particularly fixed-dose combination (FDC) pangenotypic regimens.
In addition to causing hepatic inflammation and fibrosis, the HCV core and nonstructural 5A (NS5A) proteins—particularly genotype 3 infection—can directly induce hepatic steatosis through inhibiting microsomal triglyceride transfer protein (MTP), activation of peroxisome proliferator-activated receptor-alpha (PPAR-α), and activation of sterol regulatory element-binding protein-1c (SREBP-1c) [
4,
5]. Among individuals with non-genotype 3 infection, disruption of host metabolism, including insulin resistance (IR) and obesity, may contribute to the development of hepatic steatosis, type 2 diabetes (T2D)/prediabetes and hypolipidemia [
6]. This tendency toward metabolic dysregulation is supported by epidemiologic studies which show higher prevalence rates of hepatic steatosis (40–86%) and T2D (14–68%) compared to the general population [
7].
Recently, a multisociety Delphi consensus proposed new terminology, including metabolic dysfunction-associated steatotic liver disease (MASLD), metabolic dysfunction-associated steatohepatitis (MASH), and MASLD with increased alcohol intake (MetALD), to encompass the various etiologies of steatotic liver disease (SLD) while avoiding stigmatizing language [
8]. The diagnosis of MASLD requires the presence of both SLD, as demonstrated by imaging studies, and at least one of the five cardiometabolic risk factors (CMRFs), including T2D/prediabetes, obesity, hypertension (HTN), and dyslipidemia. Among untreated individuals with HCV, the prevalence rate of MASLD is approximately 55%, compared to the pooled prevalence rate of 30%-38% in the general population [
9,
10]. After excluding individuals with excess alcohol consumption, drug-induced liver injury (DILI) or monogenic diseases, >95% of those with SLD present with CMRFs, regardless of HCV infection status, further confirming the close link between HCV infection, hepatic steatosis and metabolic dysfunction [
11-
13].
In this issue of
Clinical and Molecular Hepatology, Ryu et al. retrospectively evaluated the impact of metabolic dysfunction, particularly T2D and hypercholesterolemia, on changes of liver stiffness measurements (LSMs) using transient elastography and fibrosis index based on four parameters (FIB-4) in a large cohort of Korean patients. This study assessed these changes from pretreatment to sustained virologic response at off-treatment week12 (SVR12) following DAA therapy [
14]. Fibrosis regression was defined as a 20% reduction of either of the two noninvasive tests (NITs) over a six-month interval. Prior to antiviral treatment, 17.2% of participants had T2D, and 33.8% had hepatic steatosis. Three of the CMRFs—T2D, obesity and hypercholesterolemia—were found to adversely affect improvement of LSM or FIB-4. Based on these findings, the authors concluded that metabolic dysfunction may mitigate the beneficial effects of fibrosis regression following HCV cure. While these findings provide important insights for healthcare providers regarding the negative impact of metabolic dysfunction on short-term liver health, even after HCV eradication with DAAs, several points need clarification to better understand its role in fibrosis progression. Following successful HCV treatment—whether with interferon (IFN)-based or IFN-free regimens—paired liver histological analyses have shown a trend of improvement in both hepatic necroinflammation and fibrosis [
15]. However, the extent of fibrosis regression appears slow and modest, showing a trend of -0.28±0.03 unit per year in fibrosis stage based on the Desmet criteria (ranging from F0-F4) [
16]. Although numerous studies have demonstrated a rapid improvement in NITs, such as FIB-4, LSM, aspartate transaminase-to-platelet ratio index (APRI), or acoustic radiation force impulse (ARFI), this improvement is likely due to reduced necroinflammation rather than true fibrosis regression [
17-
22]. Therefore, caution is needed when interpreting the extent of fibrosis regression solely based on changes in NITs.
Notably, following viral eradication, the proportion of patients with SLD in the current study increased from 33.8% to 40.7%. The dynamic changes in the emergence or regression of SLD or MASLD before and after viral cure remain controversial, and this discrepancy may be attributed to the varying distribution of risk factors that could influence outcome estimation [
23-
26].
Lastly, the authors assessed the long-term liver-related outcomes, including decompensation, HCC, and overall mortality, up to 8 years post-DAA treatment. After adjusting for confounding factors, males, HCV genotype 2 infection, low platelet count, low serum albumin level, and high serum total bilirubin level were associated with an increased risk of hepatic decompensation. This finding was partly contradictory to a study from the U.K., which demonstrated that females, older age, alcohol consumption, and Child-Pugh class were independently associated with the risk of decompensation. However, both studies confirmed the lack of a significant role of metabolic dysfunction in the risk of hepatic decompensation following viral cure [
27]. Regarding the risk of HCC, the current study was consistent with a recent report from Taiwan, which showed a positive correlation between most CMRFs and HCC development. However, divergent results existed between studies concerning the role of SLD/MASLD as mediators of CMRFs for HCC, particularly through multivariable or mediation analyses [
13]. These discrepancies warrant further independent research to clarify the underlying mechanisms.
This study could generate significant interest in exploring the complex interplay between metabolic derangement and liver-related outcomes. First, it supports the presence of metabolic dysfunction, particularly T2D and dyslipidemia, in mitigating short-term improvements in FIB-4 and LSM, although it does not affect long-term hepatic decompensation. Does this finding merely reflect patient selection, or does it imply that the beneficial effects of viral eradication outweigh the impact of metabolic dysfunction on long-term fibrosis dynamics? Given that incident T2D or prediabetes remains substantial even though insulin resistance (IR) improves, and the presence of dyslipidemia, obesity, and hepatic steatosis is common following HCV cure with antiviral treatment, surveillance for CMRFs and effective management of these factors through lifestyle modification and drug therapy are crucial to ensuring a better prognosis [
28-
30].
FOOTNOTES
-
Authors’ contribution
All authors were responsible for the interpretation of data, the drafting, and the critical revision of the manuscript for important intellectual content. All authors approved the final version of the article.
-
Conflicts of Interest
The authors have no conflicts to disclose.
Abbreviations
aspartate transaminase to platelet ratio index
acoustic radiation force impulse
cardiometabolic risk factor
fibrosis index based on four parameters
liver stiffness measurement
metabolic dysfunction-associated steatohepatitis
metabolic dysfunction-associated steatotic liver disease
MASLD with increased alcohol intake
microsomal triglyceride transfer protein
PPAR-α peroxisome proliferator-activated receptor-alpha
sterol regulatory element-binding protein-1c
sustained virologic response at off-treatment week12
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Citations
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