Assessing liver fibrosis in all patients with type 2 diabetes and fatty liver disease: It's time to act now

Non-alcoholic fatty liver disease (NAFLD) consists of a range of hepatic disorders from isolated hepatic steatosis or non-alcoholic fatty liver, to non-alcoholic steatohepatitis (NASH), advanced fibrosis, cirrhosis and the development of hepatocellular carcinoma. Of the various stages within this spectrum, liver fibrosis is the major determinant of adverse long-term prognosis. In the latest and most contemporary meta-analysis involving more than 4,000 individuals with biopsy-confirmed NAFLD, it was found that liver fibrosis, irrespective of the presence of NASH, was a significant predictor of all-cause mortality, liver-related mortality and morbidity. Importantly, these risks appeared to be incremental with advancing stages of liver fibrosis. However, most of the evidence was derived from retrospective studies, and was limited by spectrum bias, insufficient adjustments for key confounders and the lack of a protocol-driven assessment for development of adverse outcomes. The recent study by Sanyal et al., published in the New England Journal of Medicine, was the first prospective study that evaluated both hepatic and extrahepatic outcomes of 1,773 adult patients with NAFLD based on a protocol-mandated approach with adjustments of covariates in the analyses. All participants were recruited from the NASH Clinical Research Network and included the full histological spectrum of NAFLD. Over a median follow-up period of 4 years, the incidence of allcause mortality, liver-related mortality and any hepatic decompensation events, which included clinically apparent ascites, overt encephalopathy and variceal hemorrhage, increased progressively with higher fibrosis stages from F0–2 (no, mild or moderate fibrosis), F3 (bridging fibrosis) to F4 (cirrhosis). Furthermore, the development of any new hepatic decompensation event was independently associated with a more than sixfold increase in the risk of all-cause mortality, even after adjustments for confounders, such as age, sex, presence of type 2 diabetes, NASH and fibrosis stage at baseline. Collectively, these prospective findings provide compelling clinical support to the conventional notion derived from retrospective studies, that liver fibrosis is indeed an important prognostic indicator in NAFLD patients. However, among the large number of individuals with NAFLD that constitute one-quarter of the global adult population, who are the ones that will develop progression leading to advanced fibrosis, cirrhosis and ultimately, mortality? Interestingly, a recent study using the longterm follow-up data of the Third National Health and Nutrition Examination Survey (NHANES III) of the USA showed that the association between NAFLD and all-cause mortality was significant only among those with evidence of metabolic dysfunction, including type 2 diabetes, obesity or central adiposity, dyslipidemia and hypertension. In other words, NAFLD on its own was not a significant predictor of mortality if adjusted for the presence of metabolic risk factors. In another recent metaanalysis involving over 24 million individuals globally, among those with NAFLD, type 2 diabetes more than doubled their risks of developing severe liver disease, namely, cirrhosis, hepatic decompensation and liver-related mortality. Notably, type 2 diabetes elevated this risk to a much larger extent than that brought by other metabolic risk factors, such as obesity, hypertension and dyslipidaemia. As hepatic steatosis is also highly prevalent in type 2 diabetes patients, it seems that patients with type 2 diabetes who also have co-existing fatty liver disease will probably derive the greatest benefits, among the NAFLD population, from fibrosis assessments for hepatic risk stratification. In contrast, NAFLD has been regarded as a multisystem disorder that is also associated with cardiovascular disease, chronic kidney disease and extrahepatic cancers, such as colorectal malignancy. However, in contrast to all-cause mortality and liver-related outcomes, Sanyal et al. did not observe significant associations between fibrosis stage and the incidence of cardiovascular disease or non-hepatic cancers, although F4 fibrosis independently increased the risk of developing a >40% decline in estimated glomerular filtration rate compared with those with F0–2 fibrosis. Similarly, the recent study of the USA NHANES III database showed that the association between NAFLD and cardiovascular mortality became insignificant after adjustments for demographic and lifestyle factors, whereas that with cancer mortality was also attenuated after adjustments for metabolic risk factors. In the prospective study by Sanyal et al., type 2 diabetes, obesity and hypertension were present in 42, 73 and 61% of the participants with NAFLD, respectively. Although all regression *Corresponding author. Karen S L Lam Tel. : +852-2255-4783 Fax: +852-2816-2863 E-mail address: ksllam@hku.hk Received 24 January 2022; revised 28 January 2022; accepted 31 January 2022