Assessment of hepatic fibrosis in MAFLD..a new player in the evaluation of residual cardiovascular risk

Assessment of hepatic fibrosis in MAFLD: a new player in the evaluation of residual cardiovascular risk? Dear Editor, We read with great interest the recently published paper by Shonmann Y et al. [1] reporting on an independent positive association between liver fibrosis and ten-year incidence of cardiovascular events (CVEs) in a large sample of community-based general population in Israel. Fibrosis was non-invasively assessed by the FIB-4 score, a simple and well validated score used to rule out (cut-off value ≤1.3) or rule in (cut-off ≥2.67) significant liver fibrosis (F2-F3) [2-3]. These results are of considerable interest since they suggest that hepatic fibrosis could therefore be interpreted as an additional non-lipid marker of residual cardiovascular risk, defined as the risk that remains after the optimal multifactorial treatment of all the coexisting risk factors in the individual. However, although the Authors emphasize in the Introduction the strong association between non-alcoholic fatty liver disease (NAFLD) and CVEs [4] and the importance to assess cardiovascular risk in this clinical setting, the present study has been performed in the general population, i.e., in a cohort of subjects who did not undergo steatosis assessment, nor evaluation of alcohol intake and of the presence of viral hepatitis B and C. Prognostic evaluation of fibrosis is of particular importance in patients with NAFLD and even more in those with metabolic associated fatty liver disease (MAFLD) [5], where such an assessment should be mandatory. In fact, it is interesting to note that in Italy, among the NAFLD population, severe hepatic fibrosis (F2-F3) is estimated to involve around 900,000 subjects, mostly asymptomatic, and that this number could reach about one and a half million over the next 10 years [6]. Furthermore, in patients with NAFLD the first cause of death is cardiovascular disease, and the severity of liver fibrosis appears to be the only marker of liver damage capable of predicting the increased cardiovascular risk [4,7]. Our group also found a significant association between non-invasive scores of liver fibrosis - FIB-4 score and NFS (NAFLD fibrosis score) - and CVEs [8], more specifically in patients with NAFLD diagnosis. In fact, we recently published prospectively collected data from 898 patients screened for liver steatosis by ultrasound in the ongoing PLINIO study (Progression of LIver Damage and Cardiometabolic Disorders in Nonalcoholic Fatty Liver dIsease: An Observational Cohort study) in Italy, where the occurrence of cardiovascular events (CVEs) is a secondary pre-specified endpoint [ClinicalTrials.gov no: NCT04036357]. In the study we excluded patients with viral or autoimmune hepatitis and those with history of alcohol abuse and of any other chronic disease. Most patients were overweight and obese, arterial hypertension was present in 58.3%, type 2 diabetes mellitus in 25.7% and metabolic syndrome in 48.6%. Current treatment with statins was present in 38.6%. Almost all patients with NAFLD had diagnostic criteria for MAFLD [5). Incident CVEs included a composite of fatal/nonfatal ischemic stroke and myocardial infarction (MI), cardiac (stent or coronary artery bypass surgery/CABG) or peripheral revascularization (carotid endarterectomy or lower limb percutaneous transluminal angioplasty, PTA), new-onset supraventricular arrhythmias (such as atrial fibrillation) and cardiovascular death. Outcomes were assessed by phone interview every 6 months and by in-person examination every 12 months. Over a median follow-up time of 41.4 months (3044.4 patient-years), 58 CVEs (1.9%/year) were registered. The rate of CVEs was more than a 2-fold higher in patients with NAFLD (n=643, 2.1%/year) vs those without NAFLD (n=255, 1.0%/year) (P=.066). In multivariable Cox proportional regression analysis, NAFLD increased risk for CVEs (hazard ratio [HR], 2.41; 95% CI, 1.06–5.47; P=.036), after adjustment for metabolic syndrome. The independent predictive value of FIB-4 and NFS for incident CVEs was evaluated in 643 subjects with NAFLD. Among NAFLD patients, FIB-4 >2.67 was independently associated with cardiovascular events (hazard ratio, 4.02; 95% CI, 1.21- 13.38), as was NFS >0.676 (hazard ratio, 2.35; 95% CI, 1.05-5.27). In addition, in our study, metabolic syndrome was also an independent predictor of CVE in NAFLD patients. Of note that an independent association with CVEs was observed also when advanced fibrosis was defined using NFS, a score largely driven by metabolic factors (e.g., diabetes and obesity), which could not be calculated in the study by Shonmann Y et al. [1]. Evidence from the above studies suggests the hypothesis that the development of hepatic fibrosis in patients with MAFLD may be the result of long-term exposure to cardio-metabolic risk factors such as obesity, diabetes, and metabolic syndrome [9]. These conditions can promote insulin resistance, inflammation, lipopolysaccharide translocation and oxidative stress which in turn can induce hepatocellular damage, activation of stellate cells and Kupfer cells with consequent increase in liver fibrogenesis [10] (Fig.1). Hepatic fibrosis could therefore be interpreted as a non-lipid marker of residual cardiovascular risk. Moreover, the great prevalence of MAFLD in the general population and in populations at increased cardio-metabolic risk (diabetes, obesity) strongly suggests monitoring the progression of hepatic fibrosis in a non-invasive way. Finally, the new diagnosis of MAFLD no longer includes the dichotomous condition of NASH or non-NASH [5]. Therefore, in MAFLD patients it is of great importance to assess the severity of fibrosis which represents the most important risk factor both for the progression of liver disease and for the risk of cardio-metabolic complications. The routine use of non-invasive tests will allow the identification of subjects with little or no fibrosis and reasonably exclude the presence of an increased risk for cardiovascular events and serious hepatic complications. On the contrary, the documentation of severe fibrosis may help to identify early subjects at greater risk of liver disease progression and to better define the residual cardiovascular risk