Metabolic Dysfunction Increases Risk of Liver-Related Events After Achieving SVR

Metabolic dysfunction may increase the risk of liver-related events and hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) who achieved sustained virologic response (SVR) with direct-acting antiviral (DAA) therapy, according to findings from a recent study.¹

The study was published in American Journal of Cancer Research and identified metabolic dysfunction as an independent predictor of liver-related events in this patient population, additionally highlighting greater predictive values for adverse outcomes with type 2 diabetes mellitus and metabolic dysregulation compared to overweight or obesity.¹

In 2020, an international panel sought to revise the nonalcoholic fatty liver disease (NAFLD) nomenclature to integrate terminology that more accurately reflected pathogenesis and could help in patient stratification for disease management. In doing so, they determined that metabolic dysfunction-associated fatty liver disease (MAFLD) more accurately reflected current knowledge about the disease. Although this was eventually changed to metabolic dysfunction-associated steatotic liver disease (MASLD) in 2023, the recognition of metabolic factors’ role in disease pathogenesis remained.²

“The impact of MAFLD or metabolic dysfunction on liver-related events in patients with chronic hepatitis C who have achieved sustained virologic response to direct-acting antiviral agents remains to be clarified,” Wei-Fan Hsu, MD, assistant professor at China Medical University and a hepatologist at China Medical University Hospital, and colleagues wrote.¹

To address this gap in research, investigators enrolled consecutive patients ≥ 18 years of age with chronic HCV who had completed DAA therapy at China Medical University Hospital between September 2012 and April 2022. After excluding patients without body mass index (BMI) data, with HBV or HIV coinfection, with hepatocellular carcinoma (HCC) before 12 or 24 weeks after DAA therapy, and with end-stage renal disease (ESRD), 924 patients were eligible for inclusion. Of these patients, 573 had MAFLD, with metabolic dysfunction defined as the presence of overweight or obesity (BMI ≥ 23 kg/m2), type 2 diabetes mellitus, or metabolic dysregulation.¹

Investigators used variables at 12 or 24 weeks after DAA therapy to identify predictors of liver-related events. Data collection ended at the first liver-related event, death, loss to follow-up, or the end of follow-up on March 31, 2022.¹

Among the cohort, the median age was 58 (49-65) years and 45.2% of patients were male. The median BMI was 24.01 (21.78-26.73) kg/m2 and 18.8% of patients had diabetes.¹

Of the 924 patients included in the study, 52 experienced liver-related events during a median follow-up of 34.09 (17.31-50.20) months. Multivariable Cox regression analysis revealed the following factors were independent predictors of liver-related events:

• Age (hazard ratio [HR], 1.046; 95% confidence interval [CI], 1.014-1.080)
• Male sex (HR, 2.459; 95% CI, 1.336-4.524)
• Albumin (HR, 0.368; 95% CI, 0.215-0.627)
• Total bilirubin (HR, 1.333; 95% CI, 1.089-1.632)
• Alpha-fetoprotein (HR, 1.048; 95% CI, 1.033-1.063)
• FIB-4 > 3.25 (HR, 3.545; 95% CI, 1.739-7.226)

Additional multivariable analysis using metabolic dysfunction instead of MAFLD showed metabolic dysfunction (HR, 1.573; 95% CI, 1.137-2.176) was also an independent predictor of liver-related events.¹

A total of 35 patients developed incident HCC. Investigators noted metabolic dysfunction was also an independent predictor of HCC (HR, 1.667; 95% CI, 1.121-2.477) was an independent predictor of HCC.¹

Investigators also used a time-dependent area under the receiver operating characteristic (AUROC) to assess the predictive performance of each type of metabolic dysfunction. The AUROCs of metabolic dysregulation for 1-, 2-, and 3-year liver-related events were 0.648 (95% CI, 0.613-0.682), 0.629 (95% CI, 0.590- 0.667), and 0.619 (95% CI, 0.570-0.666), respectively. They pointed out the AUROC for 3-year liver-related events was significantly greater than those for overweight or obesity (0.515; 95% CI, 0.466- 0.564), as was the AUROC of type 2 diabetes (0.583; 95% CI, 0.534-0.630).¹

Investigators outlined several limitations to these findings, including the small sample size, the single-center retrospective study design, the potential influence of excluding patients who were missing BMI data at baseline or during follow-up, and the lack of determination of the patterns of lipid profile, glycemic control, and IR kinetics over time following the eradication of HCV.¹

“Metabolic dysfunction, rather than simple steatosis, increased the risk of liver-related events and HCC in patients with CHC who have attained an SVR to DAA therapy. Among the three metabolic dysfunctions studied, type 2 DM and metabolic dysregulation had higher predictive values for adverse outcomes than overweight or obesity,” investigators concluded.¹

References:

1. ^{Hsu WF, Lai HC, Chen SH, et al. Effect of metabolic dysfunction on the risk of liver-related events in patients cured of hepatitis C virus. Am J Cancer Res. 2024;14(4):1914-1925. Published 2024 Apr 15. doi:10.62347/EQIR8735}
2. ^{Brooks, A. From NAFLD to MASLD: 2023 Brings New Liver Disease Nomenclature. HCPLive. December 13, 2023. Accessed May 14, 2024. https://www.hcplive.com/view/from-nafld-to-masld-2023-new-liver-disease-nomenclature}