Clinical and molecular implications of antipsychotics in MASLD.

Nonalcoholic fatty liver and left ventricular remodelling: now the prospective evidence.

Since obesity and type 2 diabetes mellitus (DM) became almost pandemic, incidence and prevalence of associated nonalcoholic fatty liver disease (NAFLD) rose accordingly. Aim of the study was assessing whether there is a link between circulating C-reactive protein(CRP), gut microbiota dysbiosis and severity of liver disease in patients with NAFLD and confirmed type 2 DM. 50 patients diagnosed with type 2 DM were consecutively enrolled in this cross-sectional, pilot study, being evenly divided in two groups, as matched pairs, on the basis of presence or absence of NAFLD confirmed by abdominal and CT exam, after ruling out a lot of diseases and conditions. Patients underwent measurements of waist circumference, blood pressure (BP), body mass index (BMI) and thoroughly physical examination. Complete blood count (CBC), liver tests, CRP, fasting plasma glucose (FPG), low density lipoprotein(LDL) and high-density lipoprotein(HDL) cholesterol, triglycerides, creatinin and uric acid, micro proteinuria as well as stool microbiology were run, using standardized methods. Fatty liver index (FLI) was also calculated. Fibromax (BioPredictive) was performed in NAFLD (+) patients. NAFLD (+) group displayed significant differences of age and BMI, as well as lab biochemistry: ALT, GGT, LDL-cholesterol and triglycerides, CRP, microprotienuria and stool microbiology.. Strong positive correlation of CRP with gut dysbiosis (DB) severity, microproteinuria, as well as with nonalcoholic steatohepatitis (NASH) score, were observed. DB range correlated positively in NAFLD (+) group with age, BMI, BP, dyspepsia as well as with NASH scores. In conclusion patients with NAFLD and associated type 2 DM displayed a specific profile with significant differences of age, BMI, FLI, diabetic treatment, biochemistry and gut microbiological charts. Strong positive correlations between CRP, gut DB and NASH score suggest the possibility of link between inflammation, gut microbiota DB and severity of liver disease.

Background: Nonalcoholic fatty liver disease (NAFLD) is a common condition driven by the obesity epidemic. It is associated with cardiometabolic risk factors including diabetes, obesity, and hyperlipidemia, but also cardiovascular disease events, independent of these factors. No prospective studies have investigated the association of NAFLD with stroke risk. Hypothesis: NAFLD is associated with the risk of stroke in the REasons for Geographic and Racial Differences in Stroke (REGARDS) case-cohort study. Methods: The REGARDS study recruited 30,239 participants from the contiguous U.S., in order to study the reasons for regional and racial differences in stroke mortality. The REGARDS case-cohort study consists of 569 cases of incident stroke with 5.4 years follow up and a cohort random sample of 1,104. The Fatty Liver Index (FLI) was used a surrogate marker for NAFLD. It is calculated as e X /(1 + e X ) x 100, where x = 0.953*log(triglycerides) + 0.139*BMI + 0.718*log(γ-glutamyltransferase) + 0.053*waist circumference - 15.745. An FLI >60 is considered a positive score, 20-60 an intermediate score, and <20 a negative score. After excluding 68 participants who reported heavy alcohol consumption and 87 with baseline stroke, Cox proportional hazards models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI) of stroke for FLI category, adjusting for age, race, sex, and the Framingham stroke risk factors and stratified by body mass index (BMI). Results: In the cohort sample, 44% of participants had NAFLD based on the FLI and 19% had a negative score. Compared to those without NAFLD, individuals with a positive score were more likely to be male (51% vs. 28%), have hypertension (69% vs. 40%), dyslipidemia (68% vs. 37%) diabetes (35% vs. 8%), and higher BMI (mean 33.7 vs. 23.0 kg/m 2 ; all p<0.001). No participant with BMI < 20 kg/m 2 had NAFLD by FLI. NAFLD was not associated with risk of stroke in a model adjusted for age, race and sex; HR 1.00 (95% CI 0.69-1.46), or a model further adjusted for Framingham stroke risk factors; HR 0.71 (95% CI 0.45-1.11). Stratifying by BMI group (20-30 kg/m 2 ), there was no association between NAFLD and stroke risk in those with BMI 20-<25 or 25-30 kg/m 2 . We were unable to analyze NAFLD in the BMI >30 group, due to low number of negative scores. When analyzed as a continuous variable among those with BMI 30 kg/m 2 , the HRs for a 10 unit higher FLI score were 0.92 (95% CI 0.84-1.01) and 1.17 (95% CI 0.97-1.42), respectively, adjusted for age, sex, race, and stroke risk factors. Discussion: NAFLD, as determined by a positive FLI score, was not associated with risk of stroke although FLI score was borderline associated with stroke risk in those with a BMI >30. Results raise the possibility that NAFLD represents end organ damage from an adverse metabolic profile, and is not a mediator of stroke risk.

ObjectiveTo investigate the risk of non-alcoholic fatty liver disease (NAFLD) for cardiovascular disease and all cause death in patients with type 2 diabetes mellitus (T2DM).DesignNationwide population based study.SettingLongitudinal cohort study...

Background: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the US, and is associated with early atherogenesis and increased risk of cardiovascular (CV) death. Although no pharmacologic therapy has proven benefit in NAFLD, recent clinical studies suggest that ezetimibe may reduce histologic evidence of liver inflammation and improve serum markers of NAFLD. In this post hoc analysis of the IMPROVE-IT trial, we assessed the impact of ezetimibe in patients with presumed NAFLD, using the Fatty Liver Index (FLI), a validated prediction score for hepatic steatosis. Methods: Of the 18,144 IMPROVE-IT patients randomized to ezetimibe/simvastatin (E/S) or placebo/simvastatin (P/S), 15,095 had both baseline ALT 2x ULN and sufficient data with which to calculate FLI, a calculated score composed of triglycerides (TG), gamma-glutamyltransferase (GGT), body mass index (BMI), and waist circumference. FLI ≥ 60 has been strongly correlated with NAFLD, while values <30 indicate low probability of NAFLD. Differences in FLI between treatment arms over time were tested with non-parametric Wilcoxon rank-sum tests. Results: Baseline FLI was ≥ 60 in 6798 (45%) patients and <30 in 3438 (23%). E/S reduced median absolute FLI from 55.0 to 51.2 over 72 months, a reduction of 6.9%, which was significantly greater than that observed in P/S group (all p<0.001 at each time-point, Fig). Of those with initial FLI ≥ 60 treated with E/S, 26.3% had 48-month FLI score < 60 (compared to 21.6% in P/S group, p<0.001). E/S significantly reduced both TG and GGT compared to P/S (both p<0.001 at 72 months). E/S significantly reduced FLI regardless of baseline ALT (normal vs. 1-2x ULN) ( p =0.002; interaction p =0.53). Conclusion: Ezetimibe significantly reduced surrogate markers of NAFLD, suggesting that it may offer protection against progression of non-alcoholic fatty liver disease, metabolic syndrome, and atherogenic risk.

Aims To investigate the association between overweight/obesity and fatty liver index (FLI) on the odds of incident prediabetes/type 2 diabetes and non-alcoholic fatty liver disease (NAFLD) in 2020 participants after 10 years follow up. Methods At baseline (in 2001) 2020 participants, males and females, aged 24–39 years, were stratified according to body mass index (BMI), normal weight (<25 kg/m2), overweight (≥25–<30 kg/m2), or obese (≥30 kg/m2) and FLI (as high FLI ≥60 or low FLI <60). We examined the incidence of prediabetes/type 2 diabetes and NAFLD (ultrasound assessed) over 10 years to 2011 to determine the relative impact of FLI and BMI. Results 514 and 52 individuals developed prediabetes and type 2 diabetes during follow-up. Such individuals were older, with higher BMI, serum glucose, insulin, alanine aminotransferase (ALT) and triglyceride (TG) concentrations than those who did not develop prediabetes or type 2 diabetes (n = 1454). The additional presence of high FLI significantly increased the risk of developing prediabetes and type 2 diabetes above the risk of being overweight/obese. Compared with normal weight, low FLI participants, the odds of prediabetes were ∼2-fold higher and the odds of type 2 diabetes were 9–10-fold higher respectively in the overweight/obese, high FLI group. No difference was observed between normal weight, low FLI and overweight/obese and low FLI groups. Conclusions An increased FLI significantly increases the odds of incident prediabetes, type 2 diabetes and NAFLD in individuals with overweight/obese highlighting the contributory role of liver fat accumulation in the pathophysiology of prediabetes/type 2 diabetes. Key messages Obesity is a risk factor for non-alcoholic fatty liver disease (NAFLD), prediabetes and type 2 diabetes. Additionally, NAFLD is more prevalent in people with prediabetes and type 2 diabetes when compared to age- and BMI-matched individuals. The presence of a raised fatty liver index (FLI) confers a significantly increased risk of developing prediabetes, type 2 diabetes and NAFLD above that conferred by being overweight/obese. The degree of elevation of FLI can risk stratify for incident prediabetes and type 2 diabetes in people with obesity.

Patients with schizophrenia spectrum disorders have increased morbidity and mortality, largely due to cardiovascular disease, which is associated with antipsychotic treatment. Because of the link between cardiometabolic risk, non-alcoholic fatty liver disease (NAFLD), and antipsychotics, we aimed to investigate the development of NAFLD during the first 3years of antipsychotic treatmentin first episode non-affective psychosis patients. A sample of 191 subjects was included in final analyses, randomly assigned to aripiprazole (N=83), risperidone (N=12), quetiapine (N=46), and ziprasidone (N=50). At intake, 180 patients were antipsychotic naïve. The NAFLD fibrosis score, FIB-4 score, and the fatty liver index (FLI) were calculated at baseline, at 3months, and then yearly for 3years. None of the patients showed significant liver fibrosis according to the mentioned scores at baseline, prior to randomization. At 3years follow-up, 25.1% individuals showed a FLI score ≥60, which is a predictor of steatosis. Of the individuals considered indeterminate at baseline, 64.7% developed a FLI score ≥60 and only 16.6% who had a FLI score <30 at baseline, showed a FLI score predictor of steatosis at endpoint. The FLI score ≥60 at endpoint was associated with an increase of more than 7% of the body mass index (FLI score≥60, 91.7%; FLI<60, 55.9%; p<0.001), increased triglyceride levels (FLI score≥60, 54.2%; FLI<60, 5.6%; p<0.001), decreased HDL levels (FLI score≥60, 41.7%; FLI<60, 17.5%; p=0.001), hypertension (FLI score≥60, 19.5%; FLI<60, 4.5%; p=0.002), and waist circumference increase (steatosis 68.8%; FLI<60, 14.0%; p<0.001). Our results support the importance of assessing the potential development of NAFLD in schizophrenia spectrum patients receiving antipsychotic medication.

Effect of omega-3 supplementation on fatty liver and visceral adiposity indices in diabetic patients with non-alcoholic fatty liver disease: A randomized controlled trial.

Dr. Xiao et al. investigated the association of nonalcoholic fatty liver disease (NAFLD) and fibrosis with incident dementia and cognition among participants in the Rotterdam Study, a prospective cohort study that included 3,975 patients with available fatty liver index (FLI), 4,577 patients with abdominal ultrasound, and 3,300 patients with liver stiffness assessments. NAFLD was defined as FLI ≥60 or steatosis on ultrasound and fibrosis as liver stiffness ≥8.0 kPa. Over 5 or more years of follow-up, NAFLD and liver fibrosis were not associated with an increased risk of incident dementia, and NAFLD was not associated with impaired cognitive function. Of interesting, NAFLD diagnosis was associated with a significantly decreased risk of incident dementia in the first 5 years of follow-up after FLI assessment. In response, Dr. Gupta notes the current lack of a biological model for linking NAFLD to protection from dementia, seeks evidence for weight loss–induced NAFLD regression, and wonders what phenomena might be occurring in these patients before vs after 5 years of follow-up to explain the study observations. Responding to these comments, the authors note that weight loss is the hallmark of NAFLD regressions, citing studies where regressions occurred even with slight weight reductions. They also note the interesting observation in several dementia cohorts (including theirs) of weight loss occurring in the years before dementia onset. By excluding the initial years of follow-up to address confounding by these intertwined mechanisms of weight loss and dementia, they note that the apparent beneficial effect of NAFLD disappeared. They posit that the presence of NAFLD may simply reflect the absence of weight loss rather than any true protective effect against dementia, but note the need for further studies to clarify these questions. This correspondence highlights the challenges of disentangling the complex interplay between weight loss and the natural history of NAFLD and dementia. Dr. Xiao et al. investigated the association of nonalcoholic fatty liver disease (NAFLD) and fibrosis with incident dementia and cognition among participants in the Rotterdam Study, a prospective cohort study that included 3,975 patients with available fatty liver index (FLI), 4,577 patients with abdominal ultrasound, and 3,300 patients with liver stiffness assessments. NAFLD was defined as FLI ≥60 or steatosis on ultrasound and fibrosis as liver stiffness ≥8.0 kPa. Over 5 or more years of follow-up, NAFLD and liver fibrosis were not associated with an increased risk of incident dementia, and NAFLD was not associated with impaired cognitive function. Of interesting, NAFLD diagnosis was associated with a significantly decreased risk of incident dementia in the first 5 years of follow-up after FLI assessment. In response, Dr. Gupta notes the current lack of a biological model for linking NAFLD to protection from dementia, seeks evidence for weight loss–induced NAFLD regression, and wonders what phenomena might be occurring in these patients before vs after 5 years of follow-up to explain the study observations. Responding to these comments, the authors note that weight loss is the hallmark of NAFLD regressions, citing studies where regressions occurred even with slight weight reductions. They also note the interesting observation in several dementia cohorts (including theirs) of weight loss occurring in the years before dementia onset. By excluding the initial years of follow-up to address confounding by these intertwined mechanisms of weight loss and dementia, they note that the apparent beneficial effect of NAFLD disappeared. They posit that the presence of NAFLD may simply reflect the absence of weight loss rather than any true protective effect against dementia, but note the need for further studies to clarify these questions. This correspondence highlights the challenges of disentangling the complex interplay between weight loss and the natural history of NAFLD and dementia.

Objectives: This study aimed to investigate the association between nonalcoholic fatty liver disease (NAFLD), assessed by the Fatty Liver Index (FLI), and the occurrence of lung abscess within a large population-based cohort. Method: We conducted a nationwide retrospective study using data from 367,930 subjects who underwent National Health check-ups between 2009 and 2018. Cox proportional hazards regression was performed to evaluate the association between the FLI and the incidence of lung abscess and community-acquired pneumonia (CAP) after adjusting for age, sex, and relevant covariates. Results: Among the study population, 455 (0.12%) and 44,934 (12.2%) patients were diagnosed with lung abscesses and CAP, respectively. The cumulative incidence of lung abscess was higher in individuals with elevated FLI values (FLI < 30, 0.10%; 30 ≤ FLI < 60, 0.16%; FLI ≥ 60, 0.18%; p < 0.001), whereas the incidence of CAP decreased across FLI groups (FLI < 30, 12.4%; 30 ≤ FLI < 60, 12.3%; FLI ≥ 60, 11.0%; p < 0.001). After adjusting for covariates, the risk of lung abscess significantly increased in the 30 ≤ FLI < 60 (Hazard ratio (HR) = 1.26; 95% confidence interval (CI), 0.95-1.68; p = 0.115) and the FLI ≥ 60 (HR = 1.67; 95% CI, 1.37-2.29; p < 0.001) groups, although the risk of CAP was relatively small in both groups (30 ≤ FLI < 60; HR = 1.06; 95% CI, 1.03-1.09; p < 0.001) (FLI ≥ 60; HR = 1.13; 95% CI, 1.08-1.12; p < 0.001). Conclusions: Our study provides compelling evidence supporting a potential link between NAFLD, as measured by FLI, and the incidence of lung abscess. These findings suggest the importance of vigilant monitoring of respiratory health in patients with NAFLD and emphasise the need for early detection of possible complications.

P134 Are hepatic steatosis predictive scores still useful to predict metabolic associated fatty liver disease (MAFLD) in Crohn’s disease patients?

Background: Non-alcoholic fatty liver disease (NAFLD) is a burgeoning health issue with a global prevalence that mirrors the rise in obesity and metabolic syndrome. Non-invasive diagnostic indices like the Waist to Height Ratio (WHtR) and the Fatty Liver Index (FLI) are crucial for early detection and management, offering an alternative to the invasive liver biopsy. These indices are particularly pertinent for populations with distinctive body compositions, such as those seen in Asian countries, where traditional measures like Body Mass Index (BMI) may not accurately reflect metabolic risk. Objective: To evaluate the efficacy of WHtR and FLI as non-invasive diagnostic tools for NAFLD in both lean and obese populations, and to identify the most reliable indicator for predicting the presence of fatty liver disease across different body compositions. Methods: This cross-sectional study was approved by the Ethical Review Board (ERC-771) and conducted at the Sindh Institute of Urology and Transplantation. It included 757 participants aged 18-70 years, with 559 lean and 298 obese individuals based on BMI classifications. Exclusion criteria included other forms of hepatitis, use of steatogenic medication, and significant gastrointestinal disorders. Diagnostic measures included abdominal ultrasonography performed by an expert radiologist and calculation of WHtR and FLI. Statistical analyses were performed using SPSS version 25, and diagnostic accuracy was assessed through sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and Area Under the Receiver Operating Characteristic (AUROC) curves. Results: Fatty liver was detected in 49% of obese patients and 33% of lean patients. The obese cohort demonstrated a WHtR &gt;0.63 with a diagnostic accuracy of 94.63%, whereas the FLI had a diagnostic accuracy of 83.6% for a cutoff &gt;74. In lean patients, FLI &gt;16.5 was more predictive of NAFLD with a diagnostic accuracy of 96.96%, as opposed to WHtR, which was less effective. The AUROC for WHtR and FLI in obese patients was 0.847 and 0.704, respectively, while in lean patients, the AUROC for FLI was 0.875, suggesting superior diagnostic performance over WHtR. Conclusion: The study confirms that WHtR and FLI are valuable non-invasive tools for predicting NAFLD, with WHtR being more effective in obese patients and FLI showing greater reliability in lean patients. These findings highlight the need for tailored approaches in diagnosing NAFLD according to body composition. Further large-scale, multicentric research is needed to generalize these diagnostic cut-offs.

Novel SNPs for screening of nonalcoholic fatty liver disease: a Korean population-based study

Background: Although non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, its influence on hypertension development is poorly understood. Hypothesis: We investigated whether fatty liver disease, as assessed by the fatty liver index (FLI), could predict the development of hypertension independently of systemic insulin resistance and inflammatory status. Methods: Prospective cohort study of 1,521 adults (484 men and 1037 women) aged 40 to 70 years without baseline hypertension examined in 2005 to 2008 as a baseline and 2008 to 2011 for follow-up. An equation was used to calculate FLI and classify patients as follows: FLI&lt;30, no NAFLD; FLI ≥60, NAFLD; and 31&lt;FLI&lt;59, intermediate FLI. Results: During an average of 2.6 years of follow-up, 153 subjects (10.06 %) developed hypertension. FLI was positively associated with baseline blood pressure, homeostasis model assessment of insulin resistance (HOMA-IR), leptin, urinary albumin/creatinine excretion, and high sensitivity C-reactive protein (hsCRP). After adjustment for confounding factors, including markers of insulin resistance and systemic inflammation, the odds ratio (95% confidence interval) for the incident hypertension increased in a graded manner with FLI (&lt;30 vs. 30-59 vs. ≥60= 1 vs. 1.77 [1.16-2.71] vs. 2.06 [1.09-3.89], respectively). Conclusions: NAFLD assessed by FLI was an independent risk factor for hypertension. Our findings suggest that FLI, a simple surrogate indicator of fatty liver disease, might be useful for identifying subjects at high risk for incident hypertension in clinical practice.

The increasing burden of non-alcoholic fatty liver disease: Non-alcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease in the world. NAFLD encompasses a spectrum of liver disease, ranging from simple hepatic steatosis to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). With the pandemic of obesity and type 2 diabetes mellitus (T2DM), there has been an exponential growth in the prevalence of NAFLD over the past two decades. The prevalence of NAFLD in most Asian countries, including China, is above 25% in the general adult population.[1] Furthermore, there is a developing childhood obesity pandemic, and a meta-analysis of 20,595 children in Asia generated a pooled NAFLD prevalence of 5.53%, which had increased by approximately 1.6-fold since 2010. The pooled prevalence of NAFLD in Asian children increased from those with normal weight (1.5%) to those who were overweight (16.7%) or obese (50.1%).[2] A recent study suggested that NAFLD is not uncommon in lean Chinese adults with a normal waist circumstance. Metabolic risk factors, rather than genetic factors, may play an important role in the development of lean NAFLD,[3] and the hepatic and extra-hepatic complications can also develop in lean patients, which reinforces the importance of considering metabolic phenotype in the assessment of NAFLD, rather than using body mass index-based approaches.[4] Renaming of NAFLD to MAFLD: A diagnosis of NAFLD is made on the basis of histological or imaging-derived evidence of steatosis, in the absence of a known etiology of fatty liver. With advances in knowledge of the pathogenesis of the condition, the "exclusive" term NAFLD no longer serves to precisely describe a highly heterogeneous disease. In 2020, the novel term of metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed in an attempt to create an "inclusive" diagnosis.[5] Zeng et al[6] performed a cross-sectional study of Chinese adults which showed that the prevalence of MAFLD is higher than that of NAFLD, and therefore the newly-defined label of MAFLD may better reflect the metabolic pathogenesis. Furthermore, a pathologic analysis of patients with MAFLD showed that a single metabolic defect can have a significant role in the development of fibrosis and that insulin resistance plays a key role in the progression of steatohepatitis and the development of significant fibrosis.[7] As Zheng et al discussed, by using the new terminology, "cryptogenic cirrhosis" and MAFLD can now be diagnosed in lean individuals using metabolic criteria, rather than being viewed as completely separate entities. The renaming of NAFLD to MAFLD may result in significant improvements in awareness, advocacy, research, and the clinical management of the condition.[8] Update on the pathogenesis of MAFLD: The pathogenesis of NAFLD/MAFLD is a multifactorial process, involving interactions among nutrition, metabolism, genetic predisposition, the gut microbiota, and environmental factors. Although a great deal of progress has been made in recent decades, the pathogenic mechanism of NAFLD/MAFLD has yet to be fully elucidated. In this issue of the Chinese Medical Journal (CMJ), Pan et al[9] give an overview of the role of hepatocyte nuclear factor 4α (HNF4α) in the pathogenesis of NAFLD. HNF4α has been shown to regulate bile acid, lipid, and glucose metabolism; and hepatic HNF4α expression is much lower in patients with NAFLD and mouse models of NASH. Furthermore, there is evidence that hepatic HNF4α plays a key role in the initiation and progression of NAFLD and may represent a therapeutic target for NAFLD.[9] Huang et al[10] presented a systematic review regarding the role of retinol-binding protein 4 (RBP4) in the development of NAFLD and its potential therapeutic application. RBP4 induces hepatic de novo lipogenesis, impairs fatty acid oxidation, increases insulin resistance, and promotes hepatic inflammation. Furthermore, a high plasma RBP4 concentration is associated with a high risk of NAFLD; and agents that reduce the circulating RBP4 concentration and/or hepatic RBP4 expression have a protective effect against NAFLD. These findings suggest that RBP4 could be targeted as a novel diagnostic marker or therapeutic target for NAFLD.[10] Jackson et al[11] summarized the essential physiology of bile acid and sphingolipid metabolism, because the dysregulation of both are potential contributors to NAFLD. Specifically, the dysregulation of bile acid and sphingolipid metabolism has been linked to hepatic steatosis, inflammation, and fibrosis, and the further exploration of the pathologic effects mediated by bile acids and sphingolipids may also lead to new diagnostic and therapeutic strategies for NAFLD. Hepatitis B and concurrent MAFLD: Concomitant NAFLD/MAFLD in patients with chronic hepatitis B (CHB) has become highly prevalent over the past two decades. However, the risks associated with the dual etiologies, outcomes, and mechanisms involved in the interaction between CHB and NAFLD have not been fully characterized. Tong et al[12] summarize the findings of recent clinical and basic research studies related to the potential interactions between CHB and NAFLD. The prevalence of hepatic steatosis in CHB has been reported to be 32.8% (95% CI, 28.9%–37.0%); and it is higher in men and patients with obesity. The presence of hepatic steatosis in patients with CHB is related to metabolic, rather than viral factors. Patients with both CHB and NAFLD are more likely to experience liver-related outcomes or death than those with CHB alone. Many studies have shown that steatosis is positively associated with the clearance of hepatitis B virus (HBV) surface antigen and a reduction in HBV DNA, and the prevalence and incidence of NAFLD in patients with CHB may be lower than in those without. In Chang and colleagues' multi-center, prospective study of 1000 treatment-naïve patients with biopsy-confirmed CHB, NASH was found in 182 patients (18.2%), 46% of these achieved resolution of NASH, and only 4% of the patients developed new-onset NASH after 72 weeks of entecavir treatment. Body mass at baseline and a slight weight change during follow-up were associated with the prevalence, incidence, and remission of NASH in patients with CHB.[13] Finally, steatosis is more prevalent in patients with CHB and is a common reason for abnormal circulating liver enzyme activities in infected patients with a low HBV-DNA load or a good response to infection. From MAFLD to HCC: Although viral hepatitis remains the most common etiology of liver cancer-related deaths, NAFLD is the most rapidly growing contributor to mortality and morbidity related to liver disease in the world. The global burden of HCC is increasing alongside the NAFLD pandemic. A recently published review in CMJ summarizes the characteristics of NAFLD-related HCC.[14] The incidence of NAFLD-related HCC is much higher in patients with severe steatohepatitis, advanced fibrosis, and cirrhosis than in individuals with NAFLD in general, and it is most likely to occur in older men with metabolic syndrome. The incidence of HCC in patients with NAFLD-related cirrhosis is lower than that in those with hepatitis C virus- or HBV-related cirrhosis. Compared with HCCs of other etiologies, NAFLD-related HCCs are generally large, well-differentiated, solitary lesions with a higher level of inflammatory infiltration, and they are less likely to metastasize extra-hepatically. Moreover, NAFLD-related HCC is more likely to develop in the absence of cirrhosis.[14] In a recent issue of CMJ, Rios et al reviewed the progression of MAFLD to HCC and stated that lipotoxicity, insulin resistance, oxidative stress, chronic inflammation, multiple gene mutations, and alterations to the fecal microbial composition are the most important factors determining hepatic carcinogenesis, whereas steatohepatitis and fibrosis are not essential for the development of HCC in obesity-related fatty liver disease.[15] Non-invasive diagnosis of MAFLD: Accumulating evidence suggests that non-invasive tests can be used to diagnose NAFLD, assess its severity, and predict its prognosis. In a recent issue of CMJ, Li et al review new developments in non-invasive testing for NAFLD, with respect to steatosis, steatohepatitis, and fibrosis.[16] For the identification of steatosis, ultrasonography remains the most common method, because of its wide availability and low cost, but magnetic resonance imaging-proton density fat fraction is currently the most accurate means of identifying hepatic steatosis, and transient elastography (TE) represents a promising technique for the evaluation of hepatic steatosis and fibrosis. Except for the widely used controlled attenuation parameter, ultrasonographic attenuation has been reported to have a low failure rate and shows moderate-to-high performance for the discrimination of degrees of steatosis in patients with chronic liver disease.[17] Various non-invasive algorithms, such as the fatty liver index (FLI) and hepatic steatosis index (HSI), have been used as screening tests for steatosis in epidemiologic studies. In Chen et al's study, both FLI and HSI were shown to be useful screening tools for NAFLD in adults with obstructive sleep apnea/hypopnea syndrome.[18] In patients with steatohepatitis, some circulating biomarkers correlate with the severity of NASH but show modest predictive accuracy. Regarding liver fibrosis, liver stiffness measurement (LSM) using TE is highly accurate and is widely used worldwide. Magnetic resonance elastography is marginally better than TE, but it is limited by its cost and availability. In contrast, simple fibrosis scores, such as the fibrosis-4 (FIB-4) index and the NAFLD fibrosis score, can be easily calculated and are recommended for use in primary care. These scores and LSM have sufficiently high negative predictive values to exclude advanced fibrosis. Recently, Shi et al found that the combination of the presence of a metabolic disorder and the FIB-4 index provides for a more accurate diagnosis of advanced fibrosis in patients with NAFLD.[19] Thus, as part of the redefinition of MAFLD, metabolic risk factors should be taken into account during diagnosis and management. Therapeutic approaches to MAFLD: In a recent issue of CMJ, Shi et al[20] discuss recent advances and provide a perspective regarding the treatment of MAFLD. Weight management through an appropriate diet and physical activity remains the most important component of the treatment of MAFLD. Weight loss through bariatric surgery may be an effective means of achieving significant improvements in patients with morbid obesity and MAFLD. Although numerous agents, including novel modulators of glucolipid metabolism, are being assessed in clinical trials, there is still no approved drug for the treatment of MAFLD. The nomenclature of MAFLD emphasizes the existence of concomitant metabolic disorders and obesity, and patients with MAFLD are therefore subject to both hepatic and other metabolic risks. Thus, drugs targeting underlying cardiometabolic risk factors are essential to improve the outcomes of patients with MAFLD. The screening of patients who are at a high risk of MAFLD and the provision of a comprehensive individual therapeutic program are critical. For example, patients with MAFLD and T2DM would benefit from the use of antidiabetic agents, patients with overweight or obesity would gain greater benefit from weight management, and those with metabolic syndrome require comprehensive individualized management. These therapeutic approaches might help identify the patients with MAFLD who are at the greatest risk of disease progression and facilitate more precise and appropriate management. Summary and prospects: The growing burden of NAFLD parallels the increasing prevalences of obesity and metabolic syndrome worldwide. Cardiometabolic risk factors have a bidirectional relationship with NAFLD. The majority of patients with NAFLD meet the diagnostic criteria for MAFLD, and this represents a more appropriate term. Further clinical studies of the changes created by the redefinition of NAFLD/MAFLD, including the epidemiologic character, prognosis, diagnosis, prevention, and treatment of the condition, are required. Currently, MAFLD and CHB are increasingly being diagnosed in the same individuals, and the pathophysiological interaction between MAFLD and HBV infection in patients is worthy of further exploration. The long-term outcomes of MAFLD are related to the severity of metabolic dysfunction and liver fibrosis, rather than obesity. Metabolic syndrome and T2DM are the most important risk factors for MAFLD-related cirrhosis and HCC. A lack of awareness regarding the factors underlying MAFLD-related HCC may lead to delay in its diagnosis. The further development and validation of non-invasive diagnostic techniques and clinical pathways will help clinicians assess the severity of MAFLD, categorize patients, and identify those requiring specific treatments. There is still no effective approved drug for MAFLD, but the in-depth study of pathologic mechanisms may provide new therapeutic targets. Measures to increase awareness and treat or prevent the associated cardiometabolic diseases are necessary to reduce the growing burden of MAFLD. Funding This study was supported by grants from the National Key Research and Development Program of China (No. 2021YFC2700802), the National Natural Science Foundation of China (Nos. 81900507 and 82170593). Conflicts of interest None.