Introduction: Non-alcoholic fatty liver disease (NAFLD) is the leading cause of chronic liver disease, with type 2 diabetes mellitus (T2DM) as a major predictor. Insulin resistance and chronic inflammation are key pathways in the pathogenesis of T2DM leading to NAFLD and vice versa, with the synergistic effect of NAFLD and T2DM increasing morbidity and mortality risks. This meta-analysis aims to quantify the prevalence of NAFLD and the prevalence of clinically significant and advanced fibrosis in people with T2DM. Methods: MEDLINE and Embase databases were searched from inception until 13 February 2023. The primary outcomes were the prevalence of NAFLD, non-alcoholic steatohepatitis (NASH) and fibrosis in people with T2DM. A generalised linear mixed model with Clopper-Pearson intervals was used for the analysis of proportions with sensitivity analysis conducted to explore heterogeneity between studies. Results: 156 studies met the inclusion criteria, and a pooled analysis of 1 832 125 patients determined that the prevalence rates of NAFLD and NASH in T2DM were 65.04% (95% CI 61.79% to 68.15%, I²=99.90%) and 31.55% (95% CI 17.12% to 50.70%, I²=97.70%), respectively. 35.54% (95% CI 19.56% to 55.56%, I²=100.00%) of individuals with T2DM with NAFLD had clinically significant fibrosis (F2–F4), while 14.95% (95% CI 11.03% to 19.95%, I²=99.00%) had advanced fibrosis (F3–F4). Conclusion: This study determined a high prevalence of NAFLD, NASH and fibrosis in people with T2DM. Increased efforts are required to prevent T2DM to combat the rising burden of NAFLD. PROSPERO registration number: CRD42022360251.

An increase in the aging population is an impending problem. A large cohort study was carried out to determine the influence of aging and other factors on hepatocarcinogenesis in patients treated with interferon. Biopsy‐proven 2547 chronic hepatitis C patients registered at our referral center since 1992 were included. Of these, 2166 were treated with interferon‐based therapy. Incidences of hepatocellular carcinoma (HCC) associated with interferon were analyzed by Kaplan‐Meier and person‐years methods for an average follow‐up of 7.5 years. Factors associated with HCC risk were determined by Cox proportional hazard analysis. HCC developed in 177 interferon‐treated patients. The risk for HCC depended on age at primary biopsy and increased more than 15‐fold after 65 years of age. Even when stratified by stage of fibrosis, the cumulative and annual incidences of HCC were significantly higher in older patients than in younger patients (P < 0.001) at the same stage of fibrosis, except for cirrhosis. Progression of fibrosis over time was significantly accelerated in older patients. The impact of viral eradication on HCC prevention was less significant in older patients than in younger patients. Multivariate analysis confirmed that age, gender, liver fibrosis, liver steatosis, total cholesterol level, fasting blood sugar level, baseline and postinterferon alpha‐fetoprotein level, and virological response to interferon were independent risk factors associated with HCC. Aging was the strongest risk factor for a nonvirological response to interferon‐based antiviral therapy. Conclusion: Elderly patients are at a higher risk for HCC. Hepatitis C viral eradication had a smaller effect on hepatocarcinogenesis in older patients. Patients should therefore be identified at an earlier age and treatment should be initiated. HEPATOLOGY 2010

The effects of interferon (IFN) treatment and the post-IFN treatment α-fetoprotein (AFP) levels on risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis C (CHC) are unknown. To determine the relationship between AFP and alanine transaminase (ALT) levels and HCC risk, a cohort consisting of 1,818 patients histologically proven to have CHC treated with IFN were studied. Cumulative incidence and HCC risk were analyzed over a mean follow-up period of 6.1 years using the Kaplan-Meier method and Cox proportional hazard analysis. HCC developed in 179 study subjects. According to multivariate analysis, older age, male gender, advanced fibrosis, severe steatosis, lower serum albumin levels, non sustained virological response (non-SVR), and higher post-IFN treatment ALT or AFP levels were identified as independent factors significantly associated with HCC development. Cutoff values for ALT and AFP for prediction of future HCC were determined as 40 IU/L and 6.0 ng/mL, respectively, and negative predictive values of these cutoffs were high at 0.960 in each value. The cumulative incidence of HCC was significantly lower in patients whose post-IFN treatment ALT and AFP levels were suppressed to less than the cutoff values even in non-SVR patients. This suppressive effect was also found in patients whose post-IFN treatment ALT and AFP levels were reduced to less than the cutoff values despite abnormal pretreatment levels. Conclusion : Post-IFN treatment ALT and AFP levels are significantly associated with hepatocarcinogenesis. Measurement of these values is useful for predicting future HCC risk after IFN treatment. Suppression of these values after IFN therapy reduces HCC risk even in patients without HCV eradication. (Hepatology 2013;58:1253–1262)

Summary: Background: Pemafibrate is a novel, selective peroxisome proliferator‐activated receptor α modulator (SPPARMα). In mice, Pemafibrate improved the histological features of non‐alcoholic steatohepatitis (NASH). In patients with dyslipidaemia, it improved serum alanine aminotransferase (ALT).Aims: To evaluate the efficacy and safety of Pemafibrate in patients with high‐risk, non‐alcoholic fatty liver disease (NAFLD).Methods: This double‐blind, placebo‐controlled, randomised multicentre, phase 2 trial randomised 118 patients (1:1) to either 0.2 mg Pemafibrate or placebo, orally, twice daily for 72 weeks. The key inclusion criteria included liver fat content of ≥10% by magnetic resonance imaging‐estimated proton density fat fraction (MRI‐PDFF); liver stiffness of ≥2.5 kPa, by magnetic resonance elastography (MRE); and elevated ALT levels. The primary endpoint was the percentage change in MRI‐PDFF from baseline to week 24. The secondary endpoints included MRE‐based liver stiffness, ALT, serum liver fibrosis markers and lipid parameters.Results: There was no significant difference between the groups in the primary endpoint (−5.3% vs −4.2%; treatment difference −1.0%, P = 0.85). However, MRE‐based liver stiffness significantly decreased compared to placebo at week 48 (treatment difference −5.7%, P = 0.036), and was maintained at week 72 (treatment difference −6.2%, P = 0.024), with significant reduction in ALT and LDL‐C. Adverse events were comparable between the treatment groups and therapy was well tolerated.Conclusions: Pemafibrate did not decrease liver fat content but had significant reduction in MRE‐based liver stiffness. Pemafibrate may be a promising therapeutic agent for NAFLD/NASH, and also be a candidate for combination therapy with agents that reduce liver fat content. ClinicalTrials.gov, number: NCT03350165.