Saroglitazar 4 Mg in Metabolic Dysfunction-Associated Steatotic Liver Disease: 24-Week Results From Phase 4 Study.

Introduction: Spontaneous haematomas in the context of cirrhosis have
\nbeen documented in the literature in numerous case reports. Management
\nstrategies described range from conservative management to radiological
\nand/or surgical interventions. Our case outlines the complex management
\nissues of a patient with Child–Pugh C cirrhosis, who presented with a spontaneous
\nsubcutaneous haematoma anterior to the rectus sheath. Our case is
\ndistinguishable from existing reports due to the use of an octreotide infusion,
\nwhich may have contributed to haemostasis.
\nBackground: A literature review was conducted in order to source cases of
\nspontaneous haematoma in patients with cirrhosis. The primary search
\nstrategy was through PubMed, utilising the MeSH terms cirrhosis AND
\nhaematoma which resulted in 301 articles. We narrowed our search based
\non articles that were accessible and written in English, and excluded cases
\nwith intracranial haematomas or haematomas directly attributable to procedures
\n(e.g. endoscopic therapy, epidural catheterization or paracentesis).
\nAlthough the 34 selected cases may be dissimilar with regards to the location
\nof bleeding, they presented similar management issues. Of the 34
\ncases, 21 were managed conservatively, 6 underwent arterial embolisation
\nor trans-catheter coiling, and 4 patients had interventional procedures (surgical
\nexploration, liver transplant, fasciotomy and/or evacuation). Of the
\ncases reviewed, only 35% survived their hospital admission. Conservative
\nmanagement resulted in a relatively lower survival rate (29%) compared
\nwith interventional management (50%). There are no documented cases
\nin the literature of octreotide use in order to achieve haemostasis in patients
\nwith non-variceal haematomas in the context of cirrhosis.
\nCase Description: This case focuses on the management issues of a 53-
\nyear-old patient with a background of Child–Pugh C cirrhosis secondary
\nto alcohol use, who presented with a spontaneous abdominal haematoma.
\nThere was significant ongoing bleeding within the haematoma following
\nadmission to hospital resulting in initiation of a massive transfusion protocol.
\nThe patient required 14 units of packed red blood cells (pRBC), 6 units
\nof fresh frozen plasma (FFP), 5 units of cryoprecipitate and daily vitamin K
\nto maintain a haemoglobin level greater than 70 mg/dL during the first four
\ndays of admission. Concurrently, medical management of his liver disease
\nwas optimised (beta blockers, spironolactone and lactulose) and regular
\nmultidisciplinary team consultation (general surgery, vascular, acute pain
\nservice, intensive care team, interventional radiology and haematology)
\nwas obtained. In view of ongoing transfusion requirement, octreotide
\n50 μg/h continuous intravenous infusion was commenced on day 4 of admission.
\nThis correlated with a significant decrease in blood product requirement,
\nwith no further pRBC transfusion required for the next 7 days.
\nThe patient had two CT angiograms and a CT abdomen/pelvis to review
\nhaematoma size and potential sources of bleeding. A bleeding vessel suitable
\nfor embolisation could not be conclusively demonstrated. Imaging
\nconfirmed that the haematoma had developed outside the rectus sheath,
\nthus reducing the likelihood of a self-tamponading effect. Definitive surgical
\nmanagement was performed on day 11 by the plastic surgery team who
\nevacuated the haematoma and ligated perforators. Multiple wash outs and
\ndebridement were required, prior to the formation of a skin graft on day
\n30. Our patient was discharged on day 40 post hospital admission.
\nConclusion: Spontaneous haematoma in the context of liver cirrhosis
\nposes a unique management challenge, with poor outcomes and limited
\ntreatment options. Our case demonstrates that octreotide may be useful in
\nthis situation by reducing transfusion requirement and contributing to
\nhaemostasis. The latter is supported by the fact that since the bleeding point
\nin our case was located beyond the rectus sheath in the subcutaneous tissues,
\nit is unlikely the tamponade effect seen in rectus sheath haematoma
\nwould have contributed to haemostasis. While further research is needed,
\noctreotide may be considered as a potential treatment option or as a bridge
\nto definitive therapy in the management of spontaneous haematomas in patients
\nwith cirrhosis.

Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease.

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

Liver stiffness measurement (LSM) is recommended for disease prognostication and monitoring. We evaluated if LSM, using transient elastography, and LSM changes predict decompensation and mortality in patients with alcohol-related liver disease (ALD). We performed an observational cohort study of compensated patients at risk of ALD from Denmark and Austria. We evaluated the risk of decompensation and all-cause mortality, stratified for compensated advanced chronic liver disease (cACLD: baseline LSM ≥10kPa) and LSM changes after a median of 2 years. In patients with cACLD, we defined LSM changes as (A) LSM increase ≥20% ("cACLD increasers") and (B) follow-up LSM <10kPa or <20kPa with LSM decrease ≥20% ("cACLD decreasers"). In patients without cACLD, we defined follow-up LSM ≥10kPa as an LSM increase ("No cACLD increasers"). The remaining patients were considered LSM stable. We followed 536 patients for 3,008 patient-years-median age 57 years (IQR 49-63), baseline LSM 8.1kPa (IQR 4.9-21.7)-371 patients (69%) had follow-up LSM after a median of 25 months (IQR 17-38), 41 subsequently decompensated and 55 died. Of 125 with cACLD at baseline, 14% were "cACLD increasers" and 43% "cACLD decreasers", while 13% of patients without cACLD were "No cACLD increasers" (n= 33/246). Baseline LSM, follow-up LSM and LSM changes accurately predicted decompensation (C-index: baseline LSM 0.85; follow-up LSM 0.89; LSM changes 0.85) and mortality (C-index: baseline LSM 0.74; follow-up LSM 0.74; LSM changes 0.70). When compared to "cACLD decreasers", "cACLD increasers" had significantly lower decompensation-free survival and higher risks of decompensation (subdistribution hazard ratio 4.39, p= 0.004) and mortality (hazard ratio 3.22, p= 0.01). LSM by transient elastography predicts decompensation and all-cause mortality in patients with compensated ALD both at diagnosis and when used for monitoring. Patients at risk of alcohol-related liver disease (ALD) are at significant risk of progressive disease and adverse outcomes. Monitoring is essential for optimal disease surveillance and patient guidance, but non-invasive monitoring tools are lacking. In this study we demonstrate that liver stiffness measurement (LSM), using transient elastography, and LSM changes after a median of 2 years, can predict decompensation and all-cause mortality in patients at risk of ALD with and without compensated advanced chronic liver disease. These findings are in line with results from non-alcoholic fatty liver disease, hepatitis C and primary sclerosing cholangitis, and support the clinical utility of LSM, using transient elastography, for disease prognostication and monitoring in chronic liver diseases including ALD, as recommended by the Baveno VII.

The global incidence of fatty liver (FL) [alcoholic and nonalcoholic FL disease (NAFLD)] is increasing. Imaging-based elastography techniques, being noninvasive, may eliminate the need for more invasive techniques for the diagnosis and staging of liver fibrosis in FL disease. Our study aims to address the gap in the current research by exploring the correlation between mean liver stiffness measurement (LSM) as obtained through magnetic resonance elastography (MRE) and transient elastography (TE), and two commonly used clinical scores, fibrosis-4 index (FIB-4) score and aspartate aminotransferase to platelet ratio index (APRI) score. In this hospital-based cross-sectional study, 62 patients diagnosed with FL on ultrasound were recruited. The patients were further subjected to MR liver elastography and TE, and LSM using both modalities was recorded. A history of diabetes mellitus and alcohol intake was taken. Moreover, noninvasive fibrosis scores such as FIB-4 and APRI were calculated using standard formulas. The correlation analysis revealed a strong positive correlation between LSM values obtained from MRE and TE (r = 0.88) (Cohen's κ = 0.87), a moderate correlation between MRE and FIB-4 score (r = 0.44), and weak positive correlations involving MRE and APRI (r = 0.34), TE and FIB-4 score (r = 0.36), and TE and APRI (r = 0.29). Additionally, significantly higher fat fractions were quantified [median (IQR)] in grade III FL [23.6 (15.9-29.5)] as compared to grades I [8.45 (2.25-13.9)] and grade II [13.1 (8.4-19.7)]. MRE shows a strong positive correlation with TE for LSM and stage of fibrosis. Our findings suggest that MRE could be a valuable tool in the diagnostic armamentarium of FLD.

Introduction: Metabolic dysfunction-associated steatohepatitis (MASH) contributes significantly to liver-related and cardiometabolic morbidity. Saroglitazar, a dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist, targets both hepatic and metabolic pathways. This study evaluated its real-world efficacy in improving liver stiffness, steatosis, hepatic transaminases, and lipid parameters.Methods: This retrospective, single-center, observational study included 204 adults with metabolic dysfunction-associated steatotic liver disease (MASLD)/MASH treated with saroglitazar 4 mg once daily for 52 weeks. Patients were categorized as Significant Fibrosis (<14 kPa; n = 104) or Advanced Fibrosis (≥14 kPa; n = 100) based on baseline liver stiffness measurement (LSM). Changes in LSM, controlled attenuation parameter (CAP), alanine aminotransferase (ALT), aspartate aminotransferase (AST), total cholesterol, and low-density lipoprotein cholesterol (LDL-C) were analyzed at baseline, 24 weeks, and 52 weeks.Results: In the Significant Fibrosis group, mean LSM reduced from 10.31 ± 2.01 to 6.27 ± 1.44 kPa (-39.1%, p < 0.001) and CAP from 295.82 ± 49.34 to 241.01 ± 63.61 dB/m (-18.4%). ALT and AST declined by 49.5% and 43.4%, respectively, with total cholesterol and LDL-C reductions of 17.6% and 25.9%. In the Advanced Fibrosis group, LSM decreased from 17.96 ± 1.85 to 13.83 ± 1.42 kPa (-23.0%) and CAP from 317.05 ± 61.28 to 272.36 ± 52.38 dB/m (-14.1%), accompanied by ALT and AST reductions of 46.6% and 45.1%, and total cholesterol and LDL-C reductions of 18.3% and 25.7% (p < 0.001 for all). Saroglitazar was well-tolerated without serious adverse events.Conclusion: Saroglitazar 4 mg daily was associated with significant improvements in liver stiffness, steatosis, transaminases, and lipid parameters over 52 weeks. These findings support its hepatometabolic potential across both early and advanced MASLD/MASH stages in real-world practice.

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

In patients with metabolic dysfunction-associated steatotic liver disease (MASLD), there are limited data on how changes in FIB4 and liver stiffness measurement (LSM) correlate in non-biopsy cohorts. Our objective was to evaluate associations between changes in FIB4 and LSM in MASLD patients. We included MASLD patients with serial VCTE from 2015-2022. The primary predictors were change in FIB4 and presence of diabetes, obesity, and high alanine aminotransferase (ALT). The primary outcome, applied only to patients with LSM1 < 8kPa, was incident significant fibrosis (SF) defined as a ≥ 20% increase in LSM2 vs. LSM1 and LSM2 ≥ 8kPa. A secondary outcome was LSM progression with a similar definition but applied to all participants, not only those with LSM1 < 8kPa. Of 285 included patients, 216 had LSM1 < 8kPa and were included in the primary analysis; of these, 34 (16%) had incident SF. Changes in FIB4 correlated with changes in LSM (R = 0.16, p = 0.016). Independent predictors of incident SF included comorbid diabetes mellitus (OR 2.43, 95% CI 1.04-6.56), obesity (OR 3.88, 95% CI 1.63-9.25), and baseline ALT ≥ 30 (OR 8.55, 95% CI 1.10-66.29). A model including ALT, diabetes, and obesity outperformed a model with FIB4 change alone. Among patients with MASLD, changes in FIB4 correlated with changes in LSM but more significant correlates of incident significant fibrosis included diabetes mellitus, obesity, and high baseline ALT.

Nonalcoholic fatty liver disease (NAFLD) is strongly associated with type 2 diabetes mellitus (T2DM). Lifestyle intervention remains a preferred treatment modality for NAFLD. The glucagon-like peptide (GLP-1) receptor agonists and sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been developed as new glucose-lowering drugs, which can improve fatty liver via an insulin-independent glucose-lowering effect. However, studies exploring the efficacy of GLP-1 receptor agonists combined with SGLT-2 inhibitors in patients with NAFLD and T2DM are scanty. Thus, the present randomised controlled trial aims at comparing the efficacy and safety of semaglutide plus empagliflozin with each treatment alone in patients with NAFLD and T2DM. This 52-week double-blinded, randomised, parallel-group, active-controlled trial evaluates the effects of semaglutide, empagliflozin and semaglutide + empagliflozin in 105 eligible overweight/obese subjects with NAFLD and T2DM. The primary outcome will be a change from baseline to week 52 in the controlled attenuation parameter, free fatty acid and glucagon. Secondary endpoints include changes in liver stiffness measurement, liver enzymes, blood glucose, lipid levels, renal function, electrolyte balances, minerals and bone metabolism, cytokines, high-sensitivity C-reactive protein, ferritin, anthropometric indicators, nonalcoholic fatty liver fibrosis score, fibrosis 4 score and homeostatic model assessment for insulin resistance. In addition, intention-to-treat, interim analysis and safety analysis will be performed. This double-blinded, randomised, clinical trial involves a multi-disciplinary approach and aims to explore the synergistic effects of the combination of semaglutide and empagliflozin. The results can provide important insights into mechanisms of GLP-1 receptor agonists and/or SGLT-2 inhibitors in patients with NAFLD and T2DM. This study has been registered with Chinese Clinical Trial Registry (ChiCTR2300070674).

Background: weight loss as a result of lifestyle intervention is effective when treating non-alcoholic fatty liver disease (NAFLD). We estimated the effects of PNPLA3 rs738409 and HSD17B13 rs6834314 variants in response to diet therapy in Japanese patients with NAFLD. Methods: we analyzed the correlation between the change in liver stiffness and change in body weight in 140 patients administered diet therapy for 1-year, according to PNPLA3 and HSD17B13 genotypes. Results: the bodyweight (BW) reduction rate was greater in patients with the PNPLA3 genotype CC than CG and GG (p = 0.035). Change in liver stiffness measurement (LSM) was significantly associated with a change in BW in PNPLA3 CG/GG (r = 0.279/0.381), but not in PNPLA3 CC (p = 0.187). Change in LSM was correlated with change in BW only in patients with HSD17B13 AG/GG (r = 0.425), but not the AA genotype (p = 0.069). A multivariate analysis identified that a change in LSM was correlated with a change in BW in carriers of HSD17B13 AG/GG (B = 3.043, p = 0.032), but not HSD17B13 AA. The change in LSM of patients with a BW reduction of more than 7% (0.50) was significantly greater than that of patients with a BW reduction of less than 7% (0.83) (p = 0.038). Conclusions: in Japanese patients with NAFLD, HSD17B13 rs6834314 polymorphism is associated with the change in LSM by lifestyle intervention. The approach, including genetic assessments, may contribute to the establishment of appropriate therapeutic strategies to treat NAFLD.

Impact of 20% Change in Vibration-controlled Transient Elastography-measured Liver Stiffness on Liver-related Outcomes: A Systematic Review and Meta-analysis.

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.

Yet more evidence that MAFLD is more than a name change

Body weight reduction leads to improvement of nonalcoholic fatty liver disease (NAFLD), but the contributions of body composition modification on its improvement have not been clarified yet. We performed a retrospective cohort study in a Japanese university hospital to clarify the effect of body fat reduction on the improvement of hepatic stiffness as well as hepatic steatosis. The skeletal muscle mass index (SMI, kg/m2), fat to muscle mass ratio, and the change in fat to muscle mass ratio after 1 year from baseline were calculated. Controlled attenuation parameter (CAP, dB/m) and liver stiffness measurement (LSM, kPa) were evaluated by elastography. Primary outcome was set as the association of the change of fat to muscle mass ratio after 1 year from baseline with the change of liver stiffness measurement. One hundred and seventeen patients (59 men and 58 women) completed the study. The average age was 63.5 years, and baseline CAP and LSM were 273.4 ± 53.5 dB/m and 6.3 ± 3.4 kPa, respectively. After 1 year, body mass index (BMI), SMI, and LSM decreased. Multiple regression analyses demonstrated that change in fat to muscle mass ratio was associated with the change in CAP (ß = 0.38, p < 0.001) or LSM (ß = 0.21, p = 0.026). The reduction of fat to muscle mass ratio was associated with improvement in liver stiffness, but the reduction of BMI was not.

To investigate longitudinal changes in the liver stiffness measurement (LSM) in the general adult population without known liver disease and to describe its association with metabolic risk factors, with a special focus on subjects with non-alcoholic fatty liver disease (NAFLD) and dysglycemia. A longitudinal adult population-based cohort study was conducted in Catalonia. LSM was measured by transient elastography (TE) at baseline and follow-up (median: 4.2 years). Subgroup with NAFLD and dysglycemia were analyzed. Moderate-to-advanced liver fibrosis was defined as LSM ≥8.0 kPa and LSM ≥9.2 kPa respectively. Among 1.478 subjects evaluated, the cumulative incidence of LSM ≥8.0 kPa and ≥9.2 kPa at follow-up was 2.8% and 1.9%, respectively. This incidence was higher in NAFLD (7.1% for LSM ≥8.0 kPa and 5% for LSM ≥9.2 kPa) and dysglycemia (6.2% for LSM ≥8.0 kPa and 4.7% for LSM ≥9.2 kPa) subgroups. In the global cohort, the multivariate analyses showed that dysglycemia, abdominal obesity and atherogenic dyslipidemia were significantly associated with progression to moderate-to-advanced liver fibrosis. Female sex was negatively associated. In subjects with NAFLD, abdominal obesity and dysglycemia were associated with changes in LSM to ≥8.0 kPa and ≥9.2 kPa at follow-up. A decline in LSM value to <8 kPa was observed in 64% of those subjects with a baseline LSM ≥8.0 kPa. In this population study, the presence of abdominal obesity and dysglycemia were the main risk metabolic factors associated with moderate-to-advanced liver fibrosis development over time in general populations as well as in subjects with NAFLD.