Targeting the LPI/GPR55 Axis in MAFLD and MASH: Novel Insights, Therapeutic Strategies and Future Directions.

NAFLD vs. MAFLD – It is not the name but the disease that decides the outcome in fatty liver

Yet more evidence that MAFLD is more than a name change

Meaning of non-overlapping patients between the MAFLD and NAFLD definitions.

Non-alcoholic fatty liver diseases in patients with COVID-19: A retrospective study

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.

Non-alcoholic fatty liver disease: Not time for an obituary just yet!

MAFLD 2022: An ELPA/ALPA/EASO-ECPO joint statement on disease stigma.

Expanding the liver exposome: Should hepatologists care about air pollution?

Changing Nomenclature from Nonalcoholic Fatty Liver Disease to Metabolic Dysfunction-Associated Fatty Liver Disease – Not Only Premature But Also Confusing

Metabolic dysfunction-associated fatty liver disease and the risk of hepatocellular carcinoma

The term metabolic dysfunction–associated fatty liver disease (MAFLD) has been proposed based on a redefinition of the nonalcoholic fatty liver disease (NAFLD) criteria. Our study aimed to address the knowledge gap by comparing the diagnostic accuracy of MAFLD and NAFLD criteria in identifying significant fibrosis among patients with hepatic steatosis. A cross-sectional study was conducted on 2626 patients with hepatic steatosis treated at Beijing Ditan Hospital between January 2009 and December 2022. Patients with viral hepatitis were excluded. Significant fibrosis was defined as a Meta-analysis of Histological Data in Viral Hepatitis (METAVIR) score F ≥ 2. MAFLD and NAFLD were diagnosed in 478 and 428 patients, respectively. Clinicopathological characteristics were compared between the MAFLD+ NAFLD– group (patients who met the criteria for MAFLD but not NAFLD) and MAFLD– NAFLD+ group (patients who met the criteria for NAFLD but not MAFLD). A total of 743 patients with histologically verified hepatic steatosis were analyzed. The MAFLD+ NAFLD– group comprised 163 (21.9%) and the MAFLD– NAFLD+ group comprised 113 (15.2%) patients. Patients in the MAFLD+ NAFLD– group were older and more likely to be male and had higher body mass index and liver stiffness levels than those in the MAFLD– NAFLD+ group. The prevalence of significant fibrosis was higher in the MAFLD+ NAFLD– group than in the MAFLD– NAFLD+ group (43.6% vs 15.9%, P < .001). The MAFLD criteria may be a better indicator of fibrosis than the NAFLD criteria. Fibrosis in patients with MAFLD can be determined by metabolic disorders, not excessive alcohol consumption.

With the rising epidemic of obesity, metabolic syndrome, and type 2 diabetes mellitus in China, metabolic dysfunction-associated non-alcoholic fatty liver disease has become the most prevalent chronic liver disease. This condition frequently occurs in Chinese patients with alcoholic liver disease and chronic hepatitis B. To address the impending public health crisis of non-alcoholic fatty liver disease and its underlying metabolic issues, the Chinese Society of Hepatology and the Chinese Medical Association convened a panel of clinical experts to revise and update the "Guideline of prevention and treatment of non-alcoholic fatty liver disease (2018, China)". The new edition, titled "Guideline for the prevention and treatment of metabolic dysfunction-associated fatty liver disease (Version 2024)", offers comprehensive recommendations on key clinical issues, including screening and monitoring, diagnosis and evaluation, treatment, and follow-up for metabolic dysfunction-associated fatty liver disease and metabolic dysfunction-associated steatotic liver disease. Metabolic dysfunction-associated fatty liver disease is now the preferred English term and is used interchangeably with metabolic dysfunction-associated steatotic liver disease. Additionally, the guideline emphasizes the importance of multidisciplinary collaboration among hepatologists and other specialists to manage cardiometabolic disorders and liver disease effectively.

BackgroundA recently proposed diagnostic criteria of metabolic dysfunction-associated fatty liver disease (MAFLD) is more available for various clinical situations than nonalcoholic fatty liver disease (NAFLD), but understanding about differences between NAFLD and MAFLD in clinical practice remains limited in the general adult urban population in China.MethodsA total of 795 subjects were recruited from Wu Song Branch of Zhongshan Hospital who participated in the general health assessment. Examination results was obtained through analysis of blood samples and abdominal ultrasonography. Participants were divided into four subgroups according to whether they had NAFLD or MAFLD (NAFLD- MAFLD-, NAFLD + MAFLD-, NAFLD- MAFLD + and NAFLD + MAFLD+).ResultsAmong the urban healthy adults investigated, 345 people (43.4%) were diagnosed with NAFLD and 356 people (44.8%) with MAFLD. No significant differences in the prevalence, age, fasting blood glucose, glycosylated hemoglobin, liver enzyme examination, percentage of overweight, hypertension or dyslipidaemia were found between NAFLD and MAFLD patients. Patients with MAFLD had worse metabolic disorders than NAFLD + MAFLD- patients. The NAFLD fibrosis score (NFS) of the NAFLD- MAFLD + group was higher than that of the NAFLD + MAFLD- group. Higher proportion of patients in the NAFLD- MAFLD + group have NFS ≥-1.455.ConclusionMAFLD criteria have similar prevalence and patient characteristics compared with previous NAFLD but help to identify a group of patients with high risks of metabolic disorders and liver fibrosis who have been missed with NAFLD, and has superior utility.

Insights into contribution of genetic variants towards the susceptibility of MAFLD revealed by the NMR-based lipoprotein profiling

Nonalcoholic fatty liver disease (NAFLD) is the most common cause of liver disease associated with various metabolic disorders. Metabolic dysfunction-associated fatty liver disease (MAFLD) emphasizes metabolic dysfunction in NAFLD. Although the relationship between NAFLD and colorectal adenomas has been suggested, the effect of MAFLD on colorectal adenoma has yet to be investigated. In this study, we examined the relationship between NAFLD/MAFLD and colorectal adenoma in comparison with other metabolic factors. Methods: Examinees who underwent colonoscopy and abdominal ultrasonography on the same day from January 2012 to December 2012 were included. NAFLD was diagnosed according to the findings of ultrasonography. The Fibrosis-4 (FIB-4) index was used as a surrogate marker for advanced hepatic fibrosis. A logistic regression model was used to analyze the risk of NAFLD/MAFLD for colorectal adenoma. Results: The prevalence of NAFLD and MAFLD was 37.5% and 32.8%, respectively. In the multivariate analysis, male sex, older age, diabetes, and smoking increased the risk of colorectal adenoma. NAFLD and MAFLD were the most important risk factors for colorectal adenoma only in females [adjusted odds ratio (OR) 1.43 and 95% confidence interval (CI) 1.01–2.03, and OR 1.55, 95% CI 1.09–2.20, respectively]. NAFLD and MAFLD with an advanced fibrosis index were significantly associated with an increased risk of colorectal adenoma. (NAFLD: OR 1.38, 95% CI, 1.04–1.83, p = 0.027; MAFLD: OR 1.45, 95% CI, 1.13–1.96, p = 0.004, respectively). Conclusion: NAFLD and MAFLD were significantly associated with a higher risk of colorectal adenomas, especially in females. NAFLD and MAFLD with advanced fibrosis were associated with an increased risk of colorectal adenoma. Colonoscopic examinations may be emphasized for patients with NAFLD/MAFLD, for women, or patients with the presence of hepatic fibrosis.