NAFLD and liver-related events: does type 2 diabetes have a key role?

The global prevalence of non-alcoholic fatty liver disease (NAFLD) is projected to increase substantially in the next decade as the population grows and ages, in parallel with the rising burden of obesity and type 2 diabetes.1Yip TC Vilar-Gomez E Petta S et al.Geographical similarity and differences in the burden and genetic predisposition of NAFLD.Hepatology. 2023; 77: 1404-1427Crossref PubMed Scopus (23) Google Scholar Cardiovascular disease represents the principal cause of morbidity and mortality among adults with NAFLD; however, the risk of hepatic decompensation and hepatocellular carcinoma increases exponentially with worsening of fibrosis, and liver-related deaths might account for a large proportion of the excess mortality among adults with NAFLD and advanced fibrosis (bridging fibrosis or cirrhosis).2Sanyal AJ Van Natta ML Clark J et al.Prospective study of outcomes in adults with nonalcoholic fatty liver disease.N Engl J Med. 2021; 385: 1559-1569Crossref PubMed Scopus (271) Google Scholar, 3Vilar-Gomez E Calzadilla-Bertot L Wai-Sun Wong V et al.Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.Gastroenterology. 2018; 155: 443-457Summary Full Text Full Text PDF PubMed Scopus (454) Google Scholar Among individuals with NAFLD, those with type 2 diabetes are at higher risk of developing advanced stages of fibrosis and subsequently hepatic decompensation, hepatocellular carcinoma, and liver-related mortality than those without type 2 diabetes.4Huang DQ Wilson LA Behling C et al.Fibrosis progression rate in biopsy-proven nonalcoholic fatty liver disease among people with diabetes versus people without diabetes: a multicenter study.Gastroenterology. 2023; (published online April 29.)https://10.1053/j.gastro.2023.04.025Summary Full Text Full Text PDF Scopus (5) Google Scholar, 5Ajmera V Cepin S Tesfai K et al.A prospective study on the prevalence of NAFLD, advanced fibrosis, cirrhosis and hepatocellular carcinoma in people with type 2 diabetes.J Hepatol. 2023; 78: 471-478Summary Full Text Full Text PDF PubMed Scopus (20) Google Scholar, 6Jarvis H Craig D Barker R et al.Metabolic risk factors and incident advanced liver disease in non-alcoholic fatty liver disease (NAFLD): a systematic review and meta-analysis of population-based observational studies.PLoS Med. 2020; 17e1003100 Crossref Google Scholar In The Lancet Gastroenterology & Hepatology, Daniel Huang and colleagues7Huang DQ Noureddin N Ajmera V et al.Type 2 diabetes, hepatic decompensation, and hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: an individual participant-level data meta-analysis.Lancet Gastroenterol Hepatol. 2023; (published online July 4.)https://doi.org/10.1016/S2468-1253(23)00157-7Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar report the findings of a comprehensive meta-analysis including six retrospective cohort studies comprising 2016 ethnically diverse participants. The study outcomes were hepatic decompensation, defined as a composite outcome of ascites, hepatic encephalopathy, or variceal bleeding (assessable in 1737 participants) and hepatocellular carcinoma (assessable in 1802 participants). Compared with participants without type 2 diabetes, individuals with diabetes had an increased risk of hepatic decompensation (subdistribution hazard ratio [sHR] 2·15 [95% CI 1·39–3·34]) and hepatocellular carcinoma (5·34 [1·67–17·09]) even after controlling for several factors known to be associated with NAFLD progression. At baseline, mean liver stiffness, measured by magnetic resonance elastography, was significantly higher among individuals with type 2 diabetes (5·10 kPa [SD 2·42]) than those without type 2 diabetes (3·59 kPa [1·82]). This finding could suggest that a higher proportion of people with type 2 diabetes had higher scores of fibrosis at baseline and therefore were at higher risk of developing hepatic decompensation and hepatocellular carcinoma. A sensitivity analysis, in which participants were stratified by liver stiffness (<5 or ≥5 kPa), consistent with the recommended thresholds used by the American Association for the Study of Liver Diseases guidance to identify cirrhosis,8Rinella ME Neuschwander-Tetri BA Siddiqui MS et al.AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease.Hepatology. 2023; 77: 1797-1835Crossref PubMed Scopus (82) Google Scholar showed that type 2 diabetes remained significantly associated with an increased risk of hepatic decompensation, regardless of the presence of cirrhosis, although the risk was higher among individuals with liver stiffness of 5 kPa or higher at baseline. The authors also reported that the risk of incident hepatocellular carcinoma was only increased in participants with type 2 diabetes with cirrhosis. These findings support previous research demonstrating that individuals with type 2 diabetes and cirrhosis are at excess risk of hepatic decompensation, hepatocellular carcinoma, and liver-specific mortality when compared with those without type 2 diabetes.3Vilar-Gomez E Calzadilla-Bertot L Wai-Sun Wong V et al.Fibrosis severity as a determinant of cause-specific mortality in patients with advanced nonalcoholic fatty liver disease: a multi-national cohort study.Gastroenterology. 2018; 155: 443-457Summary Full Text Full Text PDF PubMed Scopus (454) Google Scholar Among patients with NAFLD, severity and progression of NAFLD is likely to depend on the combination of several factors, including but not limited to glycaemic control and its variability and the concurrent use of multiple medications to manage comorbid conditions (ie, insulin-sensitisers; angiotensin II receptor blockers) and its systemic complications (ie, statins, aspirin). Few retrospective cohort studies have investigated the association between glycated haemoglobin (HbA1c) and NAFLD severity. Among 713 individuals with biopsy-proven NAFLD (49% of whom had type 2 diabetes), Angelopoulos and colleagues examined the effect of glycaemic control, as assessed via HbA1c measurements performed for several years preceding liver biopsies, and found a positive and dose-dependent response between levels of HbA1c and fibrosis severity at the time of biopsy. For every 1% increase in mean HbA1c, there was a 15% increase in risk of higher hepatic fibrosis severity.9Alexopoulos AS Crowley MJ Wang Y et al.Glycemic control predicts severity of hepatocyte ballooning and hepatic fibrosis in nonalcoholic fatty liver disease.Hepatology. 2021; 74: 1220-1233Crossref PubMed Scopus (34) Google Scholar In this meta-analysis, the authors also examined the relative contribution of HbA1c levels on the risk of hepatic decompensation, but not incident hepatocellular carcinoma. Higher levels of HbA1c were associated with an increased risk of hepatic decompensation in the entire cohort. Taken together, these findings provide compelling clinical data to indicate that type 2 diabetes is associated with advanced liver disease, faster disease progression, and worse liver-related outcomes in patients with NAFLD. Notably, individuals with type 2 diabetes with cirrhosis have a high risk of decompensation, hepatocellular carcinoma, and death, suggesting that they should undergo primary risk assessment, be followed more closely, and offered early treatment options such as intensive lifestyle interventions, metabolic surgery, or glucagon-like peptide-1 (GLP-1) agonists to reduce the risk of complications and death. High levels of HbA1c as a surrogate of poor glycaemic control have been linked to serious long-term complications, including advanced stage liver disease, and worse outcomes in NAFLD, although an ideal cutoff value to identify people at risk of those adverse clinical outcomes has not yet been identified. Although this meta-analysis highlights potential clinical implications of type 2 diabetes in NAFLD, there is an unmet need for more prospective research with a focus on: how glycaemic control via insulin-sensitisers or GLP-1 agonists might revert the NAFLD progression in people with type 2 diabetes; the effect of therapies that are currently used in the management of type 2 diabetes such as statins and aspirin on the risk of adverse liver outcomes; and cost-effectiveness analyses of screening strategies to identify people with NAFLD and type 2 diabetes at high risk of advanced fibrosis and therefore potential short-term clinical complications.10Noureddin M Jones C Alkhouri N Gomez EV Dieterich DT Rinella ME Screening for nonalcoholic fatty liver disease in persons with type 2 diabetes in the United States is cost-effective: a comprehensive cost-utility analysis.Gastroenterology. 2020; 159: 1985-1987Summary Full Text Full Text PDF PubMed Scopus (62) Google Scholar Considering the high prevalence of type 2 diabetes in NAFLD (approximately 23%), and the robust and significant association between type 2 diabetes and risk of hepatic decompensation and hepatocellular carcinoma shown in this study, successful screening strategies and timely intervention in this large population could have a major effect on public health. Individuals with type 2 diabetes and NAFLD constitute a population at high risk of liver disease and require special attention and intervention. Screening and proper management of these patients might contribute to the primary and secondary prevention of liver disease. I declare no competing interests. Type 2 diabetes, hepatic decompensation, and hepatocellular carcinoma in patients with non-alcoholic fatty liver disease: an individual participant-level data meta-analysisAmong people with NAFLD, the presence of type 2 diabetes is associated with a significantly higher risk of hepatic decompensation and hepatocellular carcinoma. Full-Text PDF Open Access