Metabolic management after sustained virologic response in elderly patients with hepatitis C virus: A multicenter study.

AIMS: Hepatocellular carcinoma (HCC) develops even in patients with hepatitis C virus (HCV) eradication by direct-acting antiviral agents. Fatty liver and metabolic dysfunction are becoming major etiologies of HCC. We aimed to evaluate the impact of metabolic dysfunction-associated steatotic liver disease (MASLD), a new definition of steatotic liver disease, on the development of HCC after HCV eradication. METHODS: We enrolled 1280 elderly patients with HCV eradication and no history of HCC. We evaluated α-fetoprotein (AFP), Fibrosis-4 index and MASLD after 24 weeks of sustained virological response. Decision tree analysis was used to investigate factors associated with HCC development after HCV eradication. RESULTS: A total of 86 patients (6.7%) developed HCC during the follow-up period (35.8 ± 23.7 months). On multivariate analysis, serum AFP level (HR 1.08, CI 1.04-1.11, P = 0.0008), Fibrosis-4 index (HR 1.17, CI 1.08-1.26, P = 0.0007), and MASLD (HR 3.04, CI 1.40-6.58, P = 0.0125) at 24 weeks of sustained virological response were independent factors associated with HCC development. In decision tree analysis, the initial classifier for HCC development was AFP ≥7 ng/mL. However, in patients with AFP <7 ng/mL, MASLD, rather than Fibrosis-4 index, was the classifier for HCC development. No significant difference was observed in the cumulative incidence of HCC between patients with AFP ≥7 ng/mL and patients with AFP <7 ng/mL and MASLD. CONCLUSION: MASLD at 24 weeks of sustained virological response is a risk factor for HCC development in elderly patients with HCV eradication. Additionally, decision tree analysis revealed that MASLD was associated with HCC development, even in patients with serum AFP levels <7 ng/mL.

Impact of non-obese metabolic dysfunction-associated fatty liver disease on risk factors for the recurrence of esophageal squamous cell carcinoma treated with endoscopic submucosal dissection: A multicenter study.

AIM: Metabolic dysfunction is a risk factor for esophageal squamous cell carcinoma (ESCC). We investigated the impact of the recently proposed metabolic dysfunction-associated fatty liver disease (MAFLD) and its subtypes on ESCC recurrence after endoscopic treatment. METHODS: This multicenter observational cohort study enrolled consecutive patients newly diagnosed with ESCC after endoscopic treatment. Patients were classified into MAFLD or non-MAFLD groups. The MAFLD group was further classified into non-obese and obese MAFLD groups with a body mass index cutoff value of 25 kg/m2 . The impact of MAFLD on the recurrence of ESCC was evaluated using a decision tree algorithm and random forest analysis. RESULTS: A total of 147 patients (average age 69 years; male : female, 127:20; observational period, 2.4 years) were enrolled. The 1-, 3-, and 5-year recurrence rates were 2.0%, 21.1%, and 33.7%, respectively. Independent risk factors for the recurrence of ESCC were MAFLD (HR 2.2812; 95% confidence interval 1.0497-4.9571; p = 0.0373), drinking status, and smoking status. Metabolic dysfunction-associated fatty liver disease was identified as the second most important classifier for recurrence, followed by drinking status. The cumulative incidence of ESCC recurrence was higher in the MAFLD group than in the non-MAFLD group. In a subanalysis, the cumulative incidence of recurrence was significantly higher in the non-obese than in the obese MAFLD group among abstainers/non-drinkers. Directed acyclic graphs revealed that MAFLD directly contributes to ESCC recurrence. CONCLUSIONS: MAFLD was independently and directly associated with ESCC recurrence after endoscopic treatment; a high recurrence rate was observed in patients with non-obese MAFLD. Metabolic dysfunction-associated fatty liver disease may identify patients at high risk for ESCC recurrence.

Resistance exercise in combination with aerobic exercise reduces the incidence of serious events in patients with liver cirrhosis: a meta-analysis of randomized controlled trials.

BACKGROUND: Exercise, particularly resistance exercise, is beneficial for sarcopenia in patients with liver cirrhosis. However, the effects of exercise on events remain unclear. We aimed to examine the effects of exercise on serious events in patients with liver cirrhosis using a meta-analysis of randomized controlled trials (RCTs). METHODS: A literature search was conducted in 2022. Eleven RCTs were selected for the meta-analysis (exercise group, n = 232; control group, n = 193). Serious events were defined as death or serious complications according to the original articles. A meta-analysis was performed using a random-effects model. The primary outcome was the incidence of serious events. RESULTS: In the 11 RCTs, the incidence of serious events was 5.6% (13/232) and 12.3% (24/193) in the exercise and control groups, respectively. However, a meta-analysis demonstrated no significant difference in the incidence of serious events between the two groups (risk difference [RD] - 0.03, 95% confidence intervals (CI) - 0.07 to 0.02). In a stratification analysis based on a combination of aerobic and resistance exercise, five RCTs (n = 185) were enrolled. The incidence of serious events was 6.25% (7/112) and 24.7% (18/73) in the combination exercise and control groups, respectively. A meta-analysis demonstrated a significant reduction in the incidence of serious events in the combination exercise group compared with the control group (RD - 0.12; 95% CI - 0.21 to - 0.03). CONCLUSIONS: Resistance exercise in combination with aerobic exercise reduces serious events in patients with liver cirrhosis. A combination of aerobic and resistance exercise may be beneficial to improve the prognosis of patients with liver cirrhosis.

Impact of metabolic dysfunction-associated fatty liver disease on the incidence of Helicobacter pylori-negative gastric cancer.

AIM: The incidence of Helicobacter pylori-negative gastric cancer (HPNGC) is increasing worldwide. Recently, metabolic dysfunction-associated fatty liver disease (MAFLD) has been reported to be associated with various cancers, but its association with HPNGC has not been reported. We aimed to identify important independent factors associated with HPNGC, including MAFLD. METHODS: This multicenter observational cohort study enrolled patients with gastric cancer (n = 1078) and health checkup examinees (n = 17 408). We analyzed patients with HPNGC (n = 26) and healthy participants with no H. pylori infection or any abnormal findings on upper gastrointestinal endoscopy (n = 1130). A logistic regression model was used to identify independent factors associated with HPNGC. The priority of the factors associated with HPNGC was evaluated using a decision-tree algorithm and random forest analysis. RESULTS: Among all patients with gastric cancer, 2.4% (26/1078) were diagnosed with HPNGC (mean age, 64 years; male/female, 13/13). In the logistic regression analysis, age, smoking, and MAFLD (odds ratio, 6.5359; 95% confidence interval, 2.5451-16.7841; p < 0.0001) were identified as independent factors associated with HPNGC. Metabolic dysfunction-associated fatty liver disease was also identified as the most important classifier for the presence of HPNGC in decision-tree analyses. Helicobacter pylori-negative gastric cancer was observed in 5.2% of patients with MAFLD and 0.8% of patients without MAFLD. In the random forest analysis of the HPNGC, MAFLD was identified as the distinguishing factor with the highest variable importance (0.32). CONCLUSIONS: Metabolic dysfunction-associated fatty liver disease was the most influential independent factor associated with HPNGC. These findings suggest that fatty liver and metabolic dysfunction could be involved in the pathogenesis of HPNGC.

A low-intensity 10-min resistance exercise program that ameliorated hepatic fibrosis indices and altered G-CSF/IP-10/PDGF-BB in a patient with nonalcoholic fatty liver disease: A case report.

We developed a low-intensity 10-min resistance exercise program for nonalcoholic fatty liver disease (NAFLD). We report a case of NAFLD with elevated hepatic fibrosis indices, which were improved by a 60-week daily exercise program. A 71-year-old female patient with NAFLD whose hepatic fibrosis stage corresponded to F2 was referred to our hospital. She performed the exercise once a day with no changes in other lifestyle habits and medications. The homeostasis model assessment-insulin resistance value and NAFLD-liver fat score, the Hepamet fibrosis score, and the enhanced liver fibrosis score decreased. The FIB-4 index and serum levels of Mac-2 binding protein glycosylation isomer decreased to the reference values. We investigated the changes in chemokines/cytokines. The serum granulocyte-colony stimulating factor level was increased, and serum interferon-gamma-induced protein-10 and platelet-derived growth factor-BB levels were decreased. Our program may be beneficial for improving hepatic fibrosis in patients with NAFLD.

The Inter-Organ Crosstalk Reveals an Inevitable Link between MAFLD and Extrahepatic Diseases.

Fatty liver is known to be associated with extra-hepatic diseases including atherosclerotic cardiovascular disease and extra-hepatic cancers, which affect the prognosis and quality of life of the patients. The inter-organ crosstalk is mediated by metabolic abnormalities such as insulin resistance and visceral adiposity. Recently, metabolic dysfunction-associated fatty liver disease (MAFLD) was proposed as a new definition for fatty liver. MAFLD is characterized by the inclusion criteria of metabolic abnormality. Therefore, MAFLD is expected to identify patients at high risk of extra-hepatic complications. In this review, we focus on the relationships between MAFLD and multi-organ diseases. We also describe the pathogenic mechanisms of the inter-organ crosstalk.

The beneficial impact of metabolic dysfunction-associated fatty liver disease on lenvatinib treatment in patients with non-viral hepatocellular carcinoma.

AIM: Lenvatinib is used to treat advanced hepatocellular carcinoma (HCC). Metabolic dysfunction-associated fatty liver disease (MAFLD) is becoming a major etiology of HCC. We aimed to evaluate the impact of MAFLD on the efficacy of lenvatinib. METHODS: We enrolled 320 patients with HCC who were treated with lenvatinib. All patients were classified into the MAFLD (n = 155) and non-MAFLD (n = 165) groups. Independent factors for overall survival (OS) were analyzed. In the stratification analysis, HCC was categorized as non-viral (n = 115) or viral HCC (n = 205). RESULTS: The OS rate was significantly higher in the MAFLD group than in the non-MAFLD group (median 21.1 vs. 15.1 months, p = 0.002). Multivariate analysis demonstrated that, in addition to albumin-bilirubin grade and Barcelona Clinic Liver Cancer stage, MAFLD was identified as an independent factor for OS (HR 0.722, 95% CI 0.539-0.966, p = 0.028). In the stratification analysis, the OS rate was significantly higher in the MAFLD group than in the non-MAFLD group among patients with non-viral HCC (median 21.1 vs. 15.1 months, p = 0.002), but not in patients with viral HCC. Furthermore, MAFLD was an independent negative risk factor for OS in patients with non-viral HCC (HR 0.506, 95% CI 0.297-0.864, P < 0.01). However, MAFLD was not an independent factor for OS in patients with viral HCC. CONCLUSIONS: MAFLD was a beneficial factor for survival in patients with HCC treated with lenvatinib. Moreover, the better OS of the MAFLD group was more pronounced in patients with non-viral HCC. Lenvatinib may be a suitable agent for patients with non-viral HCC and MAFLD.

Hepatic expression of sodium-glucose cotransporter 2 (SGLT2) in patients with chronic liver disease.

Sodium-glucose cotransporter 2 (SGLT2) occurs in the proximal renal tubule cells. We investigate the hepatic expression of SGLT2 and its related factors in patients with chronic liver disease. This is a retrospective human study. The liver tissues were biopsied from patients with chronic liver disease (n = 30). The expression levels of SGLT2 were evaluated by immunostaining. Furthermore, the undirected graphical model was used to identify factors associated with hepatic expression levels of SGLT2. The SGLT2 expression was observed in not only the kidney, but also the liver in immunostaining (SGLT2 intensity: kidney 165.8 ± 15.6, liver 114.4 ± 49.0 arbitrary units, P < 0.01) and immunoblotting. There was no significant difference in hepatic expression of SGLT2 in the stratified analysis according to age, sex, BMI, and the severity of the liver disease. In the undirected graphical model, SGLT2 directly interacted with various factors such as sex, fatty change, neutrophil-to-lymphocyte ratio, triglyceride, hemoglobin A1c, creatinine, and albumin (partial correlation coefficient 0.4-0.6 for sex and 0.2-0.4 for others). The expression of SGLT2 was observed in the hepatocytes of patients with chronic liver disease. The undirected graphical model demonstrated the complex interaction of hepatic expression levels of SGLT2 with gender, inflammation, renal function, and lipid/glucose/protein metabolisms.

MAFLD associated with COPD via systemic inflammation independent of aging and smoking in men.

BACKGROUND AND AIM: Metabolic dysfunction and associated systemic inflammation are risk factors for chronic obstructive pulmonary disease (COPD) and COPD is highly prevalent in men. We investigated the impact of metabolic-associated fatty liver disease (MAFLD) and MAFLD-related systemic inflammation on COPD in men. METHODS: We enrolled 2,041 men with fatty liver. Patients were classified into the COPD (n = 420/2041) and non-COPD (n = 1621/2041) groups. COPD and its high-risk group were diagnosed using the Japanese Respiratory Society Disease statement. Systemic inflammation was evaluated using the C-reactive protein (CRP)/albumin ratio. Independent factors for COPD were investigated by multivariate analysis and decision-tree analysis. RESULTS: The prevalence of MAFLD was significantly higher in the COPD group than in the non-COPD group. In multivariable analysis, in addition to heavy smoking and aging, MAFLD was identified as an independent factor for COPD (OR 1.46, 95% CI 1.020-2.101, P = 0.0385). Decision-tree analysis showed that MAFLD, rather than heavy smoking, was the most influential classifier for COPD in non-elderly men (14% in MAFLD vs 6% in non-MAFLD groups). MAFLD was also the second most influential factor in elderly men who were not heavy smokers. In both groups, the CRP/albumin ratio was the first classifier for COPD (16% in the high CRP/albumin ratio group vs 3% in the low CRP/albumin ratio group of non-elderly men). CONCLUSIONS: MAFLD is an independent predictor of COPD in men. MAFLD had a significant impact on COPD through systemic inflammation in men of all ages who were not heavy smokers. MAFLD may be useful to broadly identify COPD in men.

Metabolic dysfunction-associated fatty liver disease directly related to liver fibrosis independent of insulin resistance, hyperlipidemia, and alcohol intake in morbidly obese patients.

AIM: Hepatic fibrosis is associated with various factors, including metabolic dysfunction-associated fatty liver disease (MAFLD), insulin resistance, and alcohol intake in patients with morbid obesity. We investigated factors directly associated with hepatic fibrosis in patients with morbid obesity using a graphical model. METHODS: We enrolled 134 consecutive patients with morbid obesity who underwent liver biopsy during sleeve gastrectomy (median age 43.5 years; MAFLD 78.4%; homeostasis model assessment of insulin resistance [HOMA-IR] 5.97; >20 g/day alcohol intake 14.2%). Patients were classified into none/mild (F0/1; n = 77) or significant/advanced fibrosis (F2/3; n = 57) groups, based on histology. Factors associated with F2/3 were analyzed using logistic regression analysis and a graphical model. RESULTS: F2/3 was observed in 42.5% of the enrolled patients. The prevalence of MAFLD and HOMA-IR values were significantly higher in the F2/3 group than in the F0/1 group; however, no significant difference in alcohol intake was observed between the two groups. On logistic regression analysis, MAFLD, but not HOMA-IR or alcohol intake, was the only independent factor associated with F2/3 (odds ratio 7.555; 95% confidence interval 2.235-25.544; p = 0.0011). The graphical model revealed that F2/3 directly interacted with MAFLD, diabetes mellitus, HOMA-IR, and low-density lipoprotein cholesterol. Among these factors, MAFLD showed the strongest interaction with F2/3. CONCLUSIONS: We determined that MAFLD was more directly associated with significant/advanced fibrosis than insulin resistance or hyperlipidemia, and alcohol intake was not directly associated with hepatic fibrosis. Metabolic dysfunction-associated fatty liver disease could be the most important factor for hepatic fibrosis in patients with morbid obesity.

Lean/normal-weight metabolic dysfunction-associated fatty liver disease is a risk factor for reflux esophagitis.

AIM: Reflux esophagitis is associated with metabolic dysfunction. Recently, fatty liver has been redefined as metabolic dysfunction-associated fatty liver disease (MAFLD). We investigated the impact of MAFLD and its subtypes on the incidence of reflux esophagitis. METHODS: This multicenter, observational cohort study enrolled 9100 consecutive health-check examinees who underwent esophagogastroduodenoscopy and ultrasonography. All patients were classified into the MAFLD or non-MAFLD group. Based on the Asian cut-off value for body mass index (BMI), the MAFLD group was further classified into the lean/normal-weight (BMI <23 kg/m2 ) and overweight/obese (BMI ≥23 kg/m2 ) subgroups. The impact of MAFLD and its subtypes on the cumulative incidence of reflux esophagitis was evaluated using multivariable Cox proportional hazards regression analysis. RESULTS: MAFLD was diagnosed in 26.5% (2416/9100) of patients. Multivariable Cox proportional hazards regression analysis indicated that MAFLD (hazard ratio [HR] 1.2183; 95% confidence interval [CI] 1.0954-1.3550; p = 0.0003), hiatal hernia, and aging were independent risk factors for reflux esophagitis. Stratification analysis indicated that cumulative incidence of reflux esophagitis among patients with MAFLD was significantly higher in the lean/normal-weight than in the overweight/obese group (HR 1.3274; 95% CI 1.0043-1.7547; p = 0.0466). Among various metabolic factors, visceral adiposity was the only independent metabolic risk factor for reflux esophagitis (HR 2.8331; 95% CI 1.0201-7.8691; p = 0.0457) in the lean/normal-weight MAFLD group. CONCLUSIONS: MAFLD, in particular lean/normal-weight MAFLD, is independent risk factor for reflux esophagitis. Furthermore, visceral adiposity was identified as the most strong metabolic risk factor for reflux esophagitis in lean/normal-weight patients with MAFLD.

Effects of SGLT2 inhibitor on tumor-releasing chemokines/cytokines in Hep3B and Huh7 cells.

(a) Summary for SGLT2i-induced alterations in 48 chemokines/cytokines in Hep3B and Huh7 cells. (b) SGLT2i-induced changes in the medium CXCL1 level (each n = 4). (c) SGLT2i-induced changes in the medium CXCL8 level (each n = 4). (d) SGLT2i-induced changes in the medium CXCL10 level (each n = 4), (e) SGLT2i-induced changes in the medium M-CSF level (each n = 4). The SGLT2i-induced significant changes in chemokines/cytokines are expressed as the percentage of control (the mean value of the control was set as 100%). CXCL, C-X-C motif chemokine ligand; G-CSF, granulocyte colony-stimulating factor; IL, interleukin; LIF, leukemia inhibitory factor; M-CSF, macrophage colony-stimulating factor; MIP-1α, macrophage inflammatory protein-1α; SDF-1α, stromal-cell-derived factor-1α; TNFα, tumor necrosis factor-α; VEGF, vascular endothelial growth factor.

MAFLD: Renovation of clinical practice and disease awareness of fatty liver.

Recently, international expert panels have proposed a new definition of fatty liver: metabolic dysfunction-associated fatty liver disease (MAFLD). MAFLD is not just a simple renaming of non-alcoholic fatty liver disease (NAFLD). The unique feature of MAFLD is the inclusion of metabolic dysfunctions, which are high-risk factors for events. In addition, MAFLD is independent of alcohol intake and the co-existing causes of liver disease. This new concept of MAFLD may have a widespread impact on patients, medical doctors, medical staff, and various stakeholders regarding fatty liver. Thus, MAFLD may renovate clinical practice and disease awareness of fatty liver. In this review, we introduce the definition of and rationale for MAFLD. We further describe representative cases showing how the diagnostic processes differ between MAFLD and NAFLD. We also summarize recent studies comparing MAFLD with NAFLD and discuss the impact of MAFLD on clinical trials, Japanese populations, and disease awareness.

MAFLD enhances clinical practice for liver disease in the Asia-Pacific region.

Fatty liver is now a major cause of liver disease in the Asia-Pacific region. Liver diseases in this region have distinctive characteristics. First, fatty liver is frequently observed in lean/normal-weight individuals. However, there is no standard definition of this unique phenotype. Second, fatty liver is often observed in patients with concomitant viral hepatitis. The exclusion of viral hepatitis from non-alcoholic fatty liver disease limits its value and detracts from the investigation and holistic management of coexisting fatty liver in patients with viral hepatitis. Third, fatty liver-associated hepatocellular carcinoma (HCC) is generally categorized as non-B non-C HCC. Fourth, the population is aging rapidly, and it is imperative to develop a practicable, low-intensity exercise program for elderly patients. Fifth, most patients and nonspecialized healthcare professionals still lack an awareness of the significance of fatty liver both in terms of intrahepatic and extrahepatic disease and cancer. Recently, an international expert panel proposed a new definition of fatty liver: metabolic dysfunction-associated fatty liver disease (MAFLD). One feature of MAFLD is that metabolic dysfunction is a prerequisite for diagnosis. Pertinent to regional issues, MAFLD also provides its diagnostic criteria in lean/normal-weight individuals. Furthermore, MAFLD is independent of any concomitant liver disease, including viral hepatitis. Therefore, MAFLD may be a more suitable definition for fatty liver in the Asia-Pacific region. In this review, we introduce the regional characteristics of fatty liver and discuss the advantages of MAFLD for improving clinical practice for liver disease in the region.