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Metabolic Dysfunction May Better Predict Risk for HCC in Persons Cured of HCV with Advanced Fibrosis


In persons cured of chronic hepatitis C virus (HCV) who have advanced hepatic fibrosis, new research found metabolic dysfunction (MD) more prevalent than ultrasound-detected steatosis (US). Italian investigators reported also that MD may be a more accurate predictor of patients with advanced disease at highest risk of progression to hepatic cellular carcinoma (HCC) and that individual elements of MD may be more useful than US to stratify HCC risk in this patient population.

The concept of MD-associated fatty liver disease (MAFLD) has been proposed to replace nonalcoholic fatty liver disease (NAFLD) as the “official definition for fatty liver disease associated with metabolic alterations and insulin resistance,” now the most prevalent form of chronic liver disease globally,” wrote Serena Pelusi, from the Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy and colleagues in the journal Liver International. The definition of MAFLD does not rule out coexisting drivers of liver disease, the authors continued, and using specific criteria diagnostic of MAFLD could help more readily identify the contribution of MD and insulin resistance to disease progression.

Pelusi et al set out to examine the clinical implications of using the MAFLD definition to predict major clinical events (HCC and cardiovascular events [CVE]) in patients with advanced liver fibrosis after eradication of HCV.

For the study, investigators took advantage of the NAVIGATORE-Lombardia study database, a population-based real-world cohort created to study the impact of metabolic comorbidities on HCC and cardiovascular events (CVE) after antiviral treatment. They selected an initial 8740 participants with information available on age, sex, anthropometric features, fibrosis staging, metabolic co-morbidities, and pharmacologic history.

After exclusions, the final cohort numbered 2611 participants cured of chronic HCV who had advanced liver fibrosis, did not have HBV or HIV, had no history of liver transplantation, and were negative for HCC. Median age of the cohort was 61.4 years and 63.9% were men. males, median follow-up 34 months.

Participants were followed (median duration 34 months) for HCC and CVE, defined as hospitalization due to ischemic heart disease or heart failure and sudden death.


Investigators found that 58% of patients had MD, 19% based on the presence of diabetes (MD-diabetes), 37% based on increased adiposity without diabetes (MD-overweight), and just 2% based on multiple metabolic abnormalities without overweight or diabetes (MD-metabolic).

MD was more prevalent than US (32% MD-only, 13% US-only) and MD-US diagnoses were coincident in less than one-quarter of participants (23% MD-US), suggesting that MAFLD prevalence, not requiring confirmation of US to accompany a positive history, may be higher than previously expected, the authors commented.

Liver stiffness was more pronounced in participants with MD (P<.05), particularly in those subgroups with MD-diabetes and MD-only whose members were older and had more advanced MD and liver disease (P<.05), according to study findings.

Using multivariable Cox proportional hazard regression to evaluate independent predictors of clinical events, investigators reported that MD was associated with an approximately 2-fold higher risk of developing de novo HCC (hazard ratio [HR], 1.97, 95% CI, 1.27-3.04; P=.0023).

Additional classification according to MD diagnostic criteria improved risk stratification (P<.001), the authors reported, with the highest risk, by approximately 3-fold, observed in patients with MD-diabetes, (HR, 3.03, 95% CI 1.86– 4.95; P<.001) followed by those with MD-only ( HR 1.92, 95%CI 1.20-3.07; P=.0064).

Patients with MD-only appeared at highest risk of HCC after achieving sustained virologic response (P=.008), with catch up in risk later for those with MD-US. The researchers found no association between having US-only and HCC.

“By applying the [metabolic dysfunction] criteria in a real-life cohort of patients cured of CHC with advanced fibrosis, we found that [metabolic dysfunction] is more prevalent than [ultrasonographic steatosis] and identifies more accurately individuals with advanced liver disease at risk of developing de novo HCC,” the authors wrote. [Metabolic dysfunction] appears more useful than US to stratify the risk of HCC in patients cured of CHC with advanced fibrosis.”

Reference: Pelusi S, Bianco C, Colombo M, et al. Metabolic dysfunction outperforms ultrasonographic steatosis to stratify hepatocellular carcinoma risk in patients with advanced hepatitis C cured with direct‐acting antivirals. Liver Int. 2023:001:1-11. Published online April 10, 2023. doi.org/10.1111/liv.15577

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